Job Strain as a Risk Factor for Leisure-Time Physical Inactivity: An Individual-Participant Meta-Analysis of Up to 170,000 Men and Women

Unfavorable work characteristics, such as low job control and too high or too low job demands, have been suggested to increase the likelihood of physical inactivity during leisure time, but this has not been verified in large-scale studies. The authors combined individual-level data from 14 European cohort studies (baseline years from 19851988 to 20062008) to examine the association between unfavorable work characteristics and leisure-time physical inactivity in a total of 170,162 employees (50 women; mean age, 43.5 years). Of these employees, 56,735 were reexamined after 29 years. In cross-sectional analyses, the odds for physical inactivity were 26 higher (odds ratio 1.26, 95 confidence interval: 1.15, 1.38) for employees with high-strain jobs (low control/high demands) and 21 higher (odds ratio 1.21, 95 confidence interval: 1.11, 1.31) for those with passive jobs (low control/low demands) compared with employees in low-strain jobs (high control/low demands). In prospective analyses restricted to physically active participants, the odds of becoming physically inactive during follow-up were 21 and 20 higher for those with high-strain (odds ratio 1.21, 95 confidence interval: 1.11, 1.32) and passive (odds ratio 1.20, 95 confidence interval: 1.11, 1.30) jobs at baseline. These data suggest that unfavorable work characteristics may have a spillover effect on leisure-time physical activity.

Screening tests for detecting open-angle glaucoma: systematic review and meta-analysis

PURPOSE: To assess the comparative accuracy of potential screening tests for open angle glaucoma (OAG).

METHODS: Medline, Embase, Biosis (to November 2005), Science Citation Index (to December 2005), and The Cochrane Library (Issue 4, 2005) were searched. Studies assessing candidate screening tests for detecting OAG in persons older than 40 years that reported true and false positives and negatives were included. Meta-analysis was undertaken using the hierarchical summary receiver operating characteristic model.

RESULTS: Forty studies enrolling over 48,000 people reported nine tests. Most tests were reported by only a few studies. Frequency-doubling technology (FDT; C-20-1) was significantly more sensitive than ophthalmoscopy (30, 95% credible interval [CrI] 0-62) and Goldmann applanation tonometry (GAT; 45, 95% CrI 17-68), whereas threshold standard automated perimetry (SAP) and Heidelberg Retinal Tomograph (HRT II) were both more sensitive than GAT (41, 95% CrI 14-64 and 39, 95% CrI 3-64, respectively). GAT was more specific than both FDT C-20-5 (19, 95% CrI 0-53) and threshold SAP (14, 95% CrI 1-37). Judging performance by diagnostic odds ratio, FDT, oculokinetic perimetry, and HRT II are promising tests. Ophthalmoscopy, SAP, retinal photography, and GAT had relatively poor performance as single tests. These findings are based on heterogeneous data of limited quality and as such are associated with considerable uncertainty.

CONCLUSIONS: No test or group of tests was clearly superior for glaucoma screening. Further research is needed to evaluate the comparative accuracy of the most promising tests.

Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33.

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10?¹° and rs6687758, OR = 1.09, P = 2.27 × 10??, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10?8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10?¹° and rs7136702, OR = 1.06, P = 4.02 × 10?8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10?¹°). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.

Meta-analysis of randomised controlled trials comparing latanoprost with timolol in the treatment of patients with open angle glaucoma or ocular hypertension

Aim - To evaluate the comparative efficacy and tolerance of latanoprost versus timolol through a meta-analysis of randomised controlled trials (RCTs). Methods - Systematic retrieval of RCTs of latanoprost versus timolol to allow pooling of results from head to head comparison studies. Quality of trials was assessed based on randomisation, masking, and withdrawal. Sensitivity analyses were used to estimate the effects of quality of study on outcomes. The data sources were Medline, Embase, Scientific Citation Index, Merck Glaucoma, and Pharmacia and Upjohn ophthalmology databases. There were 1256 patients with open angle glaucoma or ocular hypertension reported in 11 trials of latanoprost versus timolol. The main outcome measures were (i) percentage intraocular pressure (IOP) reduction for efficacy; (ii) relative risk, risk difference, and number needed to harm for side effects such as hyperaemia, conjunctivitis, increased pigmentation, hypotension, and bradycardia expressed as dichotomous outcomes; and (iii) reduction in systemic blood pressure and heart rate as side effects. Results - Both 0.005% latanoprost once daily and 0.5% timolol twice daily reduced IOP. The percentage reductions in IOP from baseline (mean (SE)) produced by latanoprost and timolol were 30.2 (2.3) and 26.9 (3.4) at 3 months. The difference in IOP reduction between the two treatments were 5.0 (95% confidence intervals 2.8, 7.3). However, latanoprost caused iris pigmentation in more patients than timolol (relative risk = 8.01, 95% confidence intervals 1.87, 34.30). The 2 year risk with latanoprost reached 18% (51/277). Hyperaemia was also more often observed with latanoprost (relative risk = 2.20, 95% confidence intervals 1.33, 3.64). Timolol caused a significant reduction in heart rate of 4 beats/minute (95% confidence interval 2, 6). Conclusion - This meta-analysis suggests that latanoprost is more effective than timolol in lowering IOP. However, it often causes iris pigmentation. While current evidence suggests that this pigmentation is benign, careful lifetime evaluation of patients is still justified.

