Publications by authors named "Cosetta Minelli"

112 Publications

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

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. 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. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV 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 ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which 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.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

Chronic airflow obstruction and ambient particulate air pollution.

Thorax 2021 May 11. Epub 2021 May 11.

Medicine, Obafemi Awolowo University, Ile-Ife, Osun, Nigeria.

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 (PM) using negative binomial regression. The prevalence of CAO was not independently associated with PM 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.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216223DOI Listing
May 2021

The use of two-sample methods for Mendelian randomization analyses on single large datasets.

Int J Epidemiol 2021 Apr 26. Epub 2021 Apr 26.

Department of Health Sciences, University of Leicester, Leicester, UK.

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 by the: presence/absence of a true causal effect; amount of confounding; and presence and type of pleiotropy (none, balanced or directional).

Results: Even in the presence of substantial correlation due to confounding, all two-sample methods used in one-sample MR performed similarly to when used in two-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 instrument strength across variants (IGX2 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 instrument strength is very high.
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http://dx.doi.org/10.1093/ije/dyab084DOI Listing
April 2021

Risk factors for postoperative eye pain in patients with non-painful eye disease undergoing pars plana vitrectomy: the VItrectomy Pain (VIP) study.

Minerva Anestesiol 2021 05 17;87(5):541-548. Epub 2021 Feb 17.

Department of Anesthesiology, Critical Care and Emergency, Spedali Civili University Hospital, Brescia, Italy.

Background: Pars plana vitrectomy (PPV), a surgical procedure used to treat different ophthalmic pathologies, could be associated with moderate to severe eye pain. The aim of the present study was to evaluate the incidence of postoperative eye pain and its risk factors following PPV in a selected population of patients with non-painful eye disease, receiving regional anesthesia and moderate sedation with benzodiazepines, without use of narcotics.

Methods: Single-center, prospective observational cohort study. We recorded the presence of pain at operating room discharge, at 6 and 24 hours, using the numeric rating scale (NRS). We recorded also age, sex, ethnic origin, American Society of Anaesthesia physical status (ASA PS) classification, Charlson Comorbidity Index, the etiology of the vitreoretinal pathology, length of surgery, and type of surgical procedure performed.

Results: Eye pain (NRS>3) was present in three patients (0.7%) at operating room discharge, 59 (13.2%) at six and 65 (14.6%) at 24 hours after surgery. LASSO logistic regression analysis identified age, ASA PS, race, along with tamponade as independent risk factors for eye pain at six hours. Scleral buckling was selected for eye pain at 24 hrs.

Conclusions: A protocol for pain control after PPV should be considered, especially in younger, non-Caucasian people, and patients with high ASA PS grade. Moreover, attention must be paid when additional surgical procedures are requested, restricting them to selected patients, and using the appropriate agent for intraocular tamponade.
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http://dx.doi.org/10.23736/S0375-9393.21.14294-4DOI Listing
May 2021

Health impact assessment to predict the impact of tobacco price increases on COPD burden in Italy, England and Sweden.

Sci Rep 2021 01 27;11(1):2311. Epub 2021 Jan 27.

National Heart and Lung Institute, Emmanuel Kaye Building, Imperial College London, 1B Manresa Road, London, SW3 6LR, UK.

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.
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http://dx.doi.org/10.1038/s41598-021-81876-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840977PMC
January 2021

Prevalence and Population Attributable Risk for Chronic Airflow Obstruction in a Large Multinational Study.

Am J Respir Crit Care Med 2020 Nov 10. Epub 2020 Nov 10.

Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, Netherlands.

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). To estimate the attributable risk of chronic airflow obstruction (CAO), a quantifiable characteristic of COPD, due to several risk factors. 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). 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. 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.
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http://dx.doi.org/10.1164/rccm.202005-1990OCDOI Listing
November 2020

Guidelines for performing Mendelian randomization investigations.

Wellcome Open Res 2019 28;4:186. Epub 2020 Apr 28.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.

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.
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http://dx.doi.org/10.12688/wellcomeopenres.15555.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384151PMC
April 2020

Role of DNA methylation in the association of lung function with body mass index: a two-step epigenetic Mendelian randomisation study.

