Ammarin Thakkinstian

Meta-analyses of molecular association studies: Methodologic lessons for genetic epidemiology

Meta-analyses of population-based molecular association studies have become increasingly common over the last 10 years, but little attention has been paid to methodology. In addition to the traditional considerations pertinent to any meta-analysis, there are genetic issues particular to molecular association studies: checking Hardy-Weinberg equilibrium, handling data from more than two groups while avoiding multiple comparisons, and pooling data in a way that is sensitive to genetic models. We systematically reviewed all meta-analyses of molecular association studies identified via MEDLINE. Of a total of 37 studies, eight (22%) described the search terms. Nineteen (51%) did not state inclusion or exclusion criteria. Heterogeneity was assessed in 28 (76%), but only 7 of 37 (19%) studies checked for publication bias. Nine (24%) studies assessed the goodness-of-fit of Hardy-Weinberg equilibrium, and eight (22%) gave any biological rationale to justify the choice of genetic model used for pooling. There is a need for greater communication between epidemiologists and geneticists to develop methods appropriate to this area.

Meta-Analysis of Molecular Association Studies: Vitamin D Receptor Gene Polymorphisms and BMD as a Case Study†

With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta‐analysis of these studies has been a neglected area. This study performed a meta‐analysis of the association of the vitamin D receptor (VDR) gene polymorphisms and BMD. We also highlight methodological issues that need to be resolved.

Management of Chronic Prostatitis/ Chronic Pelvic Pain Syndrome: A Systematic Review and Network Meta-analysis

CONTEXT Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is common, but trial evidence is conflicting and therapeutic options are controversial. OBJECTIVE To conduct a systematic review and network meta-analysis comparing mean symptom scores and treatment response among α-blockers, antibiotics, anti-inflammatory drugs, other active drugs (phytotherapy, glycosaminoglycans, finasteride, and neuromodulators), and placebo. DATA SOURCES We searched MEDLINE from 1949 and EMBASE from 1974 to November 16, 2010, using the PubMed and Ovid search engines. STUDY SELECTION Randomized controlled trials comparing drug treatments in CP/CPPS patients. DATA EXTRACTION Two reviewers independently extracted mean symptom scores, quality-of-life measures, and response to treatment between treatment groups. Standardized mean difference and random-effects methods were applied for pooling continuous and dichotomous outcomes, respectively. A longitudinal mixed regression model was used for network meta-analysis to indirectly compare treatment effects. DATA SYNTHESIS Twenty-three of 262 studies identified were eligible. Compared with placebo, α-blockers were associated with significant improvement in symptoms with standardized mean differences in total symptom, pain, voiding, and quality-of-life scores of -1.7 (95% confidence interval [CI], -2.8 to -0.6), -1.1 (95% CI, -1.8 to -0.3), -1.4 (95% CI, -2.3 to -0.5), and -1.0 (95% CI, -1.8 to -0.2), respectively. Patients receiving α-blockers or anti-inflammatory medications had a higher chance of favorable response compared with placebo, with pooled RRs of 1.6 (95% CI, 1.1-2.3) and 1.8 (95% CI, 1.2-2.6), respectively. Contour-enhanced funnel plots suggested the presence of publication bias for smaller studies of α-blocker therapies. The network meta-analysis suggested benefits of antibiotics in decreasing total symptom scores (-9.8; 95% CI, -15.1 to -4.6), pain scores (-4.4; 95% CI, -7.0 to -1.9), voiding scores (-2.8; 95% CI, -4.1 to -1.6), and quality-of-life scores (-1.9; 95% CI, -3.6 to -0.2) compared with placebo. Combining α-blockers and antibiotics yielded the greatest benefits compared with placebo, with corresponding decreases of -13.8 (95% CI, -17.5 to -10.2) for total symptom scores, -5.7 (95% CI, -7.8 to -3.6) for pain scores, -3.7 (95% CI, -5.2 to -2.1) for voiding, and -2.8 (95% CI, -4.7 to -0.9) for quality-of-life scores. CONCLUSIONS α-Blockers, antibiotics, and combinations of these therapies appear to achieve the greatest improvement in clinical symptom scores compared with placebo. Anti-inflammatory therapies have a lesser but measurable benefit on selected outcomes. However, beneficial effects of α-blockers may be overestimated because of publication bias.

How to use an article about genetic association: B: Are the results of the study valid?