Glycated Hemoglobin and Risk of Death in Diabetic Patients Treated With Hemodialysis: A Meta-analysis

Background: Studies investigating the association between glycated hemoglobin (HbA) level and mortality risk in diabetic patients receiving hemodialysis have shown conflicting results. 
Study Design: We conducted a systematic review and meta-analysis using MEDLINE, EMBASE, Web of Science, and the Cochrane Library. 
Setting & Population: Diabetic patients on maintenance hemodialysis therapy. 
Selection Criteria for Studies: Observational studies or randomized controlled trials investigating the association between HbA values and mortality risk. Study authors were asked to provide anonymized individual patient data or reanalyze results according to a standard template. 
Predictor: Single measurement or mean HbA values. Mean HbA values were calculated using all individual-patient HbA values during the follow-up period of contributing studies. 
Outcome: HR for mortality risk. 
Results: 10 studies (83,684 participants) were included: 9 observational studies and one secondary analysis of a randomized trial. After adjustment for confounders, patients with baseline HbA levels =8.5% (=69 mmol/mol) had increased mortality (7 studies; HR, 1.14; 95% CI, 1.09-1.19) compared with patients with HbA levels of 6.5%-7.4% (48-57 mmol/mol). Likewise, patients with a mean HbA value =8.5% also had a higher adjusted risk of mortality (6 studies; HR,1.29; 95% CI, 1.23-1.35). There was a small but nonsignificant increase in mortality associated with mean HbA levels =5.4% (=36 mmol/mol; 6 studies; HR, 1.09; 95% CI, 0.89-1.34). Sensitivity analyses in incident (=90 days of hemodialysis) and prevalent patients (>90 days of hemodialysis) showed a similar pattern. In incident patients, mean HbA levels =5.4% also were associated with increased mortality risk (4 studies; HR, 1.29; 95% CI, 1.23-1.35). 
Limitations: Observational study data and inability to adjust for diabetes type in all studies. 
Conclusions: Despite concerns about the utility of HbA measurement in hemodialysis patients, high levels (=8.5%) are associated with increased mortality risk. Very low HbA levels (=5.4%) also may be associated with increased mortality risk. 

Review and quantitative meta-analysis of diet suggests the Eurasian otter (Lutra lutra) is likely to be a poor bioindicator

The Eurasian otter (Lutra lutra L.) is a top predator in aquatic systems and plays an important role in ecosystem functioning. However, it has undergone dramatic declines throughout Europe as a result of environmental degradation. We examine the putative role of the otter as a bioindicator in Ireland which remains a stronghold for the species and affords a unique opportunity to examine variation in its ecological niche. We describe diet, using spraint contents, along rivers during 2010 and conduct a review and quantitative meta-analysis of the results of a further 21 studies. We aimed to assess variation in otter diet in relation to river productivity, a proxy for natural nutrification and anthropogenic eutrophication, and availability of salmonid prey (Salmo trutta and Salmo salar), to test the hypothesis that otter diet is related to environmental quality. Otter diet did not vary with levels of productivity or availability of salmonids whilst Compositional Analysis suggested there was no selection of salmonid over non-salmonid fish. There was a distinct niche separation between riverine and lacustrine systems, the latter being dominated by Atlantic eel (Anguilla anguilla). Otters are opportunistic and may take insects, freshwater mussels, birds, mammals and even fruit. Otters living along coasts have a greatest niche breath than those in freshwater systems which encompasses a wide variety of intertidal prey though pelagic fish are rarely taken. It is concluded that the ability of the otter to feed on a wide diversity of prey taxa and the strong influence of habitat type, renders it a poor bioindicator of environmental water quality. It seems likely that the plasticity of the habitat and dietary niche of otters, and the extent of suitable habitat, may have sustained populations in Ireland despite intensification of agriculture during the 20th century.