BMC Pulm Med 2020 Jun 16;20(1):171. Epub 2020 Jun 16.

National Heart and Lung Institute, Imperial College London, London, UK.

Background: Low 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.

Methods: We 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 FEV, FVC, and FEV/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.

Results: In 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.

Conclusions: To 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 with BMI.
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http://dx.doi.org/10.1186/s12890-020-01212-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298775PMC
June 2020

Lung Development Genes and Adult Lung Function.

Am J Respir Crit Care Med 2020 09;202(6):853-865

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

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. To systematically investigate the effects of lung development genes on adult lung function. Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV/FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger subset to select the most promising signals and the smaller subset for replication. We identified 55 genes, of which 36 (16 for FVC, 19 for FEV/FVC, and one 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 replicated at nominal significance level. Of the 55 genes, 53 fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-to-cell adhesion; extracellular matrix), suggesting that these specific processes are important for adult lung health. 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.
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http://dx.doi.org/10.1164/rccm.201912-2338OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491406PMC
September 2020

Effects of the Environment and Its Interplay with Genetics in Lung Function throughout Life.

Am J Respir Crit Care Med 2020 06;201(11):1425-1427

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

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http://dx.doi.org/10.1164/rccm.201910-1937RRDOI Listing
June 2020

Polycystic ovary syndrome and lung function: a Mendelian randomization study.

Am J Obstet Gynecol 2020 09 7;223(3):455-457. Epub 2020 Mar 7.

Department of Clinical Science, University of Bergen; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.

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http://dx.doi.org/10.1016/j.ajog.2020.03.003DOI Listing
September 2020

Incidence trends of airflow obstruction among European adults without asthma: a 20-year cohort study.

Sci Rep 2020 02 26;10(1):3452. Epub 2020 Feb 26.

Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UK.

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 (AO), 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 AO was 59.1% (52.0-66.2%) in men and 42.6% (35.1-50.1%) in women. AO 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. AO incidence is expected to be half of AO incidence.
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http://dx.doi.org/10.1038/s41598-020-60478-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044325PMC
February 2020

Impact of a posttraumatic cerebral infarction on outcome in patients with TBI: the Italian multicenter cohort INCEPT study.

Crit Care 2020 02 3;24(1):33. Epub 2020 Feb 3.

Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.

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.
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http://dx.doi.org/10.1186/s13054-020-2746-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998281PMC
February 2020

Antioxidant genes and susceptibility to air pollution for respiratory and cardiovascular health.

Free Radic Biol Med 2020 05 30;151:88-98. Epub 2020 Jan 30.

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

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.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.01.181DOI Listing
May 2020

Mesothelioma mortality in Great Britain: how much longer will dockyards dominate?

Occup Environ Med 2019 12 29;76(12):908-912. Epub 2019 Oct 29.

National Heart & Lung Institute, Imperial College London, London, UK.

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 mesothelioma deaths are becoming more dispersed.
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http://dx.doi.org/10.1136/oemed-2019-105878DOI Listing
December 2019

Age at menopause and lung function: a Mendelian randomisation study.

Eur Respir J 2019 10 17;54(4). Epub 2019 Oct 17.

UMR 1152, Pathophysiology and Epidemiology of Respiratory Diseases, INSERM, Paris, France.

In observational studies, early menopause is associated with lower forced vital capacity (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 randomisation (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 the UK Biobank and performed MR analyses on the effect of age at menopause on forced expiratory volume in 1 s (FEV), FVC, FEV/FVC, spirometric restriction (FVC
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http://dx.doi.org/10.1183/13993003.02421-2018DOI Listing
October 2019

Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood.

Clin Exp Allergy 2019 10;49(10):1342-1351

Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Inserm, UMRS-1124, Université Paris Descartes, Paris, France.

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 (totalling 8273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analysed.

Results: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P = 4.3 × 10 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P < 5 × 10 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P = 4.9 × 10 ), 14q22 (rs7493885 near NIN; P = 2.9 × 10 ) and 2p22 (rs232542 near CYP1B1; P = 4.1 × 10 ). 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.

