Chun Shing Kwok

Dissemination and publication of research findings: an updated review of related biases.

OBJECTIVES To identify and appraise empirical studies on publication and related biases published since 1998; to assess methods to deal with publication and related biases; and to examine, in a random sample of published systematic reviews, measures taken to prevent, reduce and detect dissemination bias. DATA SOURCES The main literature search, in August 2008, covered the Cochrane Methodology Register Database, MEDLINE, EMBASE, AMED and CINAHL. In May 2009, PubMed, PsycINFO and OpenSIGLE were also searched. Reference lists of retrieved studies were also examined. REVIEW METHODS In Part I, studies were classified as evidence or method studies and data were extracted according to types of dissemination bias or methods for dealing with it. Evidence from empirical studies was summarised narratively. In Part II, 300 systematic reviews were randomly selected from MEDLINE and the methods used to deal with publication and related biases were assessed. RESULTS Studies with significant or positive results were more likely to be published than those with non-significant or negative results, thereby confirming findings from a previous HTA report. There was convincing evidence that outcome reporting bias exists and has an impact on the pooled summary in systematic reviews. Studies with significant results tended to be published earlier than studies with non-significant results, and empirical evidence suggests that published studies tended to report a greater treatment effect than those from the grey literature. Exclusion of non-English-language studies appeared to result in a high risk of bias in some areas of research such as complementary and alternative medicine. In a few cases, publication and related biases had a potentially detrimental impact on patients or resource use. Publication bias can be prevented before a literature review (e.g. by prospective registration of trials), or detected during a literature review (e.g. by locating unpublished studies, funnel plot and related tests, sensitivity analysis modelling), or its impact can be minimised after a literature review (e.g. by confirmatory large-scale trials, updating the systematic review). The interpretation of funnel plot and related statistical tests, often used to assess publication bias, was often too simplistic and likely misleading. More sophisticated modelling methods have not been widely used. Compared with systematic reviews published in 1996, recent reviews of health-care interventions were more likely to locate and include non-English-language studies and grey literature or unpublished studies, and to test for publication bias. CONCLUSIONS Dissemination of research findings is likely to be a biased process, although the actual impact of such bias depends on specific circumstances. The prospective registration of clinical trials and the endorsement of reporting guidelines may reduce research dissemination bias in clinical research. In systematic reviews, measures can be taken to minimise the impact of dissemination bias by systematically searching for and including relevant studies that are difficult to access. Statistical methods can be useful for sensitivity analyses. Further research is needed to develop methods for qualitatively assessing the risk of publication bias in systematic reviews, and to evaluate the effect of prospective registration of studies, open access policy and improved publication guidelines.

Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis.

OBJECTIVES:Several studies have raised concern regarding the possible association between proton-pump inhibitors (PPIs) and Clostridium difficile infection (CDI). We aimed to perform a systematic review of incident and recurrent CDI in PPI users, and to evaluate the relative impact of concurrent antibiotic use, or switching acid suppression to histamine-2-receptor antagonists (H2RAs).METHODS:We searched MEDLINE and EMBASE from inception to December 2011 for controlled observational studies that reported on the risk of CDI with and without PPI use. We performed random effects meta-analysis and assessed statistical heterogeneity using the I2 statistic.RESULTS:We included 42 observational studies (30 case-control, 12 cohort) totalling 313,000 participants overall. Pooled analysis of 39 studies showed a statistically significant association between PPI use and risk of developing CDI, odds ratio (OR) 1.74 (95% confidence interval (CI) 1.47–2.85, P<0.001, I2=85%) compared with non-users. A pooled analysis of three studies showed a significant associated risk of recurrent CDI associated with PPIs, OR 2.51 (95% CI 1.16–5.44, P=0.005, I2=78%). Subgroup analysis failed to fully clarify the source of the substantial statistical heterogeneity. Adjusted indirect comparison demonstrated that use of H2RAs as an alternative carried a lower-risk OR 0.71 (95% CI 0.53–0.97) compared with PPIs. Conversely, concomitant use of PPI and antibiotics conferred a greater-risk OR 1.96 (95% CI 1.03–3.70) above that of PPIs alone. For PPI and antibiotics, the Rothmans synergy index was 1.36 and attributable proportion of risk from interaction 0.19, indicating an increased risk from interaction beyond the effects of each drug alone.CONCLUSIONS:Despite the substantial statistical and clinical heterogeneity, our findings indicate a probable association between PPI use and incident and recurrent CDI. This risk is further increased by concomitant use of antibiotics and PPI, whereas H2RAs may be less harmful.

Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies

Objective To determine the comparative effects of the thiazolidinediones (rosiglitazone and pioglitazone) on myocardial infarction, congestive heart failure, and mortality in patients with type 2 diabetes. Design Systematic review and meta-analysis of observational studies. Data sources Searches of Medline and Embase in September 2010. Study selection Observational studies that directly compared the risk of cardiovascular outcomes for rosiglitazone and pioglitazone among patients with type 2 diabetes mellitus were included. Data extraction Random effects meta-analysis (inverse variance method) was used to calculate the odds ratios for cardiovascular outcomes with thiazolidinedione use. The I2 statistic was used to assess statistical heterogeneity. Results Cardiovascular outcomes from 16 observational studies (4 case-control studies and 12 retrospective cohort studies), including 810 000 thiazolidinedione users, were evaluated after a detailed review of 189 citations. Compared with pioglitazone, use of rosiglitazone was associated with a statistically significant increase in the odds of myocardial infarction (n=15 studies; odds ratio 1.16, 95% confidence interval 1.07 to 1.24; P<0.001; I2=46%), congestive heart failure (n=8; 1.22, 1.14 to 1.31; P<0.001; I2=37%), and death (n=8; 1.14, 1.09 to 1.20; P<0.001; I2=0%). Numbers needed to treat to harm (NNH), depending on the population at risk, suggest 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100 000 patients who receive rosiglitazone rather than pioglitazone. Conclusion Among patients with type 2 diabetes, use of rosiglitazone is associated with significantly higher odds of congestive heart failure, myocardial infarction, and death relative to pioglitazone in real world settings.

Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel

Background  Recent studies have suggested an adverse interaction between proton pump inhibitors (PPI) and clopidogrel.

Association of Obstructive Sleep Apnea With Risk of Serious Cardiovascular Events A Systematic Review and Meta-Analysis

Background—The relationship between obstructive sleep apnea (OSA) and cardiovascular events remains unclear. We conducted a systematic review to determine the incident risk of cardiovascular events among patients with OSA. Methods and Results—We searched MEDLINE and EMBASE in January 2011 for prospective studies that followed up patients with OSA for incident ischemic heart disease, stroke, and cardiovascular mortality. Outcomes data were pooled using random effects meta-analysis and heterogeneity assessed with the I2 statistic. Regression analysis was performed to evaluate the effects of different gradations of OSA severity based on apnea-hypopnea index. We identified 9 relevant studies from 1731 citations. OSA was associated with incident stroke in a meta-analysis of 5 studies (8435 participants), odds ratio (OR) 2.24; 95% confidence interval (CI), 1.57–3.19; I2=7%. A significant association was seen in studies that were predominantly on men; OR, 2.87; 95% CI, 1.91–4.31, whereas data on women were sparse. In the overall analysis of 6 studies (8785 participants), OSA was nonsignificantly associated with ischemic heart disease (OR, 1.56; 95% CI, 0.83–2.91), with significant findings in the 5 studies that recruited mainly men (OR, 1.92; 95% CI, 1.06–3.48). Substantial heterogeneity was noted (I2=74%). OSA was linked to cardiovascular death in 2 studies involving 2446 participants (OR, 2.09; 95% CI, 1.20–3.65, I2=0%). Regression analysis showed greater likelihood of stroke or cardiovascular events with increasing apnea-hypopnea index values. Conclusions—OSA appears to be associated with stroke, but the relationship with ischemic heart disease and cardiovascular mortality needs further research.