Five authors reply

We read with interest the comments offered by Drs. Hughes and Bradley (1) on our systematic review (2). Four single nucleotide polymorphisms (SNPs), rs9332739 and rs547154 in the complement component 2 gene (C2) and rs4151667 and rs641153 in the complement factor B gene (CFB), were pooled. Hughes and Bradley point out that we omitted the most common variant, rs12614. In fact, rs12614 is in high linkage disequilibrium (LD) with rs641153, which was included, and the major allele of both of these SNPs is in the range of 90% (population code, CEU, in the International HapMap Project (http://hapmap.ncbi.nlm.nih.gov/)). Moreover, our review was initiated in September 2010, at which point only 4 studies had published associations with rs12614, whereas 14 studies (n = 11,378) were available for rs641153. While it is true that both SNPs are better analyzed as a haplotype, these data were simply not available for pooling.
Hughes and Bradley also point out that we obtained and pooled new data that were not previously published. While it is recommended that contact with authors be completed as part of a comprehensive meta-analysis, we acknowledge that these additional data were not previously published and peer reviewed and, hence, do not have the same level of transparency. However, given that sample collections often increase over time and that the instrumentation for genotyping is continually improving, we thought that it would be advantageous to use the most recent information; this is a subjective decision.
We also agree that the allele frequencies given by Kaur et al. (3) were exactly opposite to those expected and were suggestive of strand flipping. However, we specifically queried this with the lead author on 2 separate occasions and were assured it was not.
Hughes and Bradley do make an interesting suggestion that SNPs in high LD should be used as a gauge of genotyping quality in HuGE reviews. This is an interesting idea but difficult to put into practice as the r2 parameter they propose as a measure of LD has some unusual properties. Although r2 is a measure of LD, it is also linked to the allele frequency; even small differences in allele frequencies between 2 linked SNPs can reduce the r2 dramatically. Wray (4) explored these effects and found that, at a baseline allele frequency of 10%, even a difference in allele frequency between 2 SNPs as small as 2% can drop the r2 value below 0.8. This degree of allele frequency difference is consistent with what could be expected for sampling error. Furthermore, when we look at 2 linked dialleleic SNPs, giving 4 possible haplotypes, the absence of 1 haplotype dramatically reduces r2, despite the 2 loci being in high LD as measured by D'. In fact, this is the situation for rs12614 and rs641153, where the low frequency of 1 haplotype means that the r2 is 0.01 but the D' is 1.
Hughes and Bradley also suggest consideration of genotype call rate restrictions as an inclusion criterion for metaanalysis. This would be more appropriate when focusing on genetic variants per se, as considered within the context of a genome-wide association study or other specific genetic analysis where large numbers of SNPs are evaluated (5).
The concerns raised by Hughes and Bradley reflect the limited ability of a meta-analysis based on summary data to tease out inconsistencies best identified at the individual level. We agree that SNPs in LD should be evaluated, but this will not necessarily be straightforward. A move to make genetic data sets publicly available, as in the Database of Genotypes and Phenotypes (http://www.ncbi.nlm.nih.gov/ gap), is a step in the right direction for greater transparency.

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II:Schizophrenia

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk

A systematic review and meta-analysis of the ethnic density effect in psychotic disorders

A number of studies have found an ethnic density effect in psychotic disorders, where the incidence for ethnic minorities increases as the neighbourhood proportional ethnic composition decreases [Morgan and Hutchinson, Psychol Med 40:705-709, (2010); Singh, Psychol Med 39:1402-1403, (2009); Schofield et al., Psychol Med 41:1263-1269, (2010)]. However, there is a mixed picture with some studies reporting no effect [Schofield et al., Psychol Med 41:1263-1269, (2010)]. This review aimed to establish the existence of the effect by answering the review question: is there an ethnic density dose effect in the prevalence of psychotic disorders?

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

The genetic contribution to the variation in human lifespan is approximately 25%.  Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality.  We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16121 younger controls (< 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P =1.74 x 10-8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 x 10-36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34103) the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Job strain and the risk of severe asthma exacerbations: A meta-analysis of individual-participant data from 100 000 European men and women

Background: Many patients and healthcare professionals believe that work-related psychosocial stress, such as job strain, can make asthma worse, but this is not corroborated by empirical evidence. We investigated the associations between job strain and the incidence of severe asthma exacerbations in working-age European men and women. Methods: We analysed individual-level data, collected between 1985 and 2010, from 102 175 working-age men and women in 11 prospective European studies. Job strain (a combination of high demands and low control at work) was self-reported at baseline. Incident severe asthma exacerbations were ascertained from national hospitalization and death registries. Associations between job strain and asthma exacerbations were modelled using Cox regression and the study-specific findings combined using random-effects meta-analyses. Results: During a median follow-up of 10 years, 1 109 individuals experienced a severe asthma exacerbation (430 with asthma as the primary diagnostic code). In the age- and sex-adjusted analyses, job strain was associated with an increased risk of severe asthma exacerbations defined using the primary diagnostic code (hazard ratio, HR: 1.27, 95% confidence interval, CI: 1.00, 1.61). This association attenuated towards the null after adjustment for potential confounders (HR: 1.22, 95% CI: 0.96, 1.55). No association was observed in the analyses with asthma defined using any diagnostic code (HR: 1.01, 95% CI: 0.86, 1.19). Conclusions: Our findings suggest that job strain is probably not an important risk factor for severe asthma exacerbations leading to hospitalization or death.

How common are myeloproliferative neoplasms? A systematic review and meta-analysis

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases including polycythemia vera (PV), essential thrombocythemia (ET), and primary(idiopathic) myelofibrosis (PMF). In this systematic review, we provide a comprehensive report on the incidence and prevalence of MPNs across the globe. Electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) were searched from their inception to August 2012 for articles reporting MPN incidence or prevalence rates. A random effects meta-analysis was undertaken to produce combined incidence rates for PV, ET, and PMF. Both heterogeneity and small study bias were assessed. Thirty-four studies were included. Reported annual incidence rates ranged from 0.01 to 2.61, 0.21 to 2.27, and 0.22 to 0.99 per 100,000 for PV, ET, and PMF, respectively. The combined annual incidence rates for PV, ET, and PMF were 0.84, 1.03, and 0.47 per 100,000. There was high heterogeneity across disease entities (I(2) 97.1-99.8%) and evidence of publication bias for ET and PMF (Egger test, P = 50.007 and P ≤ 0.001, respectively).The pooled incidence reflects the rarity of MPNs. The calculated pooled incidence rates do not reflect MPN incidence across the globe due to the high unexplained heterogeneity. Improved, widespread registration of MPNs would provide better information for global comparison of the incidence and prevalence of MPNs.

A Posteriori Dietary Patterns Are Related to Risk of Type 2 Diabetes: Findings from a Systematic Review and Meta-Analysis

Our review and meta-analysis examined the association between a posteriori–derived dietary patterns (DPs) and risk of type 2 diabetes mellitus. MEDLINE and EMBASE were searched for articles published up to July 2012 and data were extracted by two independent reviewers. Overall, 19 cross-sectional, 12 prospective cohort, and two nested case-control studies were eligible for inclusion. Results from cross-sectional studies reported an inconsistent association between DPs and measures of insulin resistance and/or glucose abnormalities, or prevalence of type 2 diabetes. A meta-analysis was carried out on nine prospective cohort studies that had examined DPs derived by principle component/factor analysis and incidence of type 2 diabetes risk (totaling 309,430 participants and 16,644 incident cases). Multivariate-adjusted odds ratios were combined using a random-effects meta-analysis. Two broad DPs (Healthy/Prudent and Unhealthy/Western) were identified based on food factor loadings published in original studies. Pooled results indicated a 15% lower type 2 diabetes risk for those in the highest category of Healthy/Prudent pattern compared with those in the lowest category (95% CI 0.80 to 0.91; P<0.0001). Compared with the lowest category of Unhealthy/Western DP, those in the highest category had a 41% increased risk of type 2 diabetes (95% CI 1.32 to 1.52; P<0.0001). These results provide evidence that DPs are consistently associated with risk of type 2 diabetes even when other lifestyle factors are controlled for. Thus, greater adherence to a DP characterized by high intakes of fruit, vegetables, and complex carbohydrate and low intakes of refined carbohydrate, processed meat, and fried food may be one strategy that could have a positive influence on the global public health burden of type 2 diabetes.