In the first article of this series, we reviewed the basic genetics concepts necessary to understand genetic association studies. In this second article, we enumerate the major issues in judging the validity of these studies, framed as critical appraisal questions. Was the disease phenotype properly defined and accurately recorded by someone blind to the genetic information? Have any potential differences between disease and nondisease groups, particularly ethnicity, been properly addressed? In genetic studies, one potential cause of spurious associations is differences between cases and controls in ethnicity, a situation termed population stratification. Was measurement of the genetic variants unbiased and accurate? Methods for determining DNA sequence variation are not perfect and may have some measurement error. Do the genotype proportions observe Hardy-Weinberg equilibrium? This simple mathematic rule about the distribution of genetic groups may be one way to check for errors in reading DNA information. Have the investigators adjusted their inferences for multiple comparisons? Given the thousands of genetic markers tested in genome-wide association studies, the potential for false-positive and false-negative results is much higher than in traditional medical studies, and it is particularly important to look for replication of results.

Relationship between hypercoagulable state and erythrocyte phosphatidylserine exposure in splenectomized haemoglobin E/β-thalassaemic patients*

Summary. Small pulmonary arterial thromboses can occur following splenectomy of patients with haemoglobin E/β‐thalassaemia (Hb E/β‐thal). We compared plasma markers of coagulation activation in vivo and red blood cell (RBC) markers of procoagulant activity in 15 Hb E/β‐thal patients who were not splenectomized (NS), 15 who had been splenectomized (S), and 15 normal controls (NC). Levels of plasma thrombin–antithrombin III complex (TAT) were significantly higher in the S group than in either the NS or the NC groups, and levels of prothrombin fragment 1.2 (F 1.2) were significantly higher in the S than in the NC group. Diluted Russells viper venom clotting times were significantly shorter when RBCs from group S patients were added to the assay compared with RBCs from the NC group. Phosphatidylserine (PS) expression (% of annexin V‐positive RBCs) on the outer leaflet of RBC membrane of both ‘larger’‐ and ‘smaller’‐sized RBCs was significantly higher for the S than the NC group. The RBC PS expression of the S and the NS groups, respectively, accounted for 25·3% (P = 0·174) and 6·3% (P = 0·675) of the variation in plasma TAT levels. Our findings indicated that, when compared with NC, splenectomized patients with Hb E/β‐thal were in a chronic low‐grade hypercoagulable state associated with increased numbers of circulating PS exposed RBCs. This condition may have a role in the risk of these patients for pulmonary arterial thromboses.

A Systematic Review and Meta-analysis of Randomised Controlled Trials Comparing Endovenous Ablation and Surgical Intervention in Patients with Varicose Vein

OBJECTIVES AND DESIGN A systematic review and meta-analysis was conducted to compare clinical outcomes between endovenous laser ablation (EVLA), radiofrequency ablation (RFA), ultrasound-guided foam sclerotherapy (UGFS) and surgery. METHODS We searched MEDLINE and Scopus from 2000 to August 2011 to identify randomised controlled trials (RCTs) comparing EVLA, RFA, UGFS, and surgery or combinations of these for treatment of varicoses. Differences in clinical outcomes were expressed as pooled risk ratio and unstandardised mean difference for dichotomous and continuous outcomes, respectively. Methodological quality was assessed using Cochrane tools. RESULTS Twenty-eight RCTs were included. The primary failure and clinical recurrences were not significantly different between EVLA and RFA versus surgery with the pooled RR of 1.5 (95%CI:0.7, 3.0) and 1.3 (95%CI:0.7, 2.4) respectively for primary failure, and, 0.6 (95%CI:0.3, 1.1) and 0.9 (95%CI:0.6, 1.4) respectively for clinical recurrences. The endovenous techniques had advantages over surgery in lowering wound infections (RR = 0.3 (95%CI:0.1, 0.8) for EVLA), haematoma (RR = 0.5 (95%CI:0.3, 0.8) and 0.4 (95%CI:0.1, 0.8) for EVLA and RFA), and return to normal activities or work (mean differences = -4.9 days (95%CI:-7.1,-2.7) for RFA). CONCLUSIONS The primary failure and recurrence in EVLA and RFA were non-significantly different compared with surgery. However, they had lower haematoma, less wound infection, less pain and quicker return to normal activities.