Cerebral microbleeds: Histopathological correlation of neuroimaging

Background: In recent years, there has been a growing interest in cerebral microbleeds (CMBs) and their role in cerebrovascular disease. A few studies have investigated the histopathological correlation between CMBs and neuroimaging findings. We conducted a systematic review in an attempt to characterize the pathological and radiological correlation. Methods: A systematic literature search was conducted for studies in which CMBs were characterized histopathologically and correlated with MRI findings. Results: Five studies met the inclusion criteria, with a total of 18 patients. Hemosiderin deposition was reported in 42 CMBs (49%), while 16 CMBs (19%) were described as old hematomas which stained for iron, 13 (15%) had no associated specific pathology, 11 (13%) contained intact erythrocytes, 1 (1%) was due to vascular pseudocalcification, 1 (1%) was a microaneurysm and 1 (1%) was a distended dissected vessel. Lipofibrohyalinosis was the most prominent associated vascular finding. Amyloid angiopathy was present primarily in patients with dementia. Conclusions: Although histopathological associations have been observed using MRI in patients with CMBs, the findings have yet to be validated and further research is warranted.

Atrial fibrillation and incidence of dementia: A systematic review and meta-analysis

Background: Previous systematic reviews that examined whether atrial fibrillation (AF) is associated with dementia have relied on different study designs (including retrospective ones) and did not evaluate risk using meta-analysis. Methods: We searched Medline, Embase, and PsychINFO in September 2010 for published prospective studies reporting on the association between baseline AF and incident dementia. Pooled odds ratios for AF and dementia were calculated using the random effects model, with heterogeneity assessed using I2. Results: We identified 15 relevant studies covering 46,637 participants, mean age 71.7 years. One study that reported no significant difference in Mini-Mental State Examination scores between patients with or without AF could not be pooled. Meta-analysis of the remaining 14 studies showed that AF was associated with a significant increase in dementia overall (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.4 to 2.7, p < 0.0001), with substantial heterogeneity (I2 = 75%). When stratified by participants, the association was significant (with little heterogeneity) in studies focusing solely on patients with stroke (7 studies, OR 2.4, 95% CI 1.7 to 3.5, p < 0.001, I2 = 10%), and of borderline significance (with substantial heterogeneity) for studies in broader populations (7 studies, OR 1.6, 95% CI 1.0 to 2.7, p = 0.05, I2 = 87%). For conversion of mild cognitive impairment to dementia, one study showed a significant association with AF (OR 4.6, 95% CI 1.7 to 12.5). Conclusion: There is consistent evidence supporting an association between AF and increased incidence of dementia in patients with stroke whereas there remains considerable uncertainty about any link in the broader population. The potential association between AF and incident dementia in mild cognitive impairment merits further investigation.

Bariatric surgery and its impact on cardiovascular disease and mortality: a systematic review and meta-analysis.

BACKGROUND Bariatric surgery has been shown to improve cardiovascular risk factors but long term benefits for survival and cardiovascular events are still uncertain. METHODS We searched MEDLINE and EMBASE for parallel group studies that evaluated the clinical outcomes associated with bariatric surgery as compared to non-surgical treatment. Relevant studies were pooled using random effects meta-analysis for risk of myocardial infarction, stroke, cardiovascular events and mortality. RESULTS 14 studies met the inclusion criteria, which included 29,208 patients who underwent bariatric surgery and 166,200 nonsurgical controls (mean age 48 years, 30% male, follow up period ranged from 2 years to 14.7 years). Four studies were considered at moderate-high risk of bias, whilst ten studies were at moderate or lower risk of bias. Compared to nonsurgical controls there was more than 50% reduction in mortality amongst patients who had bariatric surgery (OR 0.48 95% CI 0.35-0.64, I2=86%, 14 studies). In pooled analysis of four studies with adjusted data, bariatric surgery was associated with a significantly reduced risk of composite cardiovascular adverse events (OR 0.54 95% CI 0.41-0.70, I2=58%). Bariatric surgery was also associated with significant reduction in specific endpoints of myocardial infarction (OR 0.46 95% CI 0.30-0.69, I2=79%, 4 studies) and stroke (OR 0.49 95% CI 0.32-0.75, I2=59%, 4 studies). CONCLUSIONS Data from observational studies indicates that patients undergoing bariatric surgery have a reduced risk of myocardial infarction, stroke, cardiovascular events and mortality compared to non-surgical controls. Future randomized studies should investigate whether these observations are reproduced in a clinical trials setting.