Conclusions 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.
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http://dx.doi.org/10.1111/cea.13476DOI Listing
October 2019

Can't see the wood for the trees: confounders, colliders and causal inference - a clinician's approach.

Thorax 2019 04 7;74(4):321-322. Epub 2019 Feb 7.

National Heart and Lung Institute, Imperial College, London, UK.

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http://dx.doi.org/10.1136/thoraxjnl-2018-212488DOI Listing
April 2019

Time and age trends in smoking cessation in Europe.

PLoS One 2019 7;14(2):e0211976. Epub 2019 Feb 7.

Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.

Background: Smoking 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.

Methods: Data 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).

Results: Overall, 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.

Conclusions: Our 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 challenging during later life.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366773PMC
November 2019

Validation of childhood asthma predictive tools: A systematic review.

Clin Exp Allergy 2019 04 7;49(4):410-418. Epub 2019 Feb 7.

National Heart and Lung Institute, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1111/cea.13336DOI Listing
April 2019

Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption.

Int J Epidemiol 2019 06;48(3):728-742

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

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 heterogeneity and detecting outliers in the presence of weak instruments. Modified weights also have an important role to play in terms of causal estimation (in tandem with first-order weights) but further research is required to understand their strengths and weaknesses in specific settings.
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http://dx.doi.org/10.1093/ije/dyy258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659376PMC
June 2019

Trends in smoking initiation in Europe over 40 years: A retrospective cohort study.

PLoS One 2018 22;13(8):e0201881. Epub 2018 Aug 22.

Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.

Background: Tobacco consumption is the largest avoidable health risk. Understanding changes of smoking over time and across populations is crucial to implementing health policies. We evaluated trends in smoking initiation between 1970 and 2009 in random samples of European populations.

Methods: We pooled data from six multicentre studies involved in the Ageing Lungs in European Cohorts consortium, including overall 119,104 subjects from 17 countries (range of median ages across studies: 33-52 years). We estimated retrospectively trends in the rates of smoking initiation (uptake of regular smoking) by age group, and tested birth cohort effects using Age-Period-Cohort (APC) modelling. We stratified all analyses by sex and region (North, East, South, West Europe).

Results: Smoking initiation during late adolescence (16-20 years) declined for both sexes and in all regions (except for South Europe, where decline levelled off after 1990). By the late 2000s, rates of initiation during late adolescence were still high (40-80 per 1000/year) in East, South, and West Europe compared to North Europe (20 per 1000/year). Smoking initiation rates during early adolescence (11-15 years) showed a marked increase after 1990 in all regions (except for North European males) but especially in West Europe, where they reached 40 per 1000/year around 2005. APC models supported birth cohort effects in the youngest cohorts.

Conclusion: Smoking initiation is still unacceptably high among European adolescents, and increasing rates among those aged 15 or less deserve attention. Reducing initiation in adolescents is fundamental, since youngsters are particularly vulnerable to nicotine addiction and tobacco adverse effects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201881PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104979PMC
February 2019

Age at puberty and risk of asthma: A Mendelian randomisation study.

PLoS Med 2018 08 7;15(8):e1002634. Epub 2018 Aug 7.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Background: Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males.

Methods And Findings: MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12-14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10(-5)) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10(-4)), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking.

Conclusions: This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.
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http://dx.doi.org/10.1371/journal.pmed.1002634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080744PMC
August 2018

Association of Height Growth in Puberty with Lung Function. A Longitudinal Study.