Corticosteroid and antiviral therapy for Bell's palsy: A network meta-analysis

BackgroundPrevious meta-analyses of treatments for Bells palsy are still inconclusive due to different comparators, insufficient data, and lack of power. We therefore conducted a network meta-analysis combining direct and indirect comparisons for assessing efficacy of steroids and antiviral treatment (AVT) at 3 and 6 months.MethodsWe searched Medline and EMBASE until September 2010 using PubMed and Elsviere search engines. A network meta-analysis was performed to assess disease recovery using a mixed effects hierarchical model. Goodness of fit of the model was assessed, and the pooled odds ratio (OR) and 95% confidence interval (CI) were estimated.ResultsSix studies (total n = 1805)were eligible and contributed to the network meta-analysis. The pooled ORs for resolution at 3 months were 1.24 (95% CI: 0.79 - 1.94) for Acyclovir plus Prednisolone and 1.02 (95% CI: 0.73 - 1.42) for Valacyclovir plus Prednisolone, versus Prednisolone alone. Either Acyclovir or Valacyclovir singly had significantly lower efficacy than Prednisolone alone, i.e., ORs were 0·44 (95% CI: 0·28 - 0·68) and 0·60 (95% CI: 0·42 - 0·87), respectively. Neither of the antiviral agents was significantly different compared with placebo, with a pooled OR of 1·25 (95% CI: 0·78 - 1·98) for Acyclovir and 0·91 (95% CI: 0·63 - 1·31) for Valacyclovir. Overall, Prednisolone-based treatment increased the chance of recovery 2-fold (95% CI: 1·55 - 2·42) compared to non-Prednisolone-based treatment. To gain 1 extra recovery, 6 and 26 patients need to be treated with Acyclovir and prednisolone compared to placebo and prednisolone alone, respectively.ConclusionsOur evidence suggests that the current practice of treating Bells palsy with AVT plus corticosteroid may lead to slightly higher recovery rates compared to treating with prednisone alone but this does not quite reach statistical significance; prednisone remains the best evidence-based treatment.

How to Use an Article About Genetic Association: A: Background Concepts

This is the first in a series of 3 articles serving as an introduction to clinicians wishing to read and critically appraise genetic association studies. We summarize the key concepts in genetics that clinicians must understand to review these studies, including the structure of DNA, transcription and translation, patterns of inheritance, Hardy-Weinberg equilibrium, and linkage disequilibrium. We review the types of DNA variation, including single-nucleotide polymorphisms (SNPs), insertions, and deletions, and how these can affect protein function. We introduce the idea of genetic association for both single-candidate gene and genome-wide association studies, in which thousands of genetic variants are tested for association with disease. We use the APOE polymorphism and its association with dementia as a case study to demonstrate the concepts and introduce the terminology used in this field. The second and third articles will focus on issues of validity and applicability.

Efavirenz 600 mg/day versus efavirenz 800 mg/day in HIV-infected patients with tuberculosis receiving rifampicin: 48 weeks results.

The potential of drug–drug interaction between efavirenz and rifampicin is a major concern in the treatment of HIV and tuberculosis. The optimal efavirenz dosage is still unclear. Our randomized control trial study recently reported the similar efavirenz level between efavirenz 600 and 800 mg/day in HIV-infected patients receiving rifampicin. We report the similar virological and immunological outcomes at 48 weeks between the two groups. Efavirenz 600 mg/day should be sufficient for concurrent use with rifamipicin.

Reno-protective effects of renin–angiotensin system blockade in type 2 diabetic patients: a systematic review and network meta-analysis

Aims/hypothesisThis meta-analysis aimed to compare the renal outcomes between ACE inhibitor (ACEI)/angiotensin II receptor blocker (ARB) and other antihypertensive drugs or placebo in type 2 diabetes.MethodsPublications were identified from Medline and Embase up to July 2011. Only randomised controlled trials comparing ACEI/ARB monotherapy with other active drugs or placebo were eligible. The outcome of end-stage renal disease, doubling of serum creatinine, microvascular complications, microalbuminuria, macroalbuminuria and albuminuria regression were extracted. Risk ratios were pooled using a random-effects model if heterogeneity was present; a fixed-effects model was used in the absence of heterogeneity.ResultsOf 673 studies identified, 28 were eligible (n = 13–4,912). In direct meta-analysis, ACEI/ARB had significantly lower risk of serum creatinine doubling (pooled RR = 0.66 [95% CI 0.52, 0.83]), macroalbuminuria (pooled RR = 0.70 [95% CI 0.50, 1.00]) and albuminuria regression (pooled RR 1.16 [95% CI 1.00, 1.39]) than other antihypertensive drugs, mainly calcium channel blockers (CCBs). Although the risks of end-stage renal disease and microalbuminuria were lower in the ACEI/ARB group (pooled RR 0.82 [95% CI 0.64, 1.05] and 0.84 [95% CI 0.61, 1.15], respectively), the differences were not statistically significant. The ACEI/ARB benefit over placebo was significant for all outcomes except microalbuminuria. A network meta-analysis detected significant treatment effects across all outcomes for both active drugs and placebo comparisons.Conclusions/interpretationOur review suggests a consistent reno-protective effect of ACEI/ARB over other antihypertensive drugs, mainly CCBs, and placebo in type 2 diabetes. The lack of any differences in BP decrease between ACEI/ARB and active comparators suggest this benefit is not due simply to the antihypertensive effect.