Value of severity scales in predicting mortality from community-acquired pneumonia: systematic review and meta-analysis

Background Several scoring systems have been used to predict mortality in patients with community-acquired pneumonia. The properties of commonly used risk stratification scales were systematically reviewed. Methods MEDLINE and EMBASE (January 1999–October 2009) were searched for prospective studies that reported mortality at 4–8 weeks in patients with radiographically-confirmed community-acquired pneumonia. The search focused on the Pneumonia Severity Index (PSI) and the three main iterations of the CURB (confusion, urea nitrogen, respiratory rate, blood pressure) scale (CURB-65, CURB, CRB-65), and test performance was evaluated based on ‘higher risk’ categories as follows: PSI class IV/V, CURB-65 (score ≥3), CURB (score ≥2) and CRB-65 (score ≥2). Random effects meta-analysis was used to generate summary statistics of test performance and receiver operating characteristic curves were used for predicting mortality. Results 402 articles were screened and 23 studies involving 22 753 participants (average mortality 7.4%) were retrieved. The respective diagnostic odds ratios for mortality were 10.77 (PSI), 6.40 (CURB-65), 5.97 (CRB-65) and 5.75 (CURB). Overall, PSI had the highest sensitivity and lowest specificity for mortality, CRB-65 was the most specific (but least sensitive) test and CURB-65/CURB were between the two. Negative predictive values for mortality were similar among the tests, ranging from 0.94 (CRB-65) to 0.98 (PSI), whereas positive predictive values ranged from 0.14 (PSI) to 0.28 (CRB-65). Conclusions The current risk stratification scales (PSI, CURB-65, CRB-65 and CURB) have different strengths and weaknesses. All four scales had good negative predictive values for mortality in populations with a low prevalence of death but were less useful with regard to positive predictive values.

Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis

OBJECTIVE Glycemic variability is emerging as a measure of glycemic control, which may be a reliable predictor of complications. This systematic review and meta-analysis evaluates the association between HbA1c variability and micro- and macrovascular complications and mortality in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS Medline and Embase were searched (2004–2015) for studies describing associations between HbA1c variability and adverse outcomes in patients with type 1 and type 2 diabetes. Data extraction was performed independently by two reviewers. Random-effects meta-analysis was performed with stratification according to the measure of HbA1c variability, method of analysis, and diabetes type. RESULTS Seven studies evaluated HbA1c variability among patients with type 1 diabetes and showed an association of HbA1c variability with renal disease (risk ratio 1.56 [95% CI 1.08–2.25], two studies), cardiovascular events (1.98 [1.39–2.82]), and retinopathy (2.11 [1.54–2.89]). Thirteen studies evaluated HbA1c variability among patients with type 2 diabetes. Higher HbA1c variability was associated with higher risk of renal disease (1.34 [1.15–1.57], two studies), macrovascular events (1.21 [1.06–1.38]), ulceration/gangrene (1.50 [1.06–2.12]), cardiovascular disease (1.27 [1.15–1.40]), and mortality (1.34 [1.18–1.53]). Most studies were retrospective with lack of adjustment for potential confounders, and inconsistency existed in the definition of HbA1c variability. CONCLUSIONS HbA1c variability was positively associated with micro- and macrovascular complications and mortality independently of the HbA1c level and might play a future role in clinical risk assessment.