Imperial College London

DrCosettaMinelli

Faculty of MedicineNational Heart & Lung Institute

Reader in Medical Statistics
 
 
 
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Contact

 

+44 (0)20 7594 7758cosetta.minelli1 Website

 
 
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G 49Emmanuel Kaye BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
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141 results found

Gayle A, Minelli C, Quint J, 2022, Respiratory-related death in individuals with incident asthma and COPD: a competing risk analysis, BMC Pulmonary Medicine, 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.

Journal article

Adamson A, Portas L, Accordini S, Marcon A, Jarvis D, Baio G, Minelli Cet al., 2021, Communication of personalised disease risk by general practitioners to motivate smoking cessation in England: A cost-effectiveness and research prioritisation study., Addiction

BACKGROUND AND AIMS: Communication of personalised disease risk can motivate smoking cessation. We assessed whether routine implementation of this intervention by general practitioners (GPs) in England is cost-effective or whether we need further research to better establish its effectiveness. DESIGN: Cost-effectiveness analysis (CEA) with value of information (VoI) analysis from the UK National Health Service perspective, using GP communication of personalised disease risk on smoking cessation versus usual care. SETTING: GP practices in England. STUDY POPULATION: Healthy smokers aged 35-60 attending the GP practice. MEASUREMENTS: Effectiveness of GP communication of personalised disease risk on smoking cessation was estimated through systematic review and meta-analysis. A Bayesian CEA was then performed using a lifetime Markov model on smokers aged 35-60 that measured lifetime costs and quality-adjusted life-years (QALYs) assigned to the four diseases contributing the most to smoking-related morbidity, mortality and costs: chronic obstructive pulmonary disease, lung cancer, myocardial infarction, and stroke. Costs and QALYs for each disease state were obtained from the literature. VoI analysis identified sources of uncertainty in the CEA and assessed how much would be worth investing in further research to reduce this uncertainty. FINDINGS: The meta-analysis odds ratio for the effectiveness estimate of GP communication of personalised disease risk was 1.48 (95% credibility interval (CrI): 0.91-2.26), an absolute increase in smoking cessation rates of 3.84%. The probability of cost-effectiveness ranged from 89-94% depending on sex and age. VoI analysis indicated that: 1) uncertainty in the effectiveness of the intervention was the driver of the overall uncertainty in the CEA and 2) a research investment to reduce this uncertainty is justified if lower than £27.6million (£7 per smoker). CONCLUSIONS: Evidence to date shows that, in England, incorporating d

Journal article

Perret JL, Vicendese D, Simons K, Jarvis DL, Lowe AJ, Lodge CJ, Bui DS, Tan D, Burgess JA, Erbas B, Bickerstaffe A, Hancock K, Thompson BR, Hamilton GS, Adams R, Benke GP, Thomas PS, Frith P, McDonald CF, Blakely T, Abramson MJ, Walters EH, Minelli C, Dharmage SCet 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

Journal article

Amaral A, Burney P, Patel J, Minelli C, Mejza F, Mannino D, Seemungal T, Padukudru Anand M, Loh LC, Janson C, Juvekar S, Denguezli M, Harrabi I, Wouters E, Cherkaski H, Mortimer K, Jogi R, Bateman E, Fuertes E, Al Ghobain M, Tan W, Obaseki D, El Sony A, Studnicka M, Aquart-Stewart A, Koul P, Lawin H, Nafees A, Awopeju O, Erhabor G, Gislason T, Welte T, Gulsvik A, Nielsen R, Gnatiuc L, Kocabas A, Marks G, Sooronbaev T, Mbatchou Ngahane B, Barbara C, Buist ASet 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.

Journal article

Minelli C, Del Greco FM, van der Plaat DA, Bowden J, Sheehan NA, Thompson Jet 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

Journal article

Elfadaly FG, Adamson A, Patel J, Potts L, Potts J, Blangiardo M, Thompson J, Minelli Cet 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

Journal article

Burney P, Patel J, Minelli C, Gnatiuc L, Amaral A, Kocabas A, Cherkaski H, Gulsvik A, Nielsen R, Bateman E, Jithoo A, Mortimer K, Sooronbaev T, Lawin H, Nejjari C, Elbiaze M, El Rhazi K, Zheng J-P, Ran P, Welte T, Obaseki D, Erhabor G, Elsony A, Osman N, Ahmed R, Nizankowska -Mogilnicka E, Mejza F, Mannino D, Barbara C, Wouters E, Idolor L, Loh L-C, Rashid A, Juvekar S, Gislason T, Al Ghobain M, Studnicka M, Harrabi I, Denguezli M, Koul P, Jenkins C, Marks G, Jogi R, Hafizi H, Janson C, Tan W, Aquart-Stewart A, Mbatchou B, Nafees A, Gunasekera K, Seemungal T, Mahesh PA, Enright P, Vollmer W, Blangiardo M, Elfadaly F, Buist ASet 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.

