Corrigendum to: Cohort profile: Extended Cohort for E-health, Environment and DNA (EXCEED)

This is a correction to: International Journal of Epidemiology, Volume 48, Issue 3, June 2019, Pages 678–679j, https://doi.org/10.1093/ije/dyz07

Association between a variation in the phosphodiesterase 4D gene and bone mineral density

BACKGROUND: Fragility fractures caused by osteoporosis are a major cause of morbidity and mortality in aging populations. Bone mineral density (BMD) is a useful surrogate marker for risk of fracture and is a highly heritable trait. The genetic variants underlying this genetic contribution are largely unknown. METHODS: We performed a large-scale association study investigating more than 25,000 single nucleotide polymorphisms (SNPs) located within 16,000 genes. Allele frequencies were estimated in contrasting DNA pools from white females selected for low (<0.87 g/cm(2), n = 319) and high (> 1.11 g/cm(2), n = 321) BMD at the lumbar spine. Significant findings were verified in two additional sample collections. RESULTS: Based on allele frequency differences between DNA pools and subsequent individual genotyping, one of the candidate loci indicated was the phosphodiesterase 4D (PDE4D) gene region on chromosome 5q12. We subsequently tested the marker SNP, rs1498608, in a second sample of 138 white females with low (<0.91 g/cm(2)) and 138 females with high (>1.04 g/cm(2)) lumbar spine BMD. Odds ratios were 1.5 (P = 0.035) in the original sample and 2.1 (P = 0.018) in the replication sample. Association fine mapping with 80 SNPs located within 50 kilobases of the marker SNP identified a 20 kilobase region of association containing exon 6 of PDE4D. In a second, family-based replication sample with a preponderance of females with low BMD, rs1498608 showed an opposite relationship with BMD at different sites (p = 0.00044-0.09). We also replicated the previously reported association of the Ser37Ala polymorphism in BMP2, known to interact biologically with PDE4D, with BMD. CONCLUSION: This study indicates that variants in the gene encoding PDE4D account for some of the genetic contribution to bone mineral density variation in humans. The contrasting results from different samples indicate that the effect may be context-dependent. PDE4 inhibitors have been shown to increase bone mass in normal and osteopenic mice, but up until now there have been no reports implicating any member of the PDE4 gene family in human osteoporosis

Repurposing NGO data for better research outcomes: A scoping review of the use and secondary analysis of NGO data in health policy and systems research

Background Non-government organisations (NGOs) collect and generate vast amounts of potentially rich data, most of which are not used for research purposes. Secondary analysis of NGO data (their use and analysis in a study for which they were not originally collected) presents an important but largely unrealised opportunity to provide new research insights in critical areas including the evaluation of health policy and programmes. Methods A scoping review of the published literature was performed to identify the extent to which secondary analysis of NGO data has been used in health policy and systems research (HPSR). A tiered analytic approach provided a comprehensive overview and descriptive analyses of the studies which: 1) used data produced or collected by or about NGOs; 2) performed secondary analysis of the NGO data (beyond use of an NGO report as a supporting reference); 3) used NGO-collected clinical data. Results Of the 156 studies which performed secondary analysis of NGO-produced or collected data, 64% (n=100) used NGO-produced reports (e.g. to critique NGO activities and as a contextual reference) and 8% (n=13) analysed NGO-collected clinical data.. Of the studies, 55% investigated service delivery research topics, with 48% undertaken in developing countries and 17% in both developing and developed. NGO-collected clinical data enabled HPSR within marginalised groups (e.g. migrants, people in conflict-affected areas), with some limitations such as inconsistencies and missing data. Conclusion We found evidence that NGO-collected and produced data are most commonly perceived as a source of supporting evidence for HPSR and not as primary source data. However, these data can facilitate research in under-researched marginalised groups and in contexts that are hard to reach by academics, such as conflict-affected areas. NGO–academic collaboration could help address issues of NGO data quality to facilitate their more widespread use in research. Their use could enable relevant and timely research in the areas of health policy, programme evaluation and advocacy to improve health and reduce health inequalities, especially in marginalised groups and developing countries

Prescribing Data in General Practice Demonstration (PDGPD) project - a cluster randomised controlled trial of a quality improvement intervention to achieve better prescribing for chronic heart failure and hypertension

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6963/12/273 Extent: 11p.Background: Research literature consistently documents that scientifically based therapeutic recommendations are not always followed in the hospital or in the primary care setting. Currently, there is evidence that some general practitioners in Australia are not prescribing appropriately for patients diagnosed with 1) hypertension (HT) and 2) chronic heart failure (CHF). The objectives of this study were to improve general practitioner’s drug treatment management of these patients through feedback on their own prescribing and small group discussions with peers and a trained group facilitator. The impact evaluation includes quantitative assessment of prescribing changes at 6, 9, 12 and 18 months after the intervention. Methods: A pragmatic multi site cluster RCT began recruiting practices in October 2009 to evaluate the effects of a multi-faceted quality improvement (QI) intervention on prescribing practice among Australian general practitioners (GP) in relation to patients with CHF and HT. General practices were recruited nationally through General Practice Networks across Australia. Participating practices were randomly allocated to one of three groups: two groups received the QI intervention (the prescribing indicator feedback reports and small group discussion) with each group undertaking the clinical topics (CHF and HT) in reverse order to the other. The third group was waitlisted to receive the intervention 6 months later and acted as a "control" for the other two groups. De-identified data on practice, doctor and patient characteristics and their treatment for CHF and HT are extracted at six-monthly intervals before and after the intervention. Post-test comparisons will be conducted between the intervention and control arms using intention to treat analysis and models that account for clustering of practices in a Network and clustering of patients within practices and GPs. Discussion: This paper describes the study protocol for a project that will contribute to the development of acceptable and sustainable methods to promote QI activities within routine general practice, enhance prescribing practices and improve patient outcomes in the context of CHF and HT. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR), Trial # 320870.Margaret Williamson, Magnolia Cardona-Morrell, Jeffrey D Elliott, James F Reeve, Nigel P Stocks, Jon Emery, Judith M Mackson and Jane M Gun

Giardiasis in North West England: faecal specimen requesting rates by GP practice.

SUMMARY Many cases of giardiasis in the UK are undiagnosed and among other things, diagnosis is dependent upon the readiness of GPs to request a specimen. The aim of this study is to assess the rate of specimens requested per GP practice in Central Lancashire, to examine the differences between GP practices and to estimate the pattern of unexplained spatial variation in the practice rate of specimens after adjustment for deprivation. To achieve this, we fitted a set of binomial and Poisson regression models, with random effects for GP practice. Our analysis suggests that there were differences in the rate of specimens by GP practices (P &lt; 0·001) for a single year, but no difference in the proportion of positive tests per specimen submitted or in the rate of positive specimens per practice population. There was a difference in the cumulative rate of positive specimens per practice population over a 9-year period (P &lt; 0·001). Neither the specimen rate per practice for a single year nor the cumulative rate of positive specimens over multiple years demonstrated significant spatial correlation. Hence, spatial variation in the incidence of giardiasis is unlikely to be confounded by variation in GP rate of specimens

Resistome analyses of sputum from COPD and healthy subjects reveals bacterial load-related prevalence of target genes

Background: Antibiotic resistance is a major global threat. We hypothesised that the chronic obstructive pulmonary disease (COPD) airway is a reservoir of antimicrobial resistance genes (ARGs) that associate with microbiome-specific COPD subgroups. Objective: To determine the resistance gene profiles in respiratory samples from COPD patients and healthy volunteers. Methods: Quantitative PCR targeting 279 specific ARGs was used to profile the resistomes in sputum from subjects with COPD at stable, exacerbation and recovery visits (n=55; COPD-BEAT study), healthy controls with (n=7) or without (n=22) exposure to antibiotics in the preceding 12 months (EXCEED study) and in bronchial brush samples from COPD (n=8) and healthy controls (n=7) (EvA study). Results: ARG mean (SEM) prevalence was greater in stable COPD samples (35.2 (1.6)) than in healthy controls (27.6 (1.7); p=0.004) and correlated with total bacterial abundance (r2=0.23; p Conclusions: ARGs are highly prevalent in sputum, broadly in proportion to bacterial abundance in both healthy and COPD subjects. Thus, COPD appears to be an ARG reservoir due to high levels of bacterial colonisation.</p

Mendelian randomization of eosinophils and other cell types in relation to lung function and disease

Rationale Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood. Objectives We investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections. Methods We performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils. Measurements and main results Causal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1 (weighted median estimator, SD FEV1/FVC: −0.054 (95% CI −0.078 to −0.029), effect only prominent in individuals with asthma). Conclusions Broad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD.</p