Am J Respir Crit Care Med 2018 12;198(12):1539-1548

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Puberty may influence lung function, but the precise role of pubertal height growth in lung development is unclear. To examine associations of timing of puberty and peak velocity of pubertal height growth with lung function in adolescence and early adulthood. Longitudinal analyses of repeat height measurements from age 5 to 20 years for a British birth cohort with 4,772 males and 4,849 females were conducted to characterize height growth trajectories and to derive pubertal age and peak height velocity using the validated SITAR (SuperImposition by Translation and Rotation) model. Association of these estimates with prebronchodilator and post-bronchodilator spirometry measures: FEV; FVC; FEV/FVC; FEF at age 15 and 24 years were investigated using multivariable regression models adjusted for lung function at age 8 years, height and age at time of outcome measurements, and potential confounders. Later pubertal age and greater peak velocity were associated with higher FEV and FVC at 24 years in both sexes. A 1-year increase in pubertal age was associated with a 263-ml higher FVC (95% confidence interval [CI], 167-360 ml) for males ( = 567) and 100-ml (95% CI, 50-150 ml) higher FVC for females ( = 990). A 1-cm/yr increase in peak velocity was associated with 145-ml (95% CI, 56-234 ml) and 50-ml (95% CI, 2-99 ml) increases in FVC for males and females, respectively. No associations were found with FEV/FVC. Later onset and greater peak velocity of height growth in puberty are associated with increased FEV and FVC in young adults but there was no evidence of dysanapsis of pubertal lung growth.
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http://dx.doi.org/10.1164/rccm.201802-0274OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298631PMC
December 2018

Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression.

Int J Epidemiol 2018 08;47(4):1264-1278

MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.

Background: data furnishing a two-sample Mendelian randomization (MR) study are often visualized with the aid of a scatter plot, in which single-nucleotide polymorphism (SNP)-outcome associations are plotted against the SNP-exposure associations to provide an immediate picture of the causal-effect estimate for each individual variant. It is also convenient to overlay the standard inverse-variance weighted (IVW) estimate of causal effect as a fitted slope, to see whether an individual SNP provides evidence that supports, or conflicts with, the overall consensus. Unfortunately, the traditional scatter plot is not the most appropriate means to achieve this aim whenever SNP-outcome associations are estimated with varying degrees of precision and this is reflected in the analysis.

Methods: We propose instead to use a small modification of the scatter plot-the Galbraith Radial plot-for the presentation of data and results from an MR study, which enjoys many advantages over the original method. On a practical level, it removes the need to recode the genetic data and enables a more straightforward detection of outliers and influential data points. Its use extends beyond the purely aesthetic, however, to suggest a more general modelling framework to operate within when conducting an MR study, including a new form of MR-Egger regression.

Results: We illustrate the methods using data from a two-sample MR study to probe the causal effect of systolic blood pressure on coronary heart disease risk, allowing for the possible effects of pleiotropy. The Radial plot is shown to aid the detection of a single outlying variant that is responsible for large differences between IVW and MR-Egger regression estimates. Several additional plots are also proposed for informative data visualization.

Conclusions: The Radial plot should be considered in place of the scatter plot for visualizing, analysing and interpreting data from a two-sample summary data MR study. Software is provided to help facilitate its use.
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http://dx.doi.org/10.1093/ije/dyy101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124632PMC
August 2018

Age at menarche and adult body mass index: a Mendelian randomization study.

Int J Obes (Lond) 2018 09 26;42(9):1574-1581. Epub 2018 Feb 26.

Population Health and Occupational Disease, NHLI, Imperial College London, London, UK.

Background: Pubertal timing has psychological and physical sequelae. While observational studies have demonstrated an association between age at menarche and adult body mass index (BMI), confounding makes it difficult to infer causality.

Methods: The Mendelian randomization (MR) technique is not limited by traditional confounding and was used to investigate the presence of a causal effect of age at menarche on adult BMI. MR uses genetic variants as instruments under the assumption that they act on BMI only through age at menarche (no pleiotropy). Using a two-sample MR approach, heterogeneity between the MR estimates from individual instruments was used as a proxy for pleiotropy, with sensitivity analyses performed if detected. Genetic instruments and estimates of their association with age at menarche were obtained from a genome-wide association meta-analysis on 182,416 women. The genetic effects on adult BMI were estimated using data on 80,465 women from the UK Biobank. The presence of a causal effect of age at menarche on adult BMI was further investigated using data on 70,692 women from the GIANT Consortium.

Results: There was evidence of pleiotropy among instruments. Using the UK Biobank data, after removing instruments associated with childhood BMI that were likely exerting pleiotropy, fixed-effect meta-analysis across instruments demonstrated that a 1 year increase in age at menarche reduces adult BMI by 0.38 kg/m (95% CI 0.25-0.51 kg/m). However, evidence of pleiotropy remained. MR-Egger regression did not suggest directional bias, and similar estimates to the fixed-effect meta-analysis were obtained in sensitivity analyses when using a random-effect model, multivariable MR, MR-Egger regression, a weighted median estimator and a weighted mode-based estimator. The direction and significance of the causal effect were replicated using GIANT Consortium data.

Conclusion: MR provides evidence to support the hypothesis that earlier age at menarche causes higher adult BMI. Complex hormonal and psychological factors may be responsible.
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http://dx.doi.org/10.1038/s41366-018-0048-7DOI Listing
September 2018

Using reference values to define disease based on the lower limit of normal biased the population attributable fraction, but not the population excess risk: the example of chronic airflow obstruction.

J Clin Epidemiol 2018 01 6;93:76-78. Epub 2017 Nov 6.

National Heart and Lung Institute, Imperial College, Emmanuel Kaye Building, 1b Manresa Road, London SW3 6LP, UK.

Background: The impact of disease on population health is most commonly estimated by the population attributable fraction (PAF), or less commonly by the excess risk, an alternative measure that estimates the absolute risk of disease in the population that can be ascribed to the exposure. Using chronic airflow obstruction as an example, we examined the impact on these estimates of defining disease based on different "normal" values.

Method: We estimated PAF and the excess risk in scenarios in which the true rate of disease was 10% in the exposed and 5% in the unexposed, and where either 50% or 20% of the population was exposed. Disease definition was based on a "lower limit of normal", using the 5th, 1st and 0.2nd centile of values in a "normal" population as thresholds to define normality.

Results: Where normality is defined by centiles of values in a "normal" population, PAF is strongly influenced by which centile is selected to define normality. This is not true for the population excess risk.

Conclusion: Care should be taken when interpreting estimates of PAF when disease is defined from a centile of a normal population.
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http://dx.doi.org/10.1016/j.jclinepi.2017.10.020DOI Listing
January 2018

Prediction of long-term outcome subtypes in ARDS: first steps towards personalised medicine in critical care.

Thorax 2017 12 7;72(12):1067-1068. Epub 2017 Oct 7.

Department of Anesthesia, Critical and Pain Medicine, Beth Israel Deconness Medical Center, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1136/thoraxjnl-2017-210775DOI Listing
December 2017

Systematic review of statistical approaches to quantify, or correct for, measurement error in a continuous exposure in nutritional epidemiology.

BMC Med Res Methodol 2017 Sep 19;17(1):146. Epub 2017 Sep 19.

Population Health & Occupational Disease, National Heart and Lung Institute, Imperial College London, London, UK.

Background: Several statistical approaches have been proposed to assess and correct for exposure measurement error. We aimed to provide a critical overview of the most common approaches used in nutritional epidemiology.

Methods: MEDLINE, EMBASE, BIOSIS and CINAHL were searched for reports published in English up to May 2016 in order to ascertain studies that described methods aimed to quantify and/or correct for measurement error for a continuous exposure in nutritional epidemiology using a calibration study.

Results: We identified 126 studies, 43 of which described statistical methods and 83 that applied any of these methods to a real dataset. The statistical approaches in the eligible studies were grouped into: a) approaches to quantify the relationship between different dietary assessment instruments and "true intake", which were mostly based on correlation analysis and the method of triads; b) approaches to adjust point and interval estimates of diet-disease associations for measurement error, mostly based on regression calibration analysis and its extensions. Two approaches (multiple imputation and moment reconstruction) were identified that can deal with differential measurement error.

Conclusions: For regression calibration, the most common approach to correct for measurement error used in nutritional epidemiology, it is crucial to ensure that its assumptions and requirements are fully met. Analyses that investigate the impact of departures from the classical measurement error model on regression calibration estimates can be helpful to researchers in interpreting their findings. With regard to the possible use of alternative methods when regression calibration is not appropriate, the choice of method should depend on the measurement error model assumed, the availability of suitable calibration study data and the potential for bias due to violation of the classical measurement error model assumptions. On the basis of this review, we provide some practical advice for the use of methods to assess and adjust for measurement error in nutritional epidemiology.
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http://dx.doi.org/10.1186/s12874-017-0421-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606038PMC
September 2017
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