Publications by authors named "Raquel Granell"

75 Publications

High Insulin in Early Childhood is Associated with Subsequent Asthma Risk Independent of Body Mass Index.

J Allergy Clin Immunol Pract 2021 Oct 14. Epub 2021 Oct 14.

Asthma and Airway Disease Research Center, University of Arizona, Tucson AZ.

Background: Asthma and obesity are major, interconnected public health challenges that usually have their origins in childhood, and for which the relationship is strengthened among those with insulin resistance.

Objective: To determine whether high insulin in early life confers increased longitudinal risk for asthma independent of body mass index (BMI).

Methods: The study used data from the Tucson Children's Respiratory Study (TCRS) and the Avon Longitudinal Study of Parents and Children (ALSPAC). Non-fasting insulin was measured in TCRS participants at age 6 and fasting insulin in ALSPAC participants at age 8. Physician-diagnosed active asthma was determined at baseline and at subsequent assessments up to age 36 years in TCRS and 17 years in ALSPAC.

Results: In TCRS, high insulin (upper quartile) at age 6 was associated with increased odds of having active asthma from ages 8 to 36 compared to low insulin (OR 1.98, [1.28-3.05], p=0.002). Similarly, in ALSPAC, high insulin was associated with a significantly higher risk of active asthma from ages 11 to 17 compared to low insulin (1.59 [1.12-2.27], p=0.009). These findings were independent of baseline BMI in both cohorts, and were not related to other demographic and asthma risk factors nor other tested markers of systemic inflammation and metabolic syndrome.

Conclusions: In two separate birth cohorts, higher blood insulin level in early childhood was associated with increased risk of active asthma through adolescence and adulthood, independent of BMI. High insulin indicates a novel mechanism for asthma development, which may be a target for intervention.
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http://dx.doi.org/10.1016/j.jaip.2021.09.047DOI Listing
October 2021

Lung function, COPD and cognitive function: a multivariable and two sample Mendelian randomization study.

BMC Pulm Med 2021 Jul 22;21(1):246. Epub 2021 Jul 22.

MRC Integrative Epidemiology Unit (IEU), University of Bristol, Oakfield Grove, Bristol, BS8 2BN, UK.

Background: Observational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR).

Methods: Single nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates.

Results: We found only weak evidence that reduced lung function (Beta - 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (- 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV and FVC do cause lower cognitive function, but that after conditioning for height (- 0.03 (0.03), p-value 0.29 and - 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (- 0.03 (0.03) p-value 0.33 and - 0.01 (0.02), p-value 0.35) the evidence became weak.

Conclusion: We did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.
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http://dx.doi.org/10.1186/s12890-021-01611-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296721PMC
July 2021

Examining the possible causal relationship between lung function, COPD and Alzheimer's disease: a Mendelian randomisation study.

BMJ Open Respir Res 2021 07;8(1)

Academic Respiratory Unit, Southmead Hospital, Bristol, UK

Rationale: Large retrospective case-control studies have reported an association between chronic obstructive pulmonary disease (COPD), reduced lung function and an increased risk of Alzheimer's disease. However, it remains unclear if these diseases are causally linked, or due to shared risk factors. Conventional observational epidemiology suffers from unmeasured confounding and reverse causation. Additional analyses addressing causality are required.

Objectives: To examine a causal relationship between COPD, lung function and Alzheimer's disease.

Methods: Using two-sample Mendelian randomisation, we used single nucleotide polymorphisms (SNPs) identified in a genome wide association study (GWAS) for lung function as instrumental variables (exposure). Additionally, we used SNPs discovered in a GWAS for COPD in those with moderate to very severe obstruction. The effect of these SNPs on Alzheimer's disease (outcome) was taken from a GWAS based on a sample of 24 807 patients and 55 058 controls.

Results: We found minimal evidence for an effect of either lung function (OR: 1.02 per SD; 95% CI 0.91 to 1.13; p value 0.68) or liability for COPD on Alzheimer's disease (OR: 0.97 per SD; 95% CI 0.92 to 1.03; p value 0.40).

Conclusion: Neither reduced lung function nor liability COPD are likely to be causally associated with an increased risk of Alzheimer's, any observed association is likely due to unmeasured confounding. Scientific attention and health prevention policy may be better focused on overlapping risk factors, rather than attempts to reduce risk of Alzheimer's disease by targeting impaired lung function or COPD directly.
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http://dx.doi.org/10.1136/bmjresp-2020-000759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264898PMC
July 2021

Identification of OCA2 as a novel locus for the co-morbidity of asthma-plus-eczema.

Clin Exp Allergy 2021 Jun 22. Epub 2021 Jun 22.

UMRS 1124, INSERM, Université de Paris, Paris, France.

Background: Numerous genes have been associated with the three most common allergic diseases (asthma, allergic rhinitis or eczema) but these genes explain only a part of the heritability. In the vast majority of genetic studies, complex phenotypes such as co-morbidity of two of these diseases, have not been considered. This may partly explain missing heritability.

Objective: To identify genetic variants specifically associated with the co-morbidity of asthma-plus-eczema.

Methods: We first conducted a meta-analysis of four GWAS (Genome-Wide Association Study) of the combined asthma-plus-eczema phenotype (total of 8807 European-ancestry subjects of whom 1208 subjects had both asthma and eczema). To assess whether the association with SNP(s) was specific to the co-morbidity, we also conducted a meta-analysis of homogeneity test of association according to disease status ("asthma-plus-eczema" vs. the presence of only one disease "asthma only or eczema only"). We then used a joint test by combining the two test statistics from the co-morbidity-SNP association and the phenotypic heterogeneity of SNP effect meta-analyses.

Results: Seven SNPs were detected for specific association to the asthma-plus-eczema co-morbidity, two with significant and five with suggestive evidence using the joint test after correction for multiple testing. The two significant SNPs are located in the OCA2 gene (Oculocutaneous Albinism II), a new locus never detected for significant evidence of association with any allergic disease. This gene is a promising candidate gene, because of its link to skin and lung diseases, and to epithelial barrier and immune mechanisms.

Conclusion: Our study underlines the importance of studying sub-phenotypes as co-morbidities to detect new susceptibility genes.
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http://dx.doi.org/10.1111/cea.13972DOI Listing
June 2021

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

Pleiotropic associations of heterozygosity for the Z allele in the UK Biobank.

ERJ Open Res 2021 Apr 10;7(2). Epub 2021 May 10.

Division of Respiratory Medicine, University of Nottingham, and NIHR Nottingham BRC, NUH NHS Trust, Nottingham, UK.

Homozygosity for the Z allele causes α-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV) (β=19.36 mL, p=9.21×10) and FEV/forced vital capacity (β=0.0031, p=1.22×10) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk.
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http://dx.doi.org/10.1183/23120541.00049-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107350PMC
April 2021

Dietary intake of vitamin A, lung function, and incident asthma in childhood.

Eur Respir J 2021 Sep 24. Epub 2021 Sep 24.

Institute of Population Health Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Longitudinal epidemiological data are scarce on the relation between dietary intake of vitamin A and respiratory outcomes in childhood. We investigated whether a higher intake of preformed vitamin A or provitamin β-carotene in mid-childhood is associated with higher lung function and with asthma risk in adolescence.In the Avon Longitudinal Study of Parents and Children, dietary intakes of preformed vitamin A and β-carotene equivalents were estimated by food frequency questionnaire at 7 years of age. Post- bronchodilator forced expiratory volume in 1 s (FEV), forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC (FEF) were measured at 15.5 years and transformed to z scores. Incident asthma was defined by new cases of doctor-diagnosed asthma at age 11 or 14 years.In multivariable adjusted models, a higher intake of preformed vitamin A was associated with higher lung function and a lower risk of incident asthma: comparing top bottom quartiles of intake, regression coefficients (95% confidence intervals) for FEV and FEF were, respectively, 0.21 (0.05-0.38; P-trend 0.008) and 0.18 (0.03-0.32; P-trend 0.02); odds ratios (95% confidence intervals) for FEV/FVC ratio below the lower limit of normal and incident asthma were, respectively, 0.49 (0.27-0.90, P-trend 0.04) and 0.68 (0.47, 0.99; P-trend 0.07). In contrast, there was no evidence for association with β-carotene. We also found some evidence for modification of the associations between preformed vitamin A intake and lung function by and gene polymorphisms.A higher intake of preformed vitamin A, but not β-carotene, in mid-childhood is associated with higher subsequent lung function and lower risk of fixed airflow limitation and incident asthma.
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http://dx.doi.org/10.1183/13993003.04407-2020DOI Listing
September 2021

The impact of asthma on mental health and wellbeing during COVID-19 lockdown.

Eur Respir J 2021 07 29;58(1). Epub 2021 Jul 29.

MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.

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http://dx.doi.org/10.1183/13993003.04497-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996219PMC
July 2021

Lung function and cardiovascular disease: a two-sample Mendelian randomisation study.

Eur Respir J 2021 Sep 9;58(3). Epub 2021 Sep 9.

MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK

Background: Observational studies suggest an association between reduced lung function and risk of coronary artery disease and ischaemic stroke, independent of shared cardiovascular risk factors such as cigarette smoking. We use the latest genetic epidemiological methods to determine whether impaired lung function is causally associated with an increased risk of cardiovascular disease.

Methods And Findings: Mendelian randomisation uses genetic variants as instrumental variables to investigate causation. Preliminary analysis used two-sample Mendelian randomisation with lung function single nucleotide polymorphisms. To avoid collider bias, the main analysis used single nucleotide polymorphisms for lung function identified from UKBiobank in a multivariable Mendelian randomisation model conditioning for height, body mass index and smoking.Multivariable Mendelian randomisation shows strong evidence that reduced forced vital capacity (FVC) causes increased risk of coronary artery disease (OR 1.32, 95% CI 1.19-1.46 per standard deviation). Reduced forced expiratory volume in 1 s (FEV) is unlikely to cause increased risk of coronary artery disease, as evidence of its effect becomes weak after conditioning for height (OR 1.08, 95% CI 0.89-1.30). There is weak evidence that reduced lung function increases risk of ischaemic stroke.

Conclusion: There is strong evidence that reduced FVC is independently and causally associated with coronary artery disease. Although the mechanism remains unclear, FVC could be taken into consideration when assessing cardiovascular risk and considered a potential target for reducing cardiovascular events. FEV and airflow obstruction do not appear to cause increased cardiovascular events; confounding and collider bias may explain previous findings of a causal association.
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http://dx.doi.org/10.1183/13993003.03196-2020DOI Listing
September 2021

Intake of -3 polyunsaturated fatty acids in childhood, genotype and incident asthma.

Eur Respir J 2021 Sep 2;58(3). Epub 2021 Sep 2.

Institute of Population Health Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Longitudinal evidence on the relation between dietary intake of -3 (ω-3) very-long-chain polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in mid-childhood and asthma risk is scarce. We aimed to investigate whether a higher intake of EPA and DHA from fish in childhood is associated with a lower risk of incident asthma.In the Avon Longitudinal Study of Parents and Children, dietary intakes of EPA and DHA from fish were estimated by food frequency questionnaire at 7 years of age. We used logistic regression, controlling for confounders, to analyse associations between intake of EPA and DHA (quartiles) and incidence of doctor-diagnosed asthma at age 11 or 14 years, and explored potential effect modification by a fatty acid desaturase () polymorphism (rs1535). Replication was sought in the Swedish BAMSE birth cohort.There was no evidence of association between intake of EPA plus DHA from fish and incident asthma overall (n=4543). However, when stratified by genotype, the odds ratio comparing the top bottom quartile among the 2025 minor G allele carriers was 0.49 (95% CI 0.31-0.79; p=0.006), but no inverse association was observed in the homozygous major A allele group (OR 1.43, 95% CI 0.83-2.46; p=0.19) (p=0.006). This gene-nutrient interaction on incident asthma was replicated in BAMSE.In children with a common variant, higher intake of EPA and DHA from fish in childhood was strongly associated with a lower risk of incident asthma up to mid-adolescence.
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http://dx.doi.org/10.1183/13993003.03633-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411098PMC
September 2021

Trimester effects of source-specific PM on birth weight outcomes in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Environ Health 2021 01 7;20(1). Epub 2021 Jan 7.

Centre for Environmental Health and Sustainability, George Davies Centre, University of Leicester, University Road, Leicester, LE1 7RH, UK.

Background: Evidence suggests that exposure to particulate matter with aerodynamic diameter less than 10 μm (PM) is associated with reduced birth weight, but information is limited on the sources of PM and exposure misclassification from assigning exposures to place of residence at birth.

Methods: Trimester and source-specific PM exposures (PM from road source, local non-road source, and total source) in pregnancy were estimated using dispersion models and a full maternal residential history for 12,020 births from the Avon longitudinal study of parents and children (ALSPAC) cohort in 1990-1992 in the Bristol area. Information on birth outcomes were obtained from birth records. Maternal sociodemographic and lifestyle factors were obtained from questionnaires. We used linear regression models for continuous outcomes (birth weight, head circumference (HC), and birth length (BL) and logistic regression models for binary outcomes (preterm birth (PTB), term low birth weight (TLBW) and small for gestational age (SGA)). Sensitivity analysis was performed using multiple imputation for missing covariate data.

Results: After adjustment, interquartile range increases in source specific PM from traffic were associated with 17 to 18% increased odds of TLBW in all pregnancy periods. We also found odds of TLBW increased by 40% (OR: 1.40, 95%CI: 1.12, 1.75) and odds of SGA increased by 18% (OR: 1.18, 95%CI: 1.05, 1.32) per IQR (6.54 μg/m) increase of total PM exposure in the third trimester.

Conclusion: This study adds to evidence that maternal PM exposures affect birth weight, with particular concern in relation to exposures to PM from road transport sources; results for total PM suggest greatest effect in the third trimester. Effect size estimates relate to exposures in the 1990s and are higher than those for recent studies - this may relate to reduced exposure misclassification through use of full residential history information, changes in air pollution toxicity over time and/or residual confounding.
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http://dx.doi.org/10.1186/s12940-020-00684-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788701PMC
January 2021

Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use.

Eur Respir J 2021 05 13;57(5). Epub 2021 May 13.

Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Maribor, Slovenia.

Rationale: Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies.

Methods: A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed.

Results: 10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10). Of those, one variant at the locus was nominally replicated in Europeans (rs67026078; p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found.

Conclusions: The intergenic region of and was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.
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http://dx.doi.org/10.1183/13993003.03388-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122045PMC
May 2021

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

PLoS Genet 2020 06 30;16(6):e1008725. Epub 2020 Jun 30.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.
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http://dx.doi.org/10.1371/journal.pgen.1008725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367489PMC
June 2020

Residential greenspace and lung function up to 24 years of age: The ALSPAC birth cohort.

Environ Int 2020 07 4;140:105749. Epub 2020 May 4.

National Heart and Lung Institute, Imperial College London, London, United Kingdom; MRC-PHE Centre for Environment & Health, Imperial College, London, United Kingdom.

Background: Residing in greener areas is increasingly linked to beneficial health outcomes, but little is known about its effect on respiratory health.

Objective: We examined associations between residential greenness and nearby green spaces with lung function up to 24 years in the UK Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort.

Methods: Lung function was measured by spirometry at eight, 15 and 24 years of age. Greenness levels within circular buffers (100-1000 m) around the birth, eight-, 15- and 24-year home addresses were calculated using the satellite-derived Normalized Difference Vegetation Index and averaged (lifetime greenness). The presence and proportion of green spaces (urban green spaces, forests and agricultural land) within a 300 m buffer was determined. First, associations between repeated greenness and green space variables and repeated lung function parameters were assessed using generalized estimation equations (N = 7094, 47.9% male). Second, associations between lifetime average greenness and lifetime average proportion of green spaces with lung function at 24-years were assessed using linear regression models (N = 1763, 39.6% male). All models were adjusted for individual and environmental covariates.

Results: Using repeated greenspace and lung function data at eight, 15 and 24 years, greenness in a 100 m buffer was associated with higher FEV and FVC (11.4 ml [2.6, 20.3] and 12.2 ml [1.8, 22.7], respectively, per interquartile range increase), as was the presence of urban green spaces in a 300 m buffer (20.3 ml [-0.1, 40.7] and 23.1 ml [-0.3, 46.5] for FEV and FVC, respectively). These associations were independent of air pollution, urbanicity and socio-economic status. Lifetime average greenness within a 100 m buffer and proportion of agricultural land within a 300 m buffer were associated with better lung function at 24 years but adjusting for asthma attenuated these associations.

Discussion: This study provides suggestive evidence that children whose homes are in more vegetated places or are in close proximity of green spaces have better lung function up to 24 years of age.
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http://dx.doi.org/10.1016/j.envint.2020.105749DOI Listing
July 2020

Prenatal, Early-Life, and Childhood Exposure to Air Pollution and Lung Function: The ALSPAC Cohort.

Am J Respir Crit Care Med 2020 07;202(1):112-123

MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, and.

: Exposure to air pollution during intrauterine development and through childhood may have lasting effects on respiratory health.: To investigate lung function at ages 8 and 15 years in relation to air pollution exposures during pregnancy, infancy, and childhood in a UK population-based birth cohort.: Individual exposures to source-specific particulate matter ≤10 μm in aerodynamic diameter (PM) during each trimester, 0-6 months, 7-12 months (1990-1993), and up to age 15 years (1991-2008) were examined in relation to FEV% predicted and FVC% predicted at ages 8 ( = 5,276) and 15 ( = 3,446) years using linear regression models adjusted for potential confounders. A profile regression model was used to identify sensitive time periods.: We did not find clear evidence of a sensitive exposure period for PM from road traffic. At age 8 years, 1 μg/m higher exposure during the first trimester was associated with lower FEV% predicted (-0.826; 95% confidence interval [CI], -1.357 to -0.296) and FVC% predicted (-0.817; 95% CI, -1.357 to -0.276), but similar associations were seen for exposures for other trimesters, 0-6 months, 7-12 months, and 0-7 years. Associations were stronger among boys, as well as children whose mother had a lower education level or smoked during pregnancy. For PM from all sources, the third trimester was associated with lower FVC% predicted (-1.312; 95% CI, -2.100 to -0.525). At age 15 years, no adverse associations with lung function were seen.: Exposure to road-traffic PM during pregnancy may result in small but significant reductions in lung function at age 8 years.
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http://dx.doi.org/10.1164/rccm.201902-0286OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328307PMC
July 2020

Confirmed causal effect of obesity on asthma and new insights on potential underlying shared genetic mechanisms.

J Allergy Clin Immunol 2020 02 6;145(2):484-486. Epub 2019 Dec 6.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

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http://dx.doi.org/10.1016/j.jaci.2019.11.033DOI Listing
February 2020

Differential associations of allergic disease genetic variants with developmental profiles of eczema, wheeze and rhinitis.

Clin Exp Allergy 2019 11 15;49(11):1475-1486. Epub 2019 Oct 15.

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Allergic diseases (eczema, wheeze and rhinitis) in children often present as heterogeneous phenotypes. Understanding genetic associations of specific patterns of symptoms might facilitate understanding of the underlying biological mechanisms.

Objective: To examine associations between allergic disease-related variants identified in a recent genome-wide association study and latent classes of allergic diseases (LCADs) in two population-based birth cohorts.

Methods: Eight previously defined LCADs between birth and 11 years: "No disease," "Atopic march," "Persistent eczema and wheeze," "Persistent eczema with later-onset rhinitis," "Persistent wheeze with later-onset rhinitis," "Transient wheeze," "Eczema only" and "Rhinitis only" were used as the study outcome. Weighted multinomial logistic regression was used to estimate associations between 135 SNPs (and a polygenic risk score, PRS) and LCADs among 6345 individuals from The Avon Longitudinal Study of Parents and Children (ALSPAC). Heterogeneity across LCADs was assessed before and after Bonferroni correction. Results were replicated in Manchester Asthma and Allergy Study (MAAS) (n = 896) and pooled in a meta-analysis.

Results: We found strong evidence for differential genetic associations across the LCADs; pooled PRS heterogeneity P-value = 3.3 × 10 , excluding "no disease" class. The associations between the PRS and LCADs in MAAS were remarkably similar to ALSPAC. Two SNPs (a protein-truncating variant in FLG and a SNP within an intron of GSDMB) had evidence for differential association (pooled P-values ≤ 0.006). The FLG locus was differentially associated across LCADs that included eczema, with stronger associations for LCADs with comorbid wheeze and rhinitis. The GSDMB locus in contrast was equally associated across LCADs that included wheeze.

Conclusions And Clinical Relevance: We have shown complex, but distinct patterns of genetic associations with LCADs, suggesting that heterogeneous mechanisms underlie individual disease trajectories. Establishing the combination of allergic diseases with which each genetic variant is associated may inform therapeutic development and/or predictive modelling.
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http://dx.doi.org/10.1111/cea.13485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899469PMC
November 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

Physical-activity trajectories during childhood and lung function at 15 years: findings from the ALSPAC cohort.

Int J Epidemiol 2020 02;49(1):131-141

ISGlobal, Barcelona, Spain.

Background: Although physical activity has many known health benefits, its association with lung function in childhood/adolescence remains unclear. We examined the association of physical-activity trajectories between 11 and 15 years with lung function at 15 years in 2266 adolescents.

Methods: A population-based cohort of 14 305 singleton births alive at 1 year was recruited in the UK population-based Avon Longitudinal Study of Parents and Children cohort. Physical activity (counts/minute and moderate-to-vigorous physical activity) was assessed for 7 days using an accelerometer at 11, 13 and 15 years. We identified sex-specific physical-activity trajectories applying K-means for longitudinal data in children with at least two accelerometer measurements (n = 3584). We then estimated the sex-specific associations of these trajectories with post-bronchodilation lung-function parameters using multivariable linear-regression models (n = 2266, 45% boys).

Results: Fewer than 7% of participants met the WHO physical-activity recommendations (i.e. daily average of at least 60 minutes of moderate-to-vigorous physical activity). Boys were substantially more active than girls. In both sexes, we identified three distinct physical-activity trajectories ('low': 39.8% boys, 45.8% girls; 'moderate': 42.9% boys, 41.4% girls; and 'high' physical activity: 17.3% boys, 12.8% girls). Girls in the moderate and high physical-activity trajectories had 0.11 L [95% confidence interval (CI): 0.04-0.19] and 0.15 L (95% CI: 0.03-0.26) higher forced vital capacity than their less-active peers. No association was observed in boys.

Conclusions: Higher childhood physical activity relates to higher lung-function levels in adolescent girls. A better understanding of the mechanisms underlying this association should be pursued.
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http://dx.doi.org/10.1093/ije/dyz128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124497PMC
February 2020

Genetic and observational evidence supports a causal role of sex hormones on the development of asthma.

Thorax 2019 07 1;74(7):633-642. Epub 2019 Apr 1.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Introduction: Males have a higher prevalence of asthma in childhood, whereas females have a higher prevalence in adolescence and adulthood. The 'adolescent switch' observed between sexes during puberty has been hypothesised to be due to fluctuating sex hormones. Robust evidence of the involvement of sex hormones in asthma could lead to development of therapeutic interventions.

Methods: We combine observational evidence using longitudinal data on sex hormone-binding globulin (SHBG), total and bioavailable testosterone and asthma from a subset of males (n=512) in the Avon Longitudinal Study of Parents and Children, and genetic evidence of SHBG and asthma using two-sample Mendelian randomisation (MR), a method of causal inference. We meta-analysed two-sample MR results across two large data sets, the Trans-National Asthma Genetics Consortium genome-wide association study of asthma and UK Biobank (over 460 000 individuals combined).

Results: Observational evidence indicated weak evidence of a protective effect of increased circulating testosterone on asthma in males in adolescence, but no strong pattern of association with SHBG. Genetic evidence using two-sample MR indicated a protective effect of increased SHBG, with an OR for asthma of 0.86 (95% CI 0.74 to 1.00) for the inverse-variance weighted approach and an OR of 0.83 (95% CI 0.72 to 0.96) for the weighted median estimator, per unit increase in natural log SHBG. A sex-stratified sensitivity analysis suggested the protective effect of SHBG was mostly evident in females.

Conclusion: We report the first suggestive evidence of a protective effect of genetically elevated SHBG on asthma, which may provide a biological explanation behind the observed asthma sex discordance. Further work is required to disentangle the downstream effects of SHBG on asthma and the molecular pathways involved.
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http://dx.doi.org/10.1136/thoraxjnl-2018-212207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585308PMC
July 2019

Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.

Am J Hum Genet 2019 04 28;104(4):665-684. Epub 2019 Mar 28.

Department of Medical Epidemiology and Biostatistics and the Swedish Twin Registry, Karolinska Institutet, Stockholm 171 77, Sweden; Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 171 76, Sweden.

The extent to which genetic risk factors are shared between childhood-onset (COA) and adult-onset (AOA) asthma has not been estimated. On the basis of data from the UK Biobank study (n = 447,628), we found that the variance in disease liability explained by common variants is higher for COA (onset at ages between 0 and 19 years; h = 25.6%) than for AOA (onset at ages between 20 and 60 years; h = 10.6%). The genetic correlation (r) between COA and AOA was 0.67. Variation in age of onset among COA-affected individuals had a low heritability (h = 5%), which we confirmed in independent studies and also among AOA-affected individuals. To identify subtype-specific genetic associations, we performed a genome-wide association study (GWAS) in the UK Biobank for COA (13,962 affected individuals) and a separate GWAS for AOA (26,582 affected individuals) by using a common set of 300,671 controls for both studies. We identified 123 independent associations for COA and 56 for AOA (37 overlapped); of these, 98 and 34, respectively, were reproducible in an independent study (n = 262,767). Collectively, 28 associations were not previously reported. For 96 COA-associated variants, including five variants that represent COA-specific risk factors, the risk allele was more common in COA- than in AOA-affected individuals. Conversely, we identified three variants that are stronger risk factors for AOA. Variants associated with obesity and smoking had a stronger contribution to the risk of AOA than to the risk of COA. Lastly, we identified 109 likely target genes of the associated variants, primarily on the basis of correlated expression quantitative trait loci (up to n = 31,684). GWAS informed by age of onset can identify subtype-specific risk variants, which can help us understand differences in pathophysiology between COA and AOA and so can be informative for drug development.
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http://dx.doi.org/10.1016/j.ajhg.2019.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451732PMC
April 2019

Distinguishing Wheezing Phenotypes from Infancy to Adolescence. A Pooled Analysis of Five Birth Cohorts.

Ann Am Thorac Soc 2019 07;16(7):868-876

1 Department of Paediatrics, and.

Pooling data from multiple cohorts and extending the time frame across childhood should minimize study-specific effects, enabling better characterization of childhood wheezing. To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. We used latent class analysis to derive wheeze phenotypes among 7,719 participants from five birth cohorts with complete report of wheeze at five time periods. We tested the associations of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. We identified five phenotypes: never/infrequent wheeze (52.1%), early onset preschool remitting (23.9%), early onset midchildhood remitting (9%), persistent (7.9%), and late-onset wheeze (7.1%). Compared with the never/infrequent wheeze, all phenotypes had higher odds of asthma and lower forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity in adolescence. The association with asthma was strongest for persistent wheeze (adjusted odds ratio, 56.54; 95% confidence interval, 43.75-73.06). We observed considerable within-class heterogeneity at the individual level, with 913 (12%) children having low membership probability (<0.60) of any phenotype. Class membership certainty was highest in persistent and never/infrequent, and lowest in late-onset wheeze (with 51% of participants having membership probabilities <0.80). Individual wheezing patterns were particularly heterogeneous in late-onset wheeze, whereas many children assigned to early onset preschool remitting class reported wheezing at later time points. All wheeze phenotypes had significantly diminished lung function in school-age children, suggesting that the notion that early life episodic wheeze has a benign prognosis may not be true for a proportion of transient wheezers. We observed considerable within-phenotype heterogeneity in individual wheezing patterns.
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http://dx.doi.org/10.1513/AnnalsATS.201811-837OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600832PMC
July 2019

Comparison of the Associations of Early-Life Factors on Wheezing Phenotypes in Preterm-Born Children and Term-Born Children.

Am J Epidemiol 2019 03;188(3):527-536

Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Although respiratory symptoms, including wheezing, are common in preterm-born subjects, the natural history of the wheezing phenotypes and the influence of early-life factors and characteristics on phenotypes are unclear. Participants from the Millennium Cohort Study who were born between 2000 and 2002 were studied at 9 months and at 3, 5, 7, and 11 years. We used data-driven methods to define wheezing phenotypes in preterm-born children and investigated whether the association of early-life factors and characteristics with wheezing phenotypes was similar between preterm- and term-born children. A total of 1,049/1,502 (70%) preterm-born children and 12,307/17,063 (72%) term-born children had recent wheeze data for 3 or 4 time points. Recent wheeze was more common at all time points in the preterm-born group than in term-born group. Four wheezing phenotypes were defined for both groups: no/infrequent, early, persistent, and late. Early-life factors and characteristics, especially antenatal maternal smoking, atopy, and male sex, were associated with increased rates for all phenotypes in both groups, and breastfeeding was protective in both groups, except late wheeze in the preterm group. Preterm-born children had similar phenotypes to term-born children. Although early-life factors and characteristics were similarly associated with the wheezing phenotypes in both groups, the preterm-born group had higher rates of early and persistent wheeze. However, a large proportion of preterm-born children had early wheeze that resolved with time.
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http://dx.doi.org/10.1093/aje/kwy268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395162PMC
March 2019

Childhood Body Composition Trajectories and Adolescent Lung Function. Findings from the ALSPAC study.

Am J Respir Crit Care Med 2019 07;200(1):75-83

1 ISGlobal, Barcelona, Spain.

Body composition changes throughout life may explain the inconsistent associations reported between body mass index and lung function in children. To assess the associations of body weight and composition trajectories from 7 to 15 years with lung function at 15 years and lung function growth between 8 and 15 years. Sex-specific body mass index, lean body mass index, and fat mass index trajectories were developed using Group-Based Trajectory Modeling on data collected at least twice between 7 and 15 years from 6,964 children (49% boys) in the UK Avon Longitudinal Study of Parents and Children birth cohort. Associations of these trajectories with post-bronchodilation lung function parameters at 15 years and with lung function growth rates from 8 to 15 years were assessed using multivariable linear regression models, stratified by sex, in a subgroup with lung function data ( = 3,575). For all body mass measures we identified parallel trajectories that increased with age. There was no consistent evidence of an association between the body mass index trajectories and lung function measures. Higher lean body mass index trajectories were associated with higher levels and growth rates of FVC, FEV, and forced expiratory flow, midexpiratory phase in both sexes (e.g., boys in the highest lean body mass index trajectory had on average a 0.62 L [95% confidence interval, 0.44-0.79; trend < 0.0001] higher FVC at 15 yr than boys in the lowest trajectory). Increasing fat mass index trajectories were associated with lower levels and growth rates of FEV and forced expiratory flow, midexpiratory phase only in boys and lower levels of FEV/FVC in both sexes. Higher lean body mass during childhood and adolescence is consistently associated with higher lung function at 15 years in both sexes, whereas higher fat mass is associated with lower levels of only some lung function parameters.
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http://dx.doi.org/10.1164/rccm.201806-1168OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811931PMC
July 2019

Associations of sex hormone-binding globulin and testosterone with genome-wide DNA methylation.

BMC Genet 2018 12 14;19(1):113. Epub 2018 Dec 14.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Levels of sex hormone-binding globulin (SHBG) and the androgen testosterone have been associated with risk of diseases throughout the lifecourse. Although both SHBG and testosterone have been shown to be highly heritable, only a fraction of that heritability has been explained by genetic studies. Epigenetic modifications such as DNA methylation may explain some of the missing heritability and could potentially inform biological knowledge of endocrine disease mechanisms involved in development of later life disease. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we explored cross-sectional associations of SHBG, total testosterone and bioavailable testosterone in childhood (males only) and adolescence (both males and females) with genome-wide DNA methylation. We also report associations of a SHBG polymorphism (rs12150660) with DNA methylation, which leads to differential levels of SHBG in carriers, as a genetic proxy of circulating SHBG levels.

Results: We identified several novel sites and genomic regions where levels of SHBG, total testosterone, and bioavailable testosterone were associated with DNA methylation, including one region associated with total testosterone in males (annotated to the KLHL31 gene) in both childhood and adolescence and a second region associated with bioavailable testosterone (annotated to the CMYA5 gene) at both time-points. We also identified one region where both SHBG and bioavailable testosterone in males in childhood (annotated to the ZNF718 gene) was associated with DNA methylation.

Conclusion: Our findings have important implications in the understanding of the biological processes of SHBG and testosterone, with the potential for future work to determine the molecular mechanisms that could underpin these associations.
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http://dx.doi.org/10.1186/s12863-018-0703-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295101PMC
December 2018

Causes of variability in latent phenotypes of childhood wheeze.

J Allergy Clin Immunol 2019 05 5;143(5):1783-1790.e11. Epub 2018 Dec 5.

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

Background: Latent class analysis (LCA) has been used extensively to identify (latent) phenotypes of childhood wheezing. However, the number and trajectory of discovered phenotypes differed substantially between studies.

Objective: We sought to investigate sources of variability affecting the classification of phenotypes, identify key time points for data collection to understand wheeze heterogeneity, and ascertain the association of childhood wheeze phenotypes with asthma and lung function in adulthood.

Methods: We used LCA to derive wheeze phenotypes among 3167 participants in the ALSPAC cohort who had complete information on current wheeze recorded at 14 time points from birth to age 16½ years. We examined the effects of sample size and data collection age and intervals on the results and identified time points. We examined the associations of derived phenotypes with asthma and lung function at age 23 to 24 years.

Results: A relatively large sample size (>2000) underestimated the number of phenotypes under some conditions (eg, number of time points <11). Increasing the number of data points resulted in an increase in the optimal number of phenotypes, but an identical number of randomly selected follow-up points led to different solutions. A variable selection algorithm identified 8 informative time points (months 18, 42, 57, 81, 91, 140, 157, and 166). The proportion of asthmatic patients at age 23 to 24 years differed between phenotypes, whereas lung function was lower among persistent wheezers.

Conclusions: Sample size, frequency, and timing of data collection have a major influence on the number and type of wheeze phenotypes identified by using LCA in longitudinal data.
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http://dx.doi.org/10.1016/j.jaci.2018.10.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505513PMC
May 2019

The Simple 10-Item Predicting Asthma Risk in Children Tool to Predict Childhood Asthma-An External Validation.

J Allergy Clin Immunol Pract 2019 03 9;7(3):943-953.e4. Epub 2018 Oct 9.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. Electronic address:

Background: External validation of prediction models is important to assess generalizability to other populations than the one used for model development. The Predicting Asthma Risk in Children (PARC) tool, developed in the Leicestershire Respiratory Cohort (LRC), uses information on preschool respiratory symptoms to predict asthma at school age.

Objective: We performed an external validation of PARC using the Avon Longitudinal Study of Parents and Children (ALSPAC).

Methods: We defined inclusion criteria, prediction score items at baseline and asthma at follow-up in ALSPAC to match those used in LRC using information from parent-reported questionnaires. We assessed performance of PARC by calculating sensitivity, specificity, predictive values, likelihood ratios, area under the curve (AUC), Brier score and Nagelkerke's R. Sensitivity analyses varied inclusion criteria, scoring items, and outcomes.

Results: The validation population included 2690 children with preschool respiratory symptoms of whom 373 (14%) had asthma at school age. Discriminative performance of PARC was similar in ALSPAC (AUC = 0.77, Brier score 0.13) as in LRC (0.78, 0.22). The score cutoff of 4 showed the highest sum of sensitivity (69%) and specificity (76%) and positive and negative likelihood ratios of 2.87 and 0.41, respectively. Changes to inclusion criteria, scoring items, or outcome definitions barely altered the prediction performance.

Conclusions: Performing equally well in the validation cohort as in the development cohort, PARC is a valid tool for predicting asthma in population-based cohorts. Its use in clinical practice is ready to be tested.
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http://dx.doi.org/10.1016/j.jaip.2018.09.032DOI Listing
March 2019

Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet 2018 09;50(9):1343

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41588-018-0197-6DOI Listing
September 2018

Respiratory Phenotypes during Childhood and Early-Life Exposures.

Authors:
Raquel Granell

Am J Respir Crit Care Med 2019 01;199(1):7-9

1 Bristol Medical School University of Bristol Bristol, United Kingdom.

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http://dx.doi.org/10.1164/rccm.201807-1359EDDOI Listing
January 2019
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