How Often Does an Individual Trial Agree with Its Corresponding Meta-Analysis? A Meta-Epidemiologic Study

Objective

A meta-analysis may provide more conclusive results than a single trial. The major cost of meta-analysis is the time of waiting before the meta-analysis becomes available and resources spent on consequent trials that may not be necessary. The objective of this study is to address how often the result of a single trial, in particular the first trial, differs from that of its corresponding meta-analysis so as to reduce unnecessary waiting time and subsequent trials.

Study Design and Settings

A meta-epidemiologic study was conducted by collecting meta-analyses from the Cochrane Database of Systematic Reviews and five major medical journals. Effect size of a single trial was compared with that of its corresponding meta-analysis. The single trial includes the first trial, last trial and any trial randomly selected from the meta-analysis.

Results

647 meta-analyses are included and the median number of trials in a meta-analysis is 5. 233 (36.0%) meta-analyses have the first trial with a statistically significant result. When the first trial is statistically significant, 84.1% (95% CI: 79.4%, 88.8%) of the corresponding meta-analyses is both in the same direction and statistically significant. When the first trial is statistically insignificant, 57.9% (95% CI: 53.2%, 62.8%) of the meta-analysis is also statistically insignificant regardless of direction. The median number of years is 6.5 years from the first to the 5^th trial.

Conclusion

The conclusion of the first trial that the treatment is effective or harmful is mostly likely correct. A statistically significant trial agrees more often with its corresponding meta-analysis than a large trial. These findings imply that particularly in some urgent, life-saving or other critical circumstances for which no other effective methods are available, cautious recommendation based on the significant result of the first trial seems justifiable and could start use of an effective intervention by 5–8 years earlier.     

Does Fish Oil Have an Anti-Obesity Effect in Overweight/Obese Adults? A Meta-Analysis of Randomized Controlled Trials

Context

Accumulating evidence has suggested favorable effects of fish oil on weight loss in animal experiments; however, findings remain inconsistent in humans.

Objects

The meta-analysis was performed to investigate the influence of fish oil on some parameters of body composition in overweight/obese adults.

Design

Human randomized, placebo-controlled trials were identified by a systematic search of Embase, PubMed, the Cochrane Library, web of science and reference lists of related reviews and articles. The random-effects model was used to estimate the calculated results.

Results

In total, 21 studies with 30 study arms were included in this analysis. Calculated results of the meta-analysis demonstrated that fish oil had no effect on reducing body weight (overall SMD = -0.07, 95% CI -0.21 to 0.07, P = 0.31) and BMI (overall SMD = -0.09, 95% CI -0.22 to 0.03, P = 0.14) whether alone or combined with life modification intervention in overweight/obese subjects. However, waist circumference was significantly reduced (SMD = -0.23, 95% CI -0.40 to -0.06, P = 0.008) in those with fish oil supplementation combined with life modification intervention. Waist hip ratio (WHR) was significantly reduced (overall SMD = -0.52 95% CI -0.76 to -0.27, P < 0.0005) in fish oil supplemented individuals with or without combination life modification intervention.

Conclusion

Current evidence cannot support an exact anti-obesity role of n-3 polyunsaturated fatty acids (PUFAs) in overweight/obese subjects. However, these subjects may benefit from reducing abdominal fat with fish oil supplementation especially when combined with life modification intervention. Further large-scale and long-term clinical trials are needed to gain definite conclusions.     

Does Plant Origin Influence the Fitness Impact of Flower Damage? A Meta-Analysis

Herbivory has been long considered an important component of plant-animal interactions that influences the success of invasive species in novel habitats. One of the most important hypotheses linking herbivory and invasion processes is the enemy-release hypothesis, in which exotic plants are hypothesized to suffer less herbivory and fitness-costs in their novel ranges as they leave behind their enemies in the original range. Most evidence, however, comes from studies on leaf herbivory, and the importance of flower herbivory for the invasion process remains largely unknown. Here we present the results of a meta-analysis of the impact of flower herbivory on plant reproductive success, using as moderators the type of damage caused by floral herbivores and the residence status of the plant species. We found 51 papers that fulfilled our criteria. We also included 60 records from unpublished data of the laboratory, gathering a total of 143 case studies. The effects of florivory and nectar robbing were both negative on plant fitness. The methodology employed in studies of flower herbivory influenced substantially the outcome of flower damage. Experiments using natural herbivory imposed a higher fitness cost than simulated herbivory, such as clipping and petal removal, indicating that studies using artificial herbivory as surrogates of natural herbivory underestimate the real fitness impact of flower herbivory. Although the fitness cost of floral herbivory was high both in native and exotic plant species, floral herbivores had a three-fold stronger fitness impact on exotic than native plants, contravening a critical element of the enemy-release hypothesis. Our results suggest a critical but largely unrecognized role of floral herbivores in preventing the spread of introduced species into newly colonized areas.     

Does the Genetic Code Have A Eukaryotic Origin?

In the RNA world, RNA is assumed to be the dominant macromolecule performing most, if not all, core "house-keeping" functions. The ribo-cell hypothesis suggests that the genetic code and the translation machinery may both be born of the RNA world, and the introduction of DNA to ribo-cells may take over the informational role of RNA gradually, such as a mature set of genetic code and mechanism enabling stable inheritance of sequence and its variation. In this context, we modeled the genetic code in two content variables-GC and purine contents-of protein-coding sequences and measured the purine content sensitivities for each codon when the sensitivity (% usage) is plotted as a function of GC content variation. The analysis leads to a new pattern-the symmetric pattern-where the sensitivity of purine content variation shows diagonally symmetry in the codon table more significantly in the two GC content invariable quarters in addition to the two existing patterns where the table is divided into either four GC content sensitivity quarters or two amino acid diversity halves. The most insensitive codon sets are GUN (valine) and CAN (CAR for asparagine and CAY for aspartic acid) and the most biased amino acid is valine (always over-estimated) followed by alanine (always under-estimated). The unique position of valine and its codons suggests its key roles in the final recruitment of the complete codon set of the canonical table. The distinct choice may only be attributable to sequence signatures or signals of splice sites for spliceosomal introns shared by all extant eukaryotes.     

Assessment of Dental Age of Children Aged 3.5 to 16.9 Years Using Demirjian’s Method: A Meta-Analysis Based on 26 Studies

Background A method for assessing dental maturity in different populations was first developed in 1973 by Demirjian and has been widely used and accepted since then. While the accuracy for evaluating dental age using Demirjian’s method compared to children’s chronological age has been extensively studied in recent years, the results currently available remain controversial and ambiguous. Methods A literature search of PubMed, Embase, Web of Science, CNKI and CBM databases was conducted to identify all eligible studies published before July 12th, 2013. Weighted mean difference (WMD) with corresponding 95% confidence interval (95% CI) was used to evaluate the applicability of Demirjian’s method for estimating chronological age in children. Results: A meta-analysis was conducted on 26 studies with a total of 11,499 children (5,301 boys and 6,198 girls) aged 3.5 to 16.9 years. Overall, we found that Demirjian’s method overestimated dental age by 0.35 (4.2 months) and 0.39 (4.68 months) years in males and females, respectively. A subgroup analysis by age revealed that boys and girls between the ages of 5 to 14 were given a dental age estimate that was significantly more advanced than their chronological age. Differences between underestimated dental ages and actual chronological ages were lower for male and female 15- and 16-year-old subgroups, though a significant difference was found in the 16-year-old subgroup. Conclusions Demirjian’s method’s overestimation of actual chronological tooth age reveals the need for population-specific standards to better estimate the rate of human dental maturation.     

Parkinson’s Disease and Risk of Fracture: A Meta-Analysis of Prospective Cohort Studies

Backgrounds/Objective

Parkinson’s disease (PD) is the second most common neurodegenerative disease among the elderly population. However, epidemiological evidence on the relationship of PD with risk of fracture has not been systematically assessed. Therefore, we performed this meta-analysis of prospective studies to explore the association between PD and risk of fracture.

Methods

PubMed, Embase, Web of Science and Cochrane Library up to February 26, 2014 were searched to identify eligible studies. Random-effects model was used to pool the results.

Results

Six studies that totally involved 69,387 participants were included for analysis. Overall, PD patients had an increased risk of fracture compared with control subjects (pooled hazard ratio = 2.66, 95% confidence interval: 2.10–3.36). No publication bias was observed across studies and the subgroup as well as sensitivity analysis suggested that the general results were robust.

Conclusion

The present study suggested that PD is associated with an increased risk of fracture. However, given the limited number and moderate quality of included studies, well-designed prospective cohort studies are required to confirm the findings from this meta-analysis.     

Does Drug-Eluting Bead Transcatheter Arterial Chemoembolization Improve the Management of Patients with Hepatocellular Carcinoma? A Meta-Analysis

Background

Drug eluting beads (DEB) are relatively new embolic agents that allow sustained release of chemotherapeutic agents in a localized fashion to the tumor. This technique is associated with reduced systemic side effects relative to systemic chemotherapy and an increase in the dose of antineoplastic agent delivered to the lesion. The meta-analysis was undertaken to assess the effectiveness of DEB-transcatheter arterial chemoembolization (TACE) in the management of hepatocellular cancer.

Methods

We searched the Web of Science, PubMed, EBSCO, EMBASE, the Wiley Library and Google Scholar for studies on DEB-TACE in the management of hepatocellular cancer from 1979 to April 2013. The risk of bias was assessed using RevMan 5·1. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. Disease control, complications and severe complications were recorded.

Results

Five studies met the selection criteria, three RCTs and two case-control studies, published from 2010 to 2012, included 217 patients in the DEB-TACE group and 237 in the conventional-TACE group. There was no significance over disease control (OR 2.27, 95% CI 0.78–6.63) with moderate between-study heterogeneity (χ² = 6.83, degrees of freedom [df] = 3; p<0.08; I² = 56%). Complications in both groups were assessed and no significant difference was observed (χ² = 6.34, degrees of freedom [df] = 4; p<0.18; I² = 37%). Severe complications were also assessed and no significant difference was observed (χ² = 6.47, degrees of freedom [df] = 4; p<0.17; I² = 38%). No publication bias relating to the above outcomes was detected by funnel plot. DEB-TACE benefited disease control without an increase in complications and severe complications.     

The ?842G/C Polymorphisms of PIN1 Contributes to Cancer Risk: A Meta-Analysis of 10 Case-Control Studies

Background

Peptidyl-prolyl cis–trans isomerase NIMA-interacting 1 (PIN1) plays an important role in cancer development. The relationship between PIN1 −842G/C (rs2233678) polymorphism and cancer risk was inconclusive according to published literature.

Methodology/Principal Findings

A literature search, up to February 2013, was carried out using PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database. A total of 10 case-control studies including 4619 cases and 4661 controls contributed to the quantitative analysis. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, individuals with the variant CG (OR = 0.728, 95% CI: 0.585,0.906; P_{heterogeneity}<0.01) and CG/CC (OR = 0.731, 95% CI: 0.602,0.888; P_{heterogeneity}<0.01) genotypes were associated with a significantly reduced cancer risk compared with those with wild GG genotype. Sub-group analysis revealed that the variant CG (OR = 0.635, 95% CI: 0.548,0.735; P_{heterogeneity} = 0.240) and CG/CC (OR = 0.645, 95% CI: 0.559,0.744, Pheterogeneity = 0.258) genotypes still showed an reduced risk of cancer in Asians; while no significant association was observed in Caucasians (CG vs.GG: OR = 0.926, 95% CI: 0.572,1.499, P_{heterogeneity}<0.01; CG/CC vs. GG: OR = 0.892, 95% CI: 0.589,1.353; P_{heterogeneity}<0.01). Furthermore, sensitivity analysis confirmed the stability of results. Begg''s funnel plot and Egger''s test did not reveal any publication bias.

Conclusions

This meta-analysis suggests that the PIN1 −842G/C polymorphism is associated with a significantly reduced risk of cancer, especially in Asian populations.     

Does Aβ 42 Have a Function Related to Blood Homeostasis?

In this review, I discuss the possibility that Aβ42 has a physiologic function in blood vessel homeostasis and the consequences that this might have for theories concerning the pathogenesis of Alzheimer’s disease and for treatment. Dedicated with affection to John Blass, who is always willing to talk about new ideas.     

Body Mass Index and Risk of Parkinson’s Disease: A Dose-Response Meta-Analysis of Prospective Studies

Background

A number of epidemiologic studies examining the relationship between body mass index (BMI) and the future occurrence of Parkinson’s disease (PD) reported largely inconsistent findings. We conducted a dose-response meta-analysis of prospective studies to clarify this association.

Methods

Eligible prospective studies were identified by a search of PubMed and by checking the references of related publications. The generalized least squares trend estimation was employed to compute study-specific relative risks (RR) and 95% confidence intervals (CI) for an increase in BMI of 5 kg/m², and the random-effects model was used to compute summary RR and 95% CI.

Results

A total of 10 prospective studies were included in the final analysis. An increase in BMI of 5 kg/m² was not associated with PD risk, with a summary RR of 1.00 (95% CI = 0.89-1.12). Results of subgroup analysis found similar results except for a week positive association in studies that adjusted for alcohol consumption (RR = 1.13, 95% CI = 0.99-1.29), and a week inverse association in studies that did not (RR = 0.90, 95% CI = 0.78-1.04). In a separate meta-analysis, no significant association between overweight (25 kg/m² ≤ BMI ≤29.9 kg/m²), obesity (BMI≥30 kg/m²) or excess weight (BMI≥25 kg/m²) and PD risk was observed.

Conclusion

This meta-analysis does not support the notion that higher BMI materially increases PD risk. However, a week positive BMI-PD association that may be masked by confounders still cannot be excluded, and future prospective studies with a good control for potential confounding factors are needed.     

A Simple Method for Preparation of 18α-Glycyrrhetinic Acid and Its Derivatives

Treatment of 18-glycyrrhizic acid with a methanolic solution of HCl resulted in 1 : 1 mixture of methyl esters of 18- and 18-glycyrrhetinic acids. Benzoylation of the mixture led to methyl esters of 3-benzoyl-18-glycyrrhetinic acid and 3-benzoyl-18-glycyrrhetinic acid, which were separated by chromatography on silica gel. 18-Glycyrrhetinic acid was prepared by alkaline hydrolysis of methyl 3-benzoyl-18-glycyrrhetinate and was further used for the syntheses of 3-keto-18-glycyrrhetinic acid and methyl esters of 18-glycyrrhetinic acid and 3-keto-18-glycyrrhetinic acid.     

Workers’ Compensation Status: Does It Affect Orthopaedic Surgery Outcomes? A Meta-Analysis

Introduction

Previous reviews have demonstrated that patient outcomes following orthopaedic surgery are strongly influenced by the presence of Workers’ Compensation. However, the variability in the reviews’ methodology may have inflated the estimated strength of this association. The main objective of this meta-analysis is to evaluate the influence of Workers’ Compensation on the outcomes of orthopaedic surgical procedures.

Methods

We conducted a systematic search of the literature published in this area from 1992–2012, with no language restrictions. The following databases were used MEDLINE (Ovid), Embase (Ovid), CINAHL, Google Scholar, LILACS and Pubmed. We also hand-searched the reference sections of all selected papers. We included all prospective studies evaluating the effect of compensation status on outcomes in adult patients who had undergone surgery due to orthopaedic conditions or diseases. Outcomes of interest included disease specific, region specific and/or overall quality of life scales/questionnaires and surgeons’ personal judgment of the results. We used an assessment tool to appraise the quality of all included studies. We used Review Manager to create forest plots to summarize study data and funnel plots for the assessment of publication bias.

Results

Twenty studies met our eligibility criteria. The overall risk ratio for experiencing an unsatisfactory result after orthopaedic surgery for patients with compensation compared to non-compensated patients is 2.08 (95% CI 1.54–2.82). A similar association was shown for continuous data extracted from the studies using assessment scales or questionnaires (Standard Mean Difference = −0.70 95% CI -0.97- −0.43).

Conclusions

Among patients who undergo orthopaedic surgical procedures, those receiving Workers’ Compensation experience a two-fold greater risk of a negative outcome. Our findings show a considerably lower estimate of risk compared to previous reviews that include retrospective data. Further research is warranted to determine the etiological explanation for the influence of compensation status on patient outcomes.

Systematic Review Registration Number

CRD42012002121     

Effect of Diabetes Mellitus Type 2 on Salivary Glucose – A Systematic Review and Meta-Analysis of Observational Studies

Background

Early screening of type 2 diabetes mellitus (DM) is essential for improved prognosis and effective delay of clinical complications. However, testing for high glycemia often requires invasive and painful blood testing, limiting its large-scale applicability. We have combined new, unpublished data with published data comparing salivary glucose levels in type 2 DM patients and controls and/or looked at the correlation between salivary glucose and glycemia/HbA1c to systematically review the effectiveness of salivary glucose to estimate glycemia and HbA1c. We further discuss salivary glucose as a biomarker for large-scale screening of diabetes or developing type 2 DM.

Methods and Findings

We conducted a meta-analysis of peer-reviewed published articles that reported data regarding mean salivary glucose levels and/or correlation between salivary glucose levels and glycemia or HbA1c for type 2 DM and non-diabetic individuals and combined them with our own unpublished results. Our global meta-analysis of standardized mean differences on salivary glucose levels shows an overall large positive effect of type 2 DM over salivary glucose (Hedge''s g = 1.37). The global correlation coefficient (r) between salivary glucose and glycemia was large (r = 0.49), with subgroups ranging from medium (r = 0.30 in non-diabetics) to very large (r = 0.67 in diabetics). Meta-analysis of the global correlation between salivary glucose and HbA1c showed an overall association of medium strength (r = 0.37).

Conclusions

Our systematic review reports an overall meaningful salivary glucose concentration increase in type 2 DM and a significant overall relationship between salivary glucose concentration and associated glycemia/HbA1c values, with the strength of the correlation increasing for higher glycemia/HbA1c values. These results support the potential of salivary glucose levels as a biomarker for type 2 DM, providing a less painful/invasive method for screening type 2 DM, as well as for monitoring blood glucose levels in large cohorts of DM patients.     

Does Exercise Improve Glycaemic Control in Type 1 Diabetes? A Systematic Review and Meta-Analysis

Objective

Whilst regular exercise is advocated for people with type 1 diabetes, the benefits of this therapy are poorly delineated. Our objective was to review the evidence for a glycaemic benefit of exercise in type 1 diabetes.

Research Design and Methods

Electronic database searches were carried out in MEDLINE, Embase, Cochrane’s Controlled Trials Register and SPORTDiscus. In addition, we searched for as yet unpublished but completed trials. Glycaemic benefit was defined as an improvement in glycosylated haemoglobin (HbA1c). Both randomised and non-randomised controlled trials were included.

Results

Thirteen studies were identified in the systematic review. Meta-analysis of twelve of these (including 452 patients) demonstrated an HbA1c reduction but this was not statistically significant (standardised mean difference (SMD) −0.25; 95% CI, −0.59 to 0.09).

Conclusions

This meta-analysis does not reveal evidence for a glycaemic benefit of exercise as measured by HbA1c. Reasons for this finding could include increased calorie intake, insulin dose reductions around the time of exercise or lack of power. We also suggest that HbA1c may not be a sensitive indicator of glycaemic control, and that improvement in glycaemic variability may not be reflected in this measure. Exercise does however have other proven benefits in type 1 diabetes, and remains an important part of its management.     

Does Simplicity Compromise Accuracy in ACS Risk Prediction? A Retrospective Analysis of the TIMI and GRACE Risk Scores

Background

The Thrombolysis in Myocardial Infarction (TIMI) risk scores for Unstable Angina/Non-ST–elevation myocardial infarction (UA/NSTEMI) and ST-elevation myocardial infarction (STEMI) and the Global Registry of Acute Coronary Events (GRACE) risk scores for in-hospital and 6-month mortality are established tools for assessing risk in Acute Coronary Syndrome (ACS) patients. The objective of our study was to compare the discriminative abilities of the TIMI and GRACE risk scores in a broad-spectrum, unselected ACS population and to assess the relative contributions of model simplicity and model composition to any observed differences between the two scoring systems.

Methodology/Principal Findings

ACS patients admitted to the University of Michigan between 1999 and 2005 were divided into UA/NSTEMI (n = 2753) and STEMI (n = 698) subpopulations. The predictive abilities of the TIMI and GRACE scores for in-hospital and 6-month mortality were assessed by calibration and discrimination. There were 137 in-hospital deaths (4%), and among the survivors, 234 (7.4%) died by 6 months post-discharge. In the UA/NSTEMI population, the GRACE risk scores demonstrated better discrimination than the TIMI UA/NSTEMI score for in-hospital (C = 0.85, 95% CI: 0.81–0.89, versus 0.54, 95% CI: 0.48–0.60; p<0.01) and 6-month (C = 0.79, 95% CI: 0.76–0.83, versus 0.56, 95% CI: 0.52–0.60; p<0.01) mortality. Among STEMI patients, the GRACE and TIMI STEMI scores demonstrated comparably excellent discrimination for in-hospital (C = 0.84, 95% CI: 0.78–0.90 versus 0.83, 95% CI: 0.78–0.89; p = 0.83) and 6-month (C = 0.72, 95% CI: 0.63–0.81, versus 0.71, 95% CI: 0.64–0.79; p = 0.79) mortality. An analysis of refitted multivariate models demonstrated a marked improvement in the discriminative power of the TIMI UA/NSTEMI model with the incorporation of heart failure and hemodynamic variables. Study limitations included unaccounted for confounders inherent to observational, single institution studies with moderate sample sizes.

Conclusions/Significance

The GRACE scores provided superior discrimination as compared with the TIMI UA/NSTEMI score in predicting in-hospital and 6-month mortality in UA/NSTEMI patients, although the GRACE and TIMI STEMI scores performed equally well in STEMI patients. The observed discriminative deficit of the TIMI UA/NSTEMI score likely results from the omission of key risk factors rather than from the relative simplicity of the scoring system.     

A Systematic Review of Studies Eliciting Willingness-to-Pay per Quality-Adjusted Life Year: Does It Justify CE Threshold?

Background

A number of studies have been conducted to estimate willingness to pay (WTP) per quality-adjusted life years (QALY) in patients or general population for various diseases. However, there has not been any systematic review summarizing the relationship between WTP per QALY and cost-effectiveness (CE) threshold based on World Health Organization (WHO) recommendation.

Objective

To systematically review willingness-to-pay per quality-adjusted-life-year (WTP per QALY) literature, to compare WTP per QALY with Cost-effectiveness (CE) threshold recommended by WHO, and to determine potential influencing factors.

Methods

We searched MEDLINE, EMBASE, Psyinfo, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Center of Research Dissemination (CRD), and EconLit from inception through 15 July 2014. To be included, studies have to estimate WTP per QALY in health-related issues using stated preference method. Two investigators independently reviewed each abstract, completed full-text reviews, and extracted information for included studies. We compared WTP per QALY to GDP per capita, analyzed, and summarized potential influencing factors.

Results

Out of 3,914 articles founded, 14 studies were included. Most studies (92.85%) used contingent valuation method, while only one study used discrete choice experiments. Sample size varied from 104 to 21,896 persons. The ratio between WTP per QALY and GDP per capita varied widely from 0.05 to 5.40, depending on scenario outcomes (e.g., whether it extended/saved life or improved quality of life), severity of hypothetical scenarios, duration of scenario, and source of funding. The average ratio of WTP per QALY and GDP per capita for extending life or saving life (2.03) was significantly higher than the average for improving quality of life (0.59) with the mean difference of 1.43 (95% CI, 1.81 to 1.06).

Conclusion

This systematic review provides an overview summary of all studies estimating WTP per QALY studies. The variation of ratio of WTP per QALY and GDP per capita depended on several factors may prompt discussions on the CE threshold policy. Our research work provides a foundation for defining future direction of decision criteria for an evidence-informed decision making system.