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  • Journal article
    Forslund SK, Chakaroun R, Zimmermann-Kogadeeva M, Marko L, Aron-Wisnewsky J, Nielsen T, Moitinho-Silva L, Schmidt TSB, Falony G, Vieira-Silva S, Adriouch S, Alves RJ, Assmann K, Bastard J-P, Birkner T, Caesar R, Chilloux J, Coelho LP, Fezeu L, Galleron N, Helft G, Isnard R, Ji B, Kuhn M, Le Chatelier E, Myridakis A, Olsson L, Pons N, Prifti E, Quinquis B, Roume H, Salem J-E, Sokolovska N, Tremaroli V, Valles-Colomer M, Lewinter C, Sondertoft NB, Pedersen HK, Hansen TH, Gotze JP, Kober L, Vestergaard H, Hansen T, Zucker J-D, Hercberg S, Oppert J-M, Letunic I, Nielsen J, Backhed F, Ehrlich SD, Dumas M-E, Raes J, Pedersen O, Clement K, Stumvoll M, Bork Pet al., 2021,

    Combinatorial, additive and dose-dependent drug-microbiome associations

    , Nature, Vol: 600, Pages: 500-505, ISSN: 0028-0836

    During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1,2,3,4,5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.

  • Journal article
    Sundaram V, Bloom C, Zakeri R, halcox J, cohen A, bowrin K, briere J-B, banerjee A, simon D, Cleland J, Rajagopalan S, Quint Jet al., 2019,

    Temporal trends in the incidence, treatment patterns, and outcomes of coronary artery disease and peripheral artery disease in the United Kingdom, 2006-2015

    , European Heart Journal, Vol: 41, Pages: 1636-1649, ISSN: 0195-668X

    AimsMost reports estimating national incidence rates of coronary (CAD) and peripheral arterial disease (PAD) have focused on stable outpatients or acute or elective hospital admissions, but not on the overall burden of disease. In this study, we report the changing trends in the population-level incidence of CAD and PAD, respectively from 2006 to 2015, statin utilization for secondary prevention and survival outcomes using multiple nationally representative data sources from the UK (primary care encounters, hospital admissions, and procedure-level data).Methods and resultsA nationally representative study of linked primary and secondary care electronic health records of 4.6 million individuals from the UK. We calculated crude and standardized annual incidence rates separately for CAD and PAD. Statin use for secondary prevention, trends in annual major vascular event rates, and mortality between 2006 and 2015, were estimated for CAD and PAD, respectively. We identified 160 376 and 70 753 patients with incident CAD and PAD, respectively. The age- and sex-standardized incidence of CAD was similar in 2006 (443 per 100 000 person-years) and 2015 [436 per 100 000 person-years; adjusted incidence rate ratio (IRR) 0.98, 95% confidence interval (CI) 0.96–1.00]. In contrast, there was a 15% decline in the standardized incidence of PAD (236 per 100 000 person-years in 2006 to 202 per 100 000 person-years in 2015; adjusted IRR 0.85, 95% CI 0.82–0.88). The proportion of incident CAD and PAD patients prescribed long-term statins, was only 66% and 55%, respectively and was less common amongst women, patients aged >70 years, with heart failure, chronic lung disease, or depression. Cardiovascular mortality declined by 43% for incident CAD (adjusted IRR 0.57, 95% CI 0.50–0.64) between 2006 and 2015 but did not decline for incident PAD (adjusted IRR 0.84, 95% CI 0.70–1.00).Conclusion and relevanceIn the UK, the standardized incidence of CAD appears stable bu

  • Journal article
    Burney P, Amaral AFS, 2019,

    Air pollution and chronic airway disease: is the evidence always clear?

    , LANCET, Vol: 394, Pages: 2198-2200, ISSN: 0140-6736
  • Journal article
    Bloom C, douglas I, Olney J, d'Ancona G, smeeth L, Quint Jet al., 2019,

    Cost saving of switching to equivalent inhalers and its effect on health outcomes

    , Thorax, Vol: 74, Pages: 1078-1086, ISSN: 1468-3296

    BackgroundSwitching inhalers to cheaper equivalent products is often advocated as a necessary cost saving measure, yet the impact on patient’s health and healthcare utilisation has not been measured.MethodsWe identified asthma and chronic obstructive pulmonary disease (COPD) patients from UK primary care electronic healthcare records between 2000 and 2016. A self-controlled case series was used to estimate incidence rate ratios (IRR); comparing outcome rates during the risk period, 3-months after the exposure (financially-motivated switch), and control periods (pre-switch, and post-risk period). Four outcomes were assessed: disease exacerbation, GP consultation, non-specific respiratory events and adverse-medication events. Medication possession ratio (MPR) was calculated to assess adherence. 2017 NHS indicative prices were used to estimate cost differences per equivalent dose.ResultsWe identified a cohort of 569,901 asthma and 171,231 COPD regular inhaler users, 2% and 6% had been switched, respectively. Inhaler switches between a brand-to-generic inhaler, and all other switches (brand-to-brand, generic-to-generic, generic-to-brand), were associated with reduced exacerbations (brand-to-generic: IRR=0.75, 95% CI 0.64-0.88; all other: IRR=0.79, 95% CI 0.71-0.88). Gender, age, therapeutic class, inhaler device, and inhaler-technique checks did not significantly modify this association (p<0.05). The rate of consultations, respiratory-events and adverse-medication events did not change significantly (consultations: IRR=1.00, 95% CI 0.99-1.01; respiratory-events: IRR=0.96, 95% CI 0.95-0.97; adverse-medication-events: IRR=1.05, 95% CI 0.96-1.15). Adherence significantly increased post-switch (median MPR: pre-switch=54%, post-switch=62%; p<0.001). Switching patients, in the cohort of regular inhaler users, to the cheapest equivalent inhaler, could have saved around £6 million annually. ConclusionSwitching to an equivalent inhaler in patients with asthma

  • Journal article
    Pikoula M, Quint J, Nissen F, Hemingway H, Smeeth L, Denexas Set al., 2019,

    Identifying clinically important COPD sub-types using data-driven approaches in primary care population based electronic health records

    , BMC Medical Informatics and Decision Making, Vol: 19, ISSN: 1472-6947

    BackgroundCOPD is a highly heterogeneous disease composed of different phenotypes with different aetiological and prognostic profiles and current classification systems do not fully capture this heterogeneity. In this study we sought to discover, describe and validate COPD subtypes using cluster analysis on data derived from electronic health records.MethodsWe applied two unsupervised learning algorithms (k-means and hierarchical clustering) in 30,961 current and former smokers diagnosed with COPD, using linked national structured electronic health records in England available through the CALIBER resource. We used 15 clinical features, including risk factors and comorbidities and performed dimensionality reduction using multiple correspondence analysis. We compared the association between cluster membership and COPD exacerbations and respiratory and cardiovascular death with 10,736 deaths recorded over 146,466 person-years of follow-up. We also implemented and tested a process to assign unseen patients into clusters using a decision tree classifier.ResultsWe identified and characterized five COPD patient clusters with distinct patient characteristics with respect to demographics, comorbidities, risk of death and exacerbations. The four subgroups were associated with 1) anxiety/depression; 2) severe airflow obstruction and frailty; 3) cardiovascular disease and diabetes and 4) obesity/atopy. A fifth cluster was associated with low prevalence of most comorbid conditions.ConclusionsCOPD patients can be sub-classified into groups with differing risk factors, comorbidities, and prognosis, based on data included in their primary care records. The identified clusters confirm findings of previous clustering studies and draw attention to anxiety and depression as important drivers of the disease in young, female patients.

  • Journal article
    Rothnie K, mullerova H, smeeth L, Quint JKet al., 2018,

    Natural history of COPD exacerbations in a general practice based COPD population

    , American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 464-471, ISSN: 1073-449X

    Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) are important adverse events in the natural history of chronic obstructive pulmonary disease (COPD).Objectives: To investigate the natural history of AECOPDs over 10 years of follow-up.Methods: We identified 99,574 patients with COPD from January 1, 2004, to March 31, 2015, from the UK Clinical Practice Research Datalink. We defined moderate AECOPDs as those managed outside hospital and severe as those requiring hospitalization. During the baseline period (first year of follow-up), patients were grouped according to the number and severity of AECOPDs and then followed for a maximum of 10 years (mean, 4.9 yr). We investigated the effect of baseline AECOPD number and severity on risk of further events and death.Measurements and Main Results: Around one-quarter of the patients with COPD did not exacerbate during follow-up. Compared with no AECOPDs in the baseline period, AECOPD number predicted the future long-term rate of AECOPDs in a graduated fashion, ranging from hazard ratio (HR) of 1.71 (1.66–1.77) for one event to HR of 3.41 (3.27–3.56) for five or more events. Two or more moderate AECOPDs were also associated with an increased risk of death in a graduated fashion, ranging from HR of 1.10 (1.03–1.18) for two moderate AECOPDs to HR of 1.57 (1.45–1.70) for five or more moderate AECOPDs, compared with those with no AECOPDs at baseline. Severe AECOPDs were associated with an even higher risk of death (HR, 1.79; 1.65–1.94).Conclusions: A large proportion of patients with COPD do not exacerbate over a maximum 10 years of follow-up. AECOPD frequency in a single year predicts long-term AECOPD rate. Increasing frequency and severity of AECOPDs is associated with risk of death and highlights the importance of preventing AECOPDs.

  • Journal article
    Amaral AFS, Patel J, Kato BS, Obaseki DO, Lawin H, Tan WC, Juvekar SK, Harrabi I, Studnicka M, Wouters EFM, Loh L-C, Bateman ED, Mortimer K, Buist AS, Burney PGJet al., 2018,

    Airflow Obstruction and Use of Solid Fuels for Cooking or Heating BOLD (Burden of Obstructive Lung Disease) Results

  • Journal article
    Garcia Larsen V, Potts J, Omenaas E, Heinrich J, Svanes C, Garcia-Aymerich J, Burney P, Jarvis DLet al., 2017,

    Dietary antioxidants and ten year lung function decline in adults from the ECRHS survey

    , European Respiratory Journal, Vol: 50, Pages: 1-9, ISSN: 0903-1936

    The relationship between lung function decline and dietary antioxidants over 10 years in adults from three European countries was investigated.In 2002, adults from three participating countries of the European Community Respiratory Health Survey (ECRHS) answered a questionnaire and underwent spirometry (forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)), which were repeated 10 years later. Dietary intake was estimated at baseline with food frequency questionnaires (FFQ). Associations between annual lung function decline (mL) and diet (tertiles) were examined with multivariable analyses. Simes’ procedure was applied to control for multiple testing.A total of 680 individuals (baseline mean age 43.8±6.6 years) were included. A per-tertile increase in apple and banana intake was associated with a 3.59 mL·year−1 (95% CI 0.40, 7.68) and 3.69 mL·year−1 (95% CI 0.25, 7.14) slower decline in FEV1 and FVC, respectively. Tomato intake was also associated with a slower decline in FVC (4.5 mL·year−1; 95% CI 1.28, 8.02). Only the association with tomato intake remained statistically significant after the Simes’ procedure was performed. Subgroup analyses showed that apple, banana and tomato intake were all associated with a slower decline in FVC in ex-smokers.Intake of fruits and tomatoes might delay lung function decline in adults, particularly in ex-smokers.

  • Journal article
    Jarvis D, Newson R, Janson C, Corsico A, Heinrich J, Anto JM, Abramson MJ, Kirsten A-M, Zock JP, Bono R, Demoly P, Leynaert B, Raherison C, Pin I, Gislason T, Jogi R, Schlunssen V, Svanes C, Watkins J, Weyler J, Pereira-Vega A, Urrutia I, Gullón JA, Forsberg B, Probst-Hensch N, Boezen HM, Martinez-Moratalla Rovira J, Accordini S, de Marco R, Burney Pet al., 2017,

    Prevalence of asthma-like symptoms with ageing.

    , Thorax, Vol: 73, Pages: 37-48, ISSN: 1468-3296

    BACKGROUND: Change in the prevalence of asthma-like symptoms in populations of ageing adults is likely to be influenced by smoking, asthma treatment and atopy. METHODS: The European Community Respiratory Health Survey collected information on prevalent asthma-like symptoms from representative samples of adults aged 20-44 years (29 centres in 13 European countries and Australia) at baseline and 10 and 20 years later (n=7844). Net changes in symptom prevalence were determined using generalised estimating equations (accounting for non-response through inverse probability weighting), followed by meta-analysis of centre level estimates. FINDINGS: Over 20 years the prevalence of 'wheeze' and 'wheeze in the absence of a cold' decreased (-2.4%, 95% CI -3.5 to -1.3%; -1.5%, 95% CI -2.4 to -0.6%, respectively) but the prevalence of asthma attacks, use of asthma medication and hay fever/nasal allergies increased (0.6%, 95% CI 0.1 to 1.11; 3.6%, 95% CI 3.0 to 4.2; 2.7%, 95% CI 1.7 to 3.7). Changes were similar in the first 10 years compared with the second 10 years, except for hay fever/nasal allergies (increase seen in the first 10 years only). Decreases in these wheeze-related symptoms were largely seen in the group who gave up smoking, and were seen in those who reported hay fever/nasal allergies at baseline. INTERPRETATION: European adults born between 1946 and 1970 have, over the last 20 years, experienced less wheeze, although they were more likely to report asthma attacks, use of asthma medication and hay fever. Decrease in wheeze is largely attributable to smoking cessation, rather than improved treatment of asthma. It may also be influenced by reductions in atopy with ageing.

  • Journal article
    Amaral AFS, Strachan DP, Burney PGJ, Jarvis DLet al., 2017,

    Female Smokers Are at Greater Risk of Airflow Obstruction Than Male Smokers UK Biobank

  • Journal article
    Amaral AFS, Strachan DP, Gomez Real F, Burney PGJ, Jarvis DLet al., 2016,

    Lower lung function associates with cessation of menstruation: UK Biobank data

    , European Respiratory Journal, Vol: 48, Pages: 1288-1297, ISSN: 1399-3003

    Little is known about the effect of cessation of menstruation on lung function. The aims of the study were to examine the association of lung function with natural and surgical cessation of menstruation, and assess whether lower lung function is associated with earlier age at cessation of menstruation.The study was performed in 141 076 women from the UK Biobank, who had provided acceptable and reproducible spirometry measurements and information on menstrual status. The associations of lung function (forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), spirometric restriction (FVC < lower limit of normal (LLN)), airflow obstruction (FEV1/FVC <LLN)) with cessation of menstruation and age at cessation of menstruation were assessed using regression analysis.Women who had natural cessation of menstruation showed a lower FVC (−42 mL; 95% CI −53– −30) and FEV1 (−34 mL; 95% CI −43– −24) and higher risk of spirometric restriction (adjusted odds ratio 1.27; 95% CI 1.18–1.37) than women still menstruating. These associations were stronger in women who had had a hysterectomy and/or oophorectomy. The earlier the natural cessation of menstruation, the lower the lung function. There was no clear association of lung function with age at hysterectomy and/or oophorectomy. Airflow obstruction was not associated with cessation of menstruation.Lower lung function associates with cessation of menstruation, especially if it occurs early in life.

  • Journal article
    Amaral AFS, Newson RB, Abramson MJ, Anto JM, Bono R, Corsico AG, de Marco R, Demoly P, Forsberg B, Gislason T, Heinrich J, Huerta I, Janson C, Jogi R, Kim JL, Maldonado J, Martinez-Moratalla Rovira J, Neukirch C, Nowak D, Pin I, Probst-Hensch N, Raherison-Semjen C, Svanes C, Urrutia Landa I, van Ree R, Versteeg SA, Weyler J, Zock JP, Burney PGJ, Jarvis DLet al., 2015,

    Changes in IgE sensitization and total IgE levels over 20 years of follow-up

    , Journal of Allergy and Clinical Immunology, Vol: 137, Pages: 1788-1795.e9, ISSN: 1097-6825

    Background: Cross-sectional studies have reported a lower prevalence of sensitisation in older adults, but few longitudinal studies have examined whether this is an aging or a year-of birth cohort effect. Objective: To assess changes in sensitisation and total IgE in a cohort of European adults as they aged over a 20-year period.Methods: Serum specific IgE to common aeroallergens (house dust mite, cat, grass) and total IgE were measured in 3206 adults, from 25 centres in the European Community Respiratory Health Survey, on three occasions over 20 years. Changes in sensitisation and total IgE were analysed by regression analysis, corrected for potential differences in laboratory equipment, and using inverse sampling-probability weights to account for non-response.Results: Over the 20-year follow-up, the prevalence of sensitisation to at least one of the three allergens fell from 29.4% to 24.8% (-4.6%, 95%CI: -7.0% to -2.1%). The prevalence of sensitisation to house dust mite (-4.3%, 95%CI: -6.0% to -2.6%) and cat (-2.1%, 95%CI: - 3.6% to -0.7%) fell more than sensitisation to grass (-0.6%, 95%CI: -2.5% to 1.3%). Age specific prevalence of sensitisation to house dust mite and cat did not differ between year-of birth cohorts, but sensitisation to grass was most prevalent in the most recent ones. Overall, total IgE fell significantly (geometric mean ratio: 0.63, 95%CI 0.58 to 0.68), at all ages, in all year-of-birth cohorts.Conclusion: Aging was associated with lower levels of sensitisation, especially to house dust mite and cat, after the age of 20.

  • Journal article
    Amaral AFS, Coton S, Kato B, Tan WC, Studnicka M, Janson C, Gislason T, Mannino D, Bateman ED, Buist S, Burney PGJet al., 2015,

    Tuberculosis associates with both airflow obstruction and low lung function: BOLD results

    , European Respiratory Journal, Vol: 46, Pages: 1104-1112, ISSN: 1399-3003

    In small studies and cases series, a history of tuberculosis has been associated with both airflow obstruction, which is characteristic of chronic obstructive pulmonary disease, and restrictive patterns on spirometry. The objective of the present study was to assess the association between a history of tuberculosis and airflow obstruction and spirometric abnormalities in adults.The study was performed in adults, aged 40 years and above, who took part in the multicentre, cross-sectional, general population-based Burden of Obstructive Lung Disease study, and had provided acceptable post-bronchodilator spirometry measurements and information on a history of tuberculosis. The associations between a history of tuberculosis and airflow obstruction and spirometric restriction were assessed within each participating centre, and estimates combined using meta-analysis. These estimates were stratified by high- and low/middle-income countries, according to gross national income.A self-reported history of tuberculosis was associated with airflow obstruction (adjusted odds ratio 2.51, 95% CI 1.83–3.42) and spirometric restriction (adjusted odds ratio 2.13, 95% CI 1.42–3.19).A history of tuberculosis was associated with both airflow obstruction and spirometric restriction, and should be considered as a potentially important cause of obstructive disease and low lung function, particularly where tuberculosis is common.

  • Journal article
    Amaral AFS, Ramasamy A, Castro-Giner F, Minelli C, Accordini S, Sorheim I-C, Pin I, Kogevinas M, Jogi R, Balding DJ, Norback D, Verlato G, Olivieri M, Probst-Hensch N, Janson C, Zock J-P, Heinrich J, Jarvis DLet al., 2014,

    Interaction between gas cooking and <i>GSTM1</i> null genotype in bronchial responsiveness: results from the European Community Respiratory Health Survey

    , THORAX, Vol: 69, Pages: 558-564, ISSN: 0040-6376

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