Journal article

Bandera E, Piva S, Gambaretti E, Minelli C, Rizzo F, Rizzolo A, Morescalchi F, Ambrosoli L, Semeraro F, Latronico Net 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

Journal article

Fuertes E, Marcon A, Potts L, Pesce G, K Lhachimi S, Jani V, Calciano L, Adamson A, K Quint J, Jarvis D, Janson C, Accordini S, Minelli Cet 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.

Journal article

van der Plaat DA, Minelli C, Jarvis DL, Garcia-Aymerich J, Leynaert B, Gómez-Real Fet 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

Journal article

Amaral A, Imboden M, Wielscher M, Rezwan FI, Minelli C, Garcia-Aymerich J, Peralta GP, Auvinen J, Jeong A, Schaffner E, Beckmeyer-Borowko A, Holloway JW, Jarvelin M-R, Probst-Hensch NM, Jarvis DLet 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

Journal article

Fuertes E, van der Plaat D, Portas L, Minelli Cet 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

Journal article

Fawcett KA, Obeidat M, Melbourne C, Shrine N, Guyatt AL, John C, Luan J, Richmond A, Moksnes MR, Granell R, Weiss S, Imboden M, May-Wilson S, Hysi P, Boutin TS, Portas L, Flexeder C, Harris SE, Wang CA, Lyytikäinen L-P, Palviainen T, Foong RE, Keidel D, Minelli C, Langenberg C, Bossé Y, Van den Berge M, Sin DD, Hao K, Campbell A, Porteous D, Padmanabhan S, Smith BH, Evans DM, Ring S, Langhammer A, Hveem K, Willer C, Ewert R, Stubbe B, Pirastu N, Klaric L, Joshi PK, Patasova K, Massimo M, Polasek O, Starr JM, Karrasch S, Strauch K, Meitinger T, Rudan I, Rantanen T, Pietiläinen K, Kähönen M, Raitakari OT, Hall GL, Sly PD, Pennell CE, Kaprio J, Lehtimäki T, Vitart V, Deary IJ, Jarvis D, Wilson JF, Spector T, Probst-Hensch N, Wareham NJ, Völzke H, Henderson J, Strachan DP, Brumpton BM, Hayward C, Hall IP, Tobin MD, Wain LVet 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.

Journal article

Portas L, Pereira M, Shaheen SO, Wyss AB, London SJ, Burney PGJ, Hind M, Dean CH, Minelli Cet al., 2020, Lung development genes and adult lung function, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 853-865, ISSN: 1073-449X

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.

Journal article

Minelli C, Fabiola Del Greco M, van der Plaat D, Bowden J, Sheehan N, Thompson Jet 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

Working paper

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.

Journal article

Burgess S, Davey Smith G, Davies NM, Dudbridge F, Gill D, Glymour MM, Hartwig FP, Holmes MV, Minelli C, Relton CL, Theodoratou Eet 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.

Journal article

Accordini S, Calciano L, Marcon A, Pesce G, Antó JM, Beckmeyer-Borowko AB, Carsin A-E, Corsico AG, Imboden M, Janson C, Keidel D, Locatelli F, Svanes C, Burney PGJ, Jarvis D, Probst-Hensch NM, Minelli Cet 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.

Journal article

Latronico N, Piva S, Fagoni N, Pinelli L, Frigerio M, Tintori D, Berardino M, Bottazzi A, Carnevale L, Casalicchio T, Castioni CA, Cavallo S, Cerasti D, Citerio G, Fontanella M, Galiberti S, Girardini A, Gritti P, Manara O, Maremmani P, Mazzani R, Natalini G, Patassini M, Perna ME, Pesaresi I, Radolovich DK, Saini M, Stefini R, Minelli C, Gasparotti R, Rasulo FAet 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.

Journal article

Burgess S, Davey Smith G, Davies N, Dudbridge F, Gill D, Glymour M, Hartwig F, Holmes M, Minelli C, Relton C, Theodoratou Eet 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.

Journal article

Reynolds CJ, Minelli C, Darnton A, Cullinan Pet 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

Journal article

van der Plaat D, Pereira M, Pesce G, Potts J, Amaral A, Dharmage S, Garcia-Aymerich J, Thompson J, Gomez-Real F, Jarvis D, Minelli C, Leynaert Bet 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.

Journal article

Sugier P-E, Sarnowski C, Granell R, Laprise C, Ege MJ, Margaritte-Jeannin P, Dizier M-H, Minelli C, Moffatt MF, Lathrop M, Cookson WOCM, Henderson AJ, von Mutius E, Kogevinas M, Demenais F, Bouzigon Eet 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.

Journal article

Bowden J, Del Greco M F, Minelli C, Zhao Q, Lawlor DA, Sheehan NA, Thompson J, Davey Smith Get 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

Journal article

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

Journal article

Colicino S, Munblit D, Minelli C, Custovic A, Cullinan Pet 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.

Journal article

Pesce G, Marcon A, Calciano L, Perret JL, Abramson MJ, Bono R, Bousquet J, Fois AG, Janson C, Jarvis D, Jogi R, Leynaert B, Nowak D, Schlunssen V, Urrutia-Landa I, Verlato G, Villani S, Zuberbier T, Minelli C, Accordini S, Boezen M, Elger B, Gleditsch BA, Heijmans B, Romieu I, Thompson Jet 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

Journal article

Mahmoud O, Granell R, Tilling K, Minelli C, Garcia-Aymerich J, Holloway JW, Custovic A, Jarvis D, Sterne J, Henderson Jet al., 2018, Association of height growth in puberty with lung function: a longitudinal study, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 1539-1548, ISSN: 1073-449X

RATIONALE: Puberty may influence lung function, but the precise role of pubertal height growth in lung development is unclear. OBJECTIVES: To examine associations of timing of puberty and peak velocity of pubertal height growth with lung function in adolescence and early-adulthood. METHODS: Longitudinal analyses of repeat height measurements from age 5-20 years for a British birth cohort with 4,772 males and 4,849 females were conducted to characterise height growth trajectories, and derive pubertal age and peak height velocity using the validated SuperImposition by Translation and Rotation (SITAR) model. Association of these estimates with pre-bronchodilator and post-bronchodilator spirometry measures: FEV1; FVC; FEV1/FVC; FEF25-75 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. MEASUREMENTS AND MAIN RESULTS: Later pubertal age and greater peak velocity were associated with higher FEV1 and FVC at 24 years in both sexes. A 1-year advanced pubertal age was associated with a 263 ml higher FVC (95% confidence interval: 167, 360) for males (n=567), 100 ml (50, 150) for females (n=990). A 1-cm/year increase in peak velocity was associated with 145 ml (56, 234) and 50 ml (2, 99) increase in FVC for males and females respectively. No associations were found with FEV1/FVC. CONCLUSIONS: Later onset and greater peak velocity of height growth in puberty are associated with increased FEV1 and FVC in young adults but there was no evidence of dysanapsis of pubertal lung growth.

Journal article

Bowden J, Spiller W, Del Greco FM, Sheehan N, Thompson J, Minelli C, Smith GDet al., 2018, Corrigendum: Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression, International Journal of Epidemiology, Vol: 47, Pages: 2100-2100, ISSN: 1464-3685

This is a correction to: International Journal of Epidemiology, Volume 47, Issue 4, August 2018, Pages 1264–1278, https://doi.org/10.1093/ije/dyy101.Since its initial publication, the article ‘Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression’ has been updated to include a funding statement relating to the authors Jack Bowden and George Davey Smith.

Journal article

Marcon A, Pesce G, Calciano L, Bellisario V, Dharmage SC, Garcia-Aymerich J, Gislasson T, Heinrich J, Holm M, Janson C, Jarvis D, Leynaert B, Matheson MC, Pirina P, Svanes C, Villani S, Zuberbier T, Minelli C, Accordini Set al., 2018, Trends in smoking initiation in Europe over 40 years: a retrospective cohort study, PLoS ONE, Vol: 13, ISSN: 1932-6203

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.

Journal article

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