Obstructive and restrictive spirometry from school age to adulthood: three birth cohort studies

Background: Spirometric obstruction and restriction are two patterns of impaired lung function which are predictive of poor health. We investigated the development of these phenotypes and their transitions through childhood to early adulthood. Methods: In this study, we analysed pooled data from three UK population−based birth cohorts established between 1989 and 1995. We applied descriptive statistics, regression modelling and data-driven modelling to data from three population−based birth cohorts with at least three spirometry measures from childhood to adulthood (mid-school: 8–10 years, n = 8404; adolescence: 15–18, n = 5764; and early adulthood: 20–26, n = 4680). Participants were assigned to normal, restrictive, and obstructive spirometry based on adjusted regression residuals. We considered two transitions: from 8–10 to 15–18 and from 15–18 to 20–26 years. Findings: Obstructive phenotype was observed in ∼10%, and restrictive in ∼9%. A substantial proportion of children with impaired lung function in school age (between one third in obstructive and a half in restricted phenotype) improved and achieved normal and stable lung function to early adulthood. Of those with normal lung function in school-age, <5% declined to adulthood. Underweight restrictive and obese obstructive participants were less likely to transit to normal. Maternal smoking during pregnancy and current asthma diagnosis increased the risk of persistent obstruction and worsening. Significant associate of worsening in restrictive phenotypes was lower BMI at the first lung function assessment. Data-driven methodologies identified similar risk factors for obstructive and restrictive clusters. Interpretation: The worsening and improvement in obstructive and restrictive spirometry were observed at all ages. Maintaining optimal weight during childhood and reducing maternal smoking during pregnancy may reduce spirometry obstruction and restriction and improve lung function. Funding: MRC Grant MR/S025340/1

Integration of genomic risk scores to improve the prediction of childhood asthma diagnosis

Genome-wide and epigenome-wide association studies have identified genetic variants and differentially methylated nucleotides associated with childhood asthma. Incorporation of such genomic data may improve performance of childhood asthma prediction models which use phenotypic and environmental data. Using genome-wide genotype and methylation data at birth from the Isle of Wight Birth Cohort (n = 1456), a polygenic risk score (PRS), and newborn (nMRS) and childhood (cMRS) methylation risk scores, were developed to predict childhood asthma diagnosis. Each risk score was integrated with two previously published childhood asthma prediction models (CAPE and CAPP) and were validated in the Manchester Asthma and Allergy Study. Individually, the genomic risk scores demonstrated modest-to-moderate discriminative performance (area under the receiver operating characteristic curve, AUC: PRS = 0.64, nMRS = 0.55, cMRS = 0.54), and their integration only marginally improved the performance of the CAPE (AUC: 0.75 vs. 0.71) and CAPP models (AUC: 0.84 vs. 0.82). The limited predictive performance of each genomic risk score individually and their inability to substantially improve upon the performance of the CAPE and CAPP models suggests that genetic and epigenetic predictors of the broad phenotype of asthma are unlikely to have clinical utility. Hence, further studies predicting specific asthma endotypes are warranted.</p

Lung function trajectories from school age to adulthood and their relationship with markers of cardiovascular disease risk

Rationale: Lung function in early adulthood is associated with subsequent adverse health outcomes. Objectives: To ascertain whether stable and reproducible lung function trajectories can be derived in different populations and investigate their association with objective measures of cardiovascular structure and function. Methods: Using latent profile modelling, we studied three population-based birth cohorts with repeat spirometry data from childhood into early adulthood to identify trajectories of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). We used multinomial logistic regression models to investigate early-life predictors of the derived trajectories. We then ascertained the extent of the association between the derived FEV1/FVC trajectories and blood pressure and echocardiographic markers of increased cardiovascular risk and stroke in ∼3200 participants at age 24 years in one of our cohorts. Results: We identified four FEV1/FVC trajectories with strikingly similar latent profiles across cohorts (pooled N=6377): above average (49.5%); average (38.3%); below average (10.6%); and persistently low (1.7%). Male sex, wheeze, