144 results found
Gayle A, Lenoir A, Minelli C, et al., 2022, Are we missing lifetime COPD diagnosis among people with COPD recorded death?, British Journal of General Practice Open, ISSN: 2398-3795
Background: The British Lung Foundation previously estimated that 2.2 million symptomatic but undiagnosed people with COPD live in the UK. Aim: This study investigates the proportion of patients with a missed COPD diagnosis among those with COPD as the cause of death on their death certificate and how this has changed over the past 17 years. Design and Setting: We linked Clinical Practice Research Datalink Aurum and GOLD primary care data with Office for National Statistics mortality data and Hospital Episode Statistics data. We included adults who died between 2000 and 2017 with COPD as their main cause of death. Method: Using a range of diagnostic COPD criteria, we estimated the proportion of patients with a missed COPD diagnosis, and described the demographic and clinical characteristics of patients with and without prior COPD diagnosis using a mixed effect logistic regression model. Results: Depending on the COPD definition used, between 96% and 27% of the 78,621 patients included received a diagnosis of COPD prior to death. Using presence of a COPD Read or SNOMED CT code and performed spirometry as a main definition, just over half of the patients (52%) had received a COPD diagnosis overall, with a proportion of those who did not decreasing from 91% in 2000 to 31% in 2017 (p-trend <0.001). Conclusion: The proportion of people with COPD-recorded death who had received a diagnosis of COPD has improved over time and currently represents the majority of them, suggesting that few patients are being missed.
Konstantinoudis G, Cosetta M, Vicedo Cabrera AM, et al., 2022, Ambient heat exposure and COPD hospitalisations in England: a nationwide case-crossover study during 2007-2018, Thorax, ISSN: 0040-6376
Background: There is emerging evidence suggesting a link between ambient heat exposure and chronic obstructive pulmonary disease (COPD) hospitalisations. Individual and contextual characteristics can affect population vulnerabilities to COPD hospitalisation due to heat exposure. This study quantifies the effect of ambient heat on COPD hospitalisations and examines population vulnerabilities by age, sex and contextual characteristics.Methods: Individual data on COPD hospitalisation at high geographical resolution (postcodes) during 2007–2018 in England was retrieved from the small area health statistics unit. Maximum temperature at 1 km ×1 km resolution was available from the UK Met Office. We employed a case-crossover study design and fitted Bayesian conditional Poisson regression models. We adjusted for relative humidity and national holidays, and examined effect modification by age, sex, green space, average temperature, deprivation and urbanicity.Results: After accounting for confounding, we found 1.47% (95% Credible Interval (CrI) 1.19% to 1.73%) increase in the hospitalisation risk for every 1°C increase in temperatures above 23.2°C (lags 0–2 days). We reported weak evidence of an effect modification by sex and age. We found a strong spatial determinant of the COPD hospitalisation risk due to heat exposure, which was alleviated when we accounted for contextual characteristics. 1851 (95% CrI 1 576 to 2 079) COPD hospitalisations were associated with temperatures above 23.2°C annually.Conclusion: Our study suggests that resources should be allocated to support the public health systems, for instance, through developing or expanding heat-health alerts, to challenge the increasing future heat-related COPD hospitalisation burden.
Stone P, Minelli C, Feary J, et al., 2022, NEWS2’ as an objective assessment of hospitalised COPD exacerbation severity, International Journal of COPD, Vol: 17, Pages: 763-772, ISSN: 1176-9106
Introduction: There is currently no accepted way to risk-stratify hospitalised exacerbations of chronic obstructive pulmonary disease (COPD). We hypothesised that the revised UK National Early Warning Score (NEWS2) calculated at admission would predict inpatient mortality, need for non-invasive ventilation (NIV) and length-of-stay.Methods: We included data from 52,284 admissions for exacerbation of COPD. Data were divided into development and validation cohorts. Logistic regression was used to examine relationships between admission NEWS2 and outcome measures. Predictive ability of NEWS2 was assessed using area under receiver operating characteristic curves (AUC). We assessed the benefit of including other baseline data in the prediction models and assessed whether these variables themselves predicted admission NEWS2.Results: 53% of admissions had low risk, 24% medium risk and 23% a high risk NEWS2 in the development cohort. The proportions dying as an inpatient were 2.2%, 3.6% and 6.5% by NEWS2 risk category, respectively. The proportions needing NIV were 4.4%, 9.2% and 18.0%, respectively. NEWS2 was poorly predictive of length-of-stay (AUC: 0.59[0.57– 0.61]). In the external validation cohort, the AUC (95% CI) for NEWS2 to predict inpatient death and need for NIV were 0.72 (0.68– 0.77) and 0.70 (0.67– 0.73). Inclusion of patient demographic factors, co-morbidity and COPD severity improved model performance. However, only 1.34% of the variation in admission NEWS2 was explained by these baseline variables.Conclusion: The generic NEWS2 risk assessment tool, readily calculated from simple physiological data, predicts inpatient mortality and need for NIV (but not length-of-stay) at exacerbations of COPD. NEWS2 therefore provides a classification of hospitalised COPD exacerbation severity.
Adamson A, Portas L, Accordini S, et al., 2022, Communication of personalised disease risk by general practitioners to motivate smoking cessation in England: a cost-effectiveness and research prioritisation study, ADDICTION, Vol: 117, Pages: 1438-1449, ISSN: 0965-2140
Gayle A, Minelli C, Quint J, 2022, Respiratory-related death in individuals with incident asthma and COPD: a competing risk analysis, BMC Pulmonary Medicine, Vol: 22, ISSN: 1471-2466
Background Distinguishing between mortality attributed to respiratory causes and other causes among people with asthma, COPD, and asthma-COPD overlap (ACO) is important. This study used electronic health records in England to estimate excess risk of death from respiratory-related causes after accounting for other causes of death.Methods We used linked Clinical Practice Research Datalink (CPRD) primary care and Office for National Statistics mortality data to identify adults with asthma and COPD from 2005-2015. Causes of death were ascertained using death certificates. Hazard ratios (HR) and excess risk of death were estimated using Fine-Gray competing risk models and adjusting for age, sex, smoking status, body mass index and socio economic status.Results 65,021 people with asthma and 45,649 with COPD in the CPRD dataset were frequency matched 5:1 with people without the disease on age, sex and general practice. Only 14 in 100,000 people with asthma are predicted to experience a respiratory-related death up to 10 years post-diagnosis, whereas in COPD this is 98 in 100,000. Asthma is associated with an 0.01% excess incidence of respiratory related mortality whereas COPD is associated with an 0.07% excess. Among people with asthma-COPD overlap (N=22,145) we observed an increased risk of respiratory-related death compared to those with asthma alone (HR=1.30; 95%CI: 1.21 – 1.40) but not COPD alone (HR=0.89; 95%CI: 0.83 – 0.94).Conclusions Asthma and COPD are associated with an increased risk of respiratory-related death after accounting for other causes; however, diagnosis of COPD carries a much higher probability. ACO is associated with a lower risk compared to COPD alone but higher risk compared to asthma alone.
Perret JL, Vicendese D, Simons K, et al., 2021, Ten-year prediction model for post-bronchodilator airflow obstruction and early detection of COPD: development and validation in two middle-aged population-based cohorts, BMJ OPEN RESPIRATORY RESEARCH, Vol: 8
Amaral A, Burney P, Patel J, et al., 2021, Chronic airflow obstruction and ambient particulate air pollution, Thorax, Vol: 76, Pages: 1236-1241, ISSN: 0040-6376
Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised.
Elfadaly FG, Adamson A, Patel J, et al., 2021, BIMAM-a tool for imputing variables missing across datasets using a Bayesian imputation and analysis model, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 50, Pages: 1419-1425, ISSN: 0300-5771
Burney P, Patel J, Minelli C, et al., 2021, Prevalence and population attributable risk for chronic airflow obstruction in a large multinational study, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 1353-1365, ISSN: 1073-449X
Rationale: The Global Burden of Disease programme identified smoking, and ambient and household air pollution as the main drivers of death and disability from Chronic Obstructive Pulmonary Disease (COPD). Objective: To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. Methods: The Burden of Obstructive Lung Disease study is a cross-sectional study of adults, aged≥40, in a globally distributed sample of 41 urban and rural sites. Based on data from 28,459 participants, we estimated the prevalence of CAO, defined as a post-bronchodilator one-second forced expiratory volume to forced vital capacity ratio < lower limit of normal, and the relative risks associated with different risk factors. Local RR were estimated using a Bayesian hierarchical model borrowing information from across sites. From these RR and the prevalence of risk factors, we estimated local Population Attributable Risks (PAR). Measurements and Main Results: Mean prevalence of CAO was 11.2% in men and 8.6% in women. Mean PAR for smoking was 5.1% in men and 2.2% in women. The next most influential risk factors were poor education levels, working in a dusty job for ≥10 years, low body mass index (BMI), and a history of tuberculosis. The risk of CAO attributable to the different risk factors varied across sites. Conclusions: While smoking remains the most important risk factor for CAO, in some areas poor education, low BMI and passive smoking are of greater importance. Dusty occupations and tuberculosis are important risk factors at some sites.
Bandera E, Piva S, Gambaretti E, et al., 2021, Risk factors for postoperative eye pain in patients with non-painful eye disease undergoing pars plana vitrectomy: the VItrectomy Pain (VIP) study, MINERVA ANESTESIOLOGICA, Vol: 87, Pages: 541-548, ISSN: 0375-9393
Minelli C, Del Greco FM, van der Plaat DA, et al., 2021, The use of two-sample methods for Mendelian randomization analyses on single large datasets, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 50, Pages: 1651-1659, ISSN: 0300-5771
Fuertes E, Marcon A, Potts L, et al., 2021, Health Impact assessment to predict the impact of tobacco price increases on COPD burden in Italy, England and Sweden, Scientific Reports, Vol: 11, ISSN: 2045-2322
Raising tobacco prices effectively reduces smoking, the main risk factor for chronic obstructive pulmonary disease (COPD). Using the Health Impact Assessment tool “DYNAMO-HIA”, this study quantified the reduction in COPD burden that would occur in Italy, England and Sweden over 40 years if tobacco prices were increased by 5%, 10% and 20% over current local prices, with larger increases considered in secondary analyses. A dynamic Markov-based multi-state simulation modelling approach estimated the effect of changes in smoking prevalence states and probabilities of transitioning between smoking states on future smoking prevalence, COPD burden and life expectancy in each country. Data inputs included demographics, smoking prevalences and behaviour and COPD burden from national data resources, large observational cohorts and datasets within DYNAMO-HIA. In the 20% price increase scenario, the cumulative number of COPD incident cases saved over 40 years was 479,059 and 479,302 in Italy and England (populous countries with higher smoking prevalences) and 83,694 in Sweden (smaller country with lower smoking prevalence). Gains in overall life expectancy ranged from 0.25 to 0.45 years for a 20 year-old. Increasing tobacco prices would reduce COPD burden and increase life expectancy through smoking behavior changes, with modest but important public health benefits observed in all three countries.
van der Plaat DA, Minelli C, Jarvis DL, et al., 2020, Polycystic ovary syndrome and lung function: a Mendelian randomization study, American Journal of Obstetrics and Gynecology, Vol: 223, Pages: 455-457, ISSN: 0002-9378
Amaral A, Imboden M, Wielscher M, et al., 2020, Role of DNA methylation in the association of lung function with body mass index: A two-step epigenetic Mendelian randomisation study, BMC Pulmonary Medicine, Vol: 20, Pages: 1-8, ISSN: 1471-2466
BackgroundLow lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation.MethodsWe used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV1, FVC, and FEV1/FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2.ResultsIn step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs.ConclusionsTo our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function
Fuertes E, van der Plaat D, Portas L, et al., 2020, Recommended reading from the genomic and environmental medicine section, American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 1425-1427, ISSN: 1073-449X
Fawcett KA, Obeidat M, Melbourne C, et al., 2020, Variants associated with HHIP expression have sex-differential effects on lung function, Wellcome Open Research, Vol: 5, Pages: 1-16, ISSN: 2398-502X
Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females.Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium.Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10-8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression.Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
RATIONALE: Poor lung health in adult life may occur partly through suboptimal growth and development, as suggested by epidemiological evidence pointing to early life risk factors. OBJECTIVES: To systematically investigate the effects of lung development genes on adult lung function. METHODS: Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV1/FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger to select the most promising signals and the smaller for replication. MEASUREMENTS AND MAIN RESULTS: We identified 55 genes, of which 36 (16 for FVC; 19 for FEV1/FVC; 1 for both) had not been identified in the largest, most recent genome-wide study of lung function. Most of these 36 signals were intronic variants; expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 at nominal significance level. 53 of the 55 genes fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-cell adhesion; extra-cellular matrix), suggesting that these specific processes are important for adult lung health. CONCLUSIONS: Our study demonstrates the importance of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns. Further investigation of these developmental pathways could lead to druggable targets.
Minelli C, Fabiola Del Greco M, van der Plaat D, et al., 2020, The use of two-sample methods for Mendelian randomization analyses on single large datasets, Publisher: bioRxiv
Abstract Background With genome-wide association data for many exposures and outcomes now available from large biobanks, one-sample Mendelian randomization (MR) is increasingly used to investigate causal relationships. Many robust MR methods are available to address pleiotropy, but these assume independence between the gene-exposure and gene-outcome association estimates. Unlike in two-sample MR, in one-sample MR the two estimates are obtained from the same individuals, and the assumption of independence does not hold in the presence of confounding. Methods With simulations mimicking a typical study in UK Biobank we assessed the performance, in terms of bias and precision of the MR estimate, of the fixed-effect and (multiplicative) random-effects meta-analysis method, weighted median estimator, weighted mode estimator and MR-Egger regression, used in both one-sample and two-sample data. We considered scenarios differing for: presence/absence of a true causal effect; amount of confounding; presence and type of pleiotropy (none, balanced or directional). Results Even in the presence of substantial correlation due to confounding, all methods performed well when used in one-sample MR except for MR-Egger, which resulted in bias reflecting direction and magnitude of the confounding. Such bias was much reduced in the presence of very high variability in instrumental strength across variants (I 2 GX of 97%). Conclusions Two-sample MR methods can be safely used for one-sample MR performed within large biobanks, expect for MR-Egger. MR-Egger is not recommended for one-sample MR unless the correlation between the gene-exposure and gene-outcome estimates due to confounding can be kept low, or the variability in instrumental strength is very high. Key Messages <jats:list list-type="bullet"><jats:list-item> Current availability of phenotypic and genetic data from large biobanks, such as UK Biobank, has led to increasing use of one-sample Mendelian randomizat
Fuertes E, van der Plaat D, Minelli C, 2020, Antioxidant genes and susceptibility to air pollution for respiratory and cardiovascular health, Free Radical Biology and Medicine, Vol: 151, Pages: 88-98, ISSN: 0891-5849
Oxidative stress occurs when antioxidant defences, which are regulated by a complex network of genes, are insufficient to maintain the level of reactive oxygen species below a toxic threshold. Outdoor air pollution has long been known to adversely affect health and one prominent mechanism of action common to all pollutants is the induction of oxidative stress. An individual's susceptibility to the effects of air pollution partly depends on variation in their antioxidant genes. Thus, understanding antioxidant gene-pollution interactions has significant potential clinical and public health impacts, including the development of targeted and cost-effective preventive measures, such as setting appropriate standards which protect all members of the population. In this review, we aimed to summarize the latest epidemiological evidence on interactions between antioxidant genes and outdoor air pollution, in the context of respiratory and cardiovascular health. The evidence supporting the existence of interactions between antioxidant genes and outdoor air pollution is strongest for childhood asthma and wheeze, especially for interactions with GSTT1, GSTM1 and GSTP1, for lung function in both children and adults for several antioxidant genes (GSTT1, GSTM1, GSTP1, HMOX1, NQO1, and SOD2) and, to a more limited extent, for heart rate variability in adults for GSTM1 and HMOX1. Methodological challenges hampering a clear interpretation of these findings and understanding of true potential heterogeneity are discussed.
Burgess S, Davey Smith G, Davies NM, et al., 2020, Guidelines for performing Mendelian randomization investigations [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 4, Pages: 1-27, ISSN: 2398-502X
This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months.
Accordini S, Calciano L, Marcon A, et al., 2020, Incidence trends of airflow obstruction among European adults without asthma: a 20-year cohort study, Scientific Reports, Vol: 10, ISSN: 2045-2322
Investigating COPD trends may help healthcare providers to forecast future disease burden. We estimated sex- and smoking-specific incidence trends of pre-bronchodilator airflow obstruction (AO) among adults without asthma from 11 European countries within a 20-year follow-up (ECRHS and SAPALDIA cohorts). We also quantified the extent of misclassification in the definition based on pre-bronchodilator spirometry (using post-bronchodilator measurements from a subsample of subjects) and we used this information to estimate the incidence of post-bronchodilator AO (AOpost-BD), which is the primary characteristic of COPD. AO incidence was 4.4 (95% CI: 3.5-5.3) male and 3.8 (3.1-4.6) female cases/1,000/year. Among ever smokers (median pack-years: 20, males; 12, females), AO incidence significantly increased with ageing in men only [incidence rate ratio (IRR), 1-year increase: 1.05 (1.03-1.07)]. A strong exposure-response relationship with smoking was found both in males [IRR, 1-pack-year increase: 1.03 (1.02-1.04)] and females [1.03 (1.02-1.05)]. The positive predictive value of AO for AOpost-BD was 59.1% (52.0-66.2%) in men and 42.6% (35.1-50.1%) in women. AOpost-BD incidence was 2.6 (1.7-3.4) male and 1.6 (1.0-2.2) female cases/1,000/year. AO incidence was considerable in Europe and the sex-specific ageing-related increase among ever smokers was strongly related to cumulative tobacco exposure. AOpost-BD incidence is expected to be half of AO incidence.
Latronico N, Piva S, Fagoni N, et al., 2020, Impact of a posttraumatic cerebral infarction on outcome in patients with TBI: the Italian multicenter cohort INCEPT study, Critical Care (UK), Vol: 24, ISSN: 1364-8535
BACKGROUND: Post-traumatic cerebral infarction (PTCI) is common after traumatic brain injury (TBI). It is unclear what the occurrence of a PTCI is, how it impacts the long-term outcome, and whether it adds incremental prognostic value to established outcome predictors. METHODS: This was a prospective multicenter cohort study of moderate and severe TBI patients. The primary objective was to evaluate if PTCI was an independent risk factor for the 6-month outcome assessed with the Glasgow Outcome Scale (GOS). We also assessed the PTCI occurrence and if it adds incremental value to the International Mission for Prognosis and Clinical Trial design in TBI (IMPACT) core and extended models. RESULTS: We enrolled 143 patients, of whom 47 (32.9%) developed a PTCI. In the multiple ordered logistic regression, PTCI was retained in both the core and extended IMPACT models as an independent predictor of the GOS. The predictive performances increased significantly when PTCI was added to the IMPACT core model (AUC = 0.73, 95% C.I. 0.66-0.82; increased to AUC = 0.79, 95% CI 0.71-0.83, p = 0.0007) and extended model (AUC = 0.74, 95% C.I. 0.65-0.81 increased to AUC = 0.80, 95% C.I. 0.69-0.85; p = 0.00008). Patients with PTCI showed higher ICU mortality and 6-month mortality, whereas hospital mortality did not differ between the two groups. CONCLUSIONS: PTCI is a common complication in patients suffering from a moderate or severe TBI and is an independent risk factor for long-term disability. The addition of PTCI to the IMPACT core and extended predictive models significantly increased their performance in predicting the GOS. TRIAL REGISTRATION: The present study was registered in ClinicalTrial.gov with the ID number NCT02430324.
Burgess S, Davey Smith G, Davies N, et al., 2019, Guidelines for performing Mendelian randomization investigations [version 1; peer review: 1 approved, 1 approved with reservations], Wellcome Open Research, Vol: 4, Pages: 1-19, ISSN: 2398-502X
This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months.
Reynolds CJ, Minelli C, Darnton A, et al., 2019, Mesothelioma mortality in Great Britain: how much longer will dockyards dominate?, Occupational and Environmental Medicine, Vol: 76, Pages: 908-912, ISSN: 1351-0711
OBJECTIVES: We aimed to investigate whether there has been a geographic shift in the distribution of mesothelioma deaths in Great Britain given the decline of shipbuilding and progressive exposure regulation. METHODS: We calculated age-adjusted mesothelioma mortality rates and estimated rate ratios for areas with and without a dockyard. We compared spatial autocorrelation statistics (Moran's I) for age-adjusted rates at local authority district level for 2002-2008 and 2009-2015. We measured the mean distance of the deceased's postcode to the nearest dockyard at district level and calculated the association of average distance to dockyard and district mesothelioma mortality using simple linear regression for men, for 2002-2008 and 2009-2015. RESULTS: District age-adjusted male mortality rates fell during 2002-2015 for 80 of 348 districts (23%), rose for 267 (77%) and were unchanged for one district; having one or more dockyards in a district was associated with rates falling (OR=2.43, 95% CI 1.22 to 4.82, p=0.02). The mortality rate ratio for men in districts with a dockyard, compared with those without a dockyard was 1.41 (95% CI 1.35 to 1.48, p<0.05) for 2002-2008 and 1.18 (95% CI 1.13 to 1.23, p<0.05) for 2009-2015. Spatial autocorrelation (measured by Moran's I) decreased from 0.317 (95% CI 0.316 to 0.319, p=0.001) to 0.312 (95% CI 0.310 to 0.314, p=0.001) for men and the coefficient of the association between distance to dockyard and district level age-adjusted male mortality (per million population) from -0.16 (95% CI -0.21 to -0.10, p<0.01) to -0.13 (95% CI -0.18 to -0.07, p<0.01) for men, when comparing 2002-2008 with 2009-2015. CONCLUSION: For most districts age-adjusted mesothelioma mortality rates increased through 2002-2015 but the relative contribution from districts with a dockyard fell. Dockyards remain strongly spatially associated with mesothelioma mortality but the strength of this association appears to be falling and mesotheliom
van der Plaat D, Pereira M, Pesce G, et al., 2019, Age at menopause and lung function: a mendelian randomization study, European Respiratory Journal, Vol: 54, Pages: 1-10, ISSN: 0903-1936
In observational studies, early menopause is associated with lower FVC and a higher risk of spirometric restriction, but not airflow obstruction. It is however unclear if this association is causal. We therefore used a Mendelian randomization (MR) approach, which is not affected by classical confounding, to assess the effect of age at natural menopause on lung function. We included 94,742 naturally post-menopausal women from UK Biobank and performed MR analyses on the effect of age at menopause on FEV1, FVC, FEV1/FVC, spirometric restriction (FVC<LLN) and airflow obstruction (FEV1/FVC<LLN). We used the inverse variance-weighted (IVW) method, as well as methods that adjust for pleiotropy, and compared MR with observational analyses. The MR analyses showed higher FEV1/FVC and a 15% lower risk of airflow obstruction for women with early (<45 years) compared to normal (45-55) menopause. Despite some evidence of pleiotropy, the results were consistent when using MR methods robust to pleiotropy. Similar results were found among never- and ever-smokers, while the protective effect seemed less strong in women ever using menopause hormone treatment and in overweight women. There was no strong evidence of association with FVC or spirometric restriction. In observational analyses of the same dataset, early menopause was associated with a pronounced reduction in FVC and a 13% higher spirometric restriction risk.Our MR results suggest that early menopause has a protective effect on airflow obstruction. Further studies are warranted to better understand the inconsistency with observational findings, and to investigate the underlying mechanisms and role of female sex hormones.
Sugier P-E, Sarnowski C, Granell R, et al., 2019, Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood, Clinical and Experimental Allergy, Vol: 49, Pages: 1342-1351, ISSN: 0954-7894
BACKGROUND: Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. OBJECTIVE: Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood. METHODS: We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totaling 8,273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analyzed. RESULTS: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P=4.3x10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P<5x10-6 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P=4.9x10-7 ), 14q22 (rs7493885 near NIN; P=2.9x10-6 ) and 2p22 (rs232542 near CYP1B1; P=4.1x10-6 ). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings. CONCLUSION AND CLINICAL RELEVANCE: We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms. This article is protected by copyright. All rights reserved.
Bowden J, Del Greco M F, Minelli C, et al., 2019, Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption, International Journal of Epidemiology, Vol: 48, Pages: 728-742, ISSN: 1464-3685
Background: Two-sample summary-data Mendelian randomization (MR) incorporating multiple genetic variants within a meta-analysis framework is a popular technique for assessing causality in epidemiology. If all genetic variants satisfy the instrumental variable (IV) and necessary modelling assumptions, then their individual ratio estimates of causal effect should be homogeneous. Observed heterogeneity signals that one or more of these assumptions could have been violated. Methods: Causal estimation and heterogeneity assessment in MR require an approximation for the variance, or equivalently the inverse-variance weight, of each ratio estimate. We show that the most popular 'first-order' weights can lead to an inflation in the chances of detecting heterogeneity when in fact it is not present. Conversely, ostensibly more accurate 'second-order' weights can dramatically increase the chances of failing to detect heterogeneity when it is truly present. We derive modified weights to mitigate both of these adverse effects. Results: Using Monte Carlo simulations, we show that the modified weights outperform first- and second-order weights in terms of heterogeneity quantification. Modified weights are also shown to remove the phenomenon of regression dilution bias in MR estimates obtained from weak instruments, unlike those obtained using first- and second-order weights. However, with small numbers of weak instruments, this comes at the cost of a reduction in estimate precision and power to detect a causal effect compared with first-order weighting. Moreover, first-order weights always furnish unbiased estimates and preserve the type I error rate under the causal null. We illustrate the utility of the new method using data from a recent two-sample summary-data MR analysis to assess the causal role of systolic blood pressure on coronary heart disease risk. Conclusions: We propose the use of modified weights within two-sample summary-data MR studies for accurately quantifying het
Quint J, Minelli C, 2019, Can’t see the wood for the trees: confounders, colliders and causal inference - a clinician’s approach, Thorax, Vol: 74, Pages: 321-322, ISSN: 1468-3296
Colicino S, Munblit D, Minelli C, et al., 2019, Validation of childhood asthma predictive tools: A systematic review, Clinical and Experimental Allergy, Vol: 49, Pages: 410-418, ISSN: 0954-7894
BACKGROUND: There is uncertainty about the clinical usefulness of currently available asthma predictive tools. Validation of predictive tools in different populations and clinical settings is an essential requirement for the assessment of their predictive performance, reproducibility and generalizability. We aimed to critically appraise asthma predictive tools which have been validated in external studies. METHODS: We searched MEDLINE and EMBASE (1946-2017) for all available childhood asthma prediction models and focused on externally validated predictive tools alongside the studies in which they were originally developed. We excluded non-English and non-original studies. PROSPERO registration number is CRD42016035727. RESULTS: From 946 screened papers, eight were included in the review. Statistical approaches for creation of prediction tools included chi-square tests, logistic regression models and the least absolute shrinkage and selection operator. Predictive models were developed and validated in general and high-risk populations. Only three prediction tools were externally validated: the Asthma Predictive Index, the PIAMA and the Leicester asthma prediction tool. A variety of predictors has been tested, but no studies examined the same combination. There was heterogeneity in definition of the primary outcome among development and validation studies, and no objective measurements were used for asthma diagnosis. The performance of tools varied at different ages of outcome assessment. We observed a discrepancy between the development and validation studies in the tools' predictive performance in terms of sensitivity and positive predictive values. CONCLUSIONS: Validated asthma predictive tools, reviewed in this paper, provided poor predictive accuracy with performance variation in sensitivity and positive predictive value.
Pesce G, Marcon A, Calciano L, et al., 2019, Time and age trends in smoking cessation in Europe, PLoS ONE, Vol: 14, ISSN: 1932-6203
BackgroundSmoking is the main risk factor for most of the leading causes of death. Cessation is the single most important step that smokers can take to improve their health. With the aim of informing policy makers about decisions on future tobacco control strategies, we estimated time and age trends in smoking cessation in Europe between 1980 and 2010.MethodsData on the smoking history of 50,228 lifetime smokers from 17 European countries were obtained from six large population-based studies included in the Ageing Lungs in European Cohorts (ALEC) consortium. Smoking cessation rates were assessed retrospectively, and age trends were estimated for three decades (1980–1989, 1990–1999, 2000–2010). The analyses were stratified by sex and region (North, East, South, West Europe).ResultsOverall, 21,735 subjects (43.3%) quit smoking over a total time-at-risk of 803,031 years. Cessation rates increased between 1980 and 2010 in young adults (16–40 years), especially females, from all the regions, and in older adults (41–60 years) from North Europe, while they were stable in older adults from East, South and West Europe. In the 2000s, the cessation rates for men and women combined were highest in North Europe (49.9 per 1,000/year) compared to the other regions (range: 26.5–32.7 per 1,000/year). A sharp peak in rates was observed for women around the age of 30, possibly as a consequence of pregnancy-related smoking cessation. In most regions, subjects who started smoking before the age of 16 were less likely to quit than those who started later.ConclusionsOur findings suggest an increasing awareness on the detrimental effects of smoking across Europe. However, East, South and West European countries are lagging behind North Europe, suggesting the need to intensify tobacco control strategies in these regions. Additional efforts should be made to keep young adolescents away from taking up smoking, as early initiation could make quitting more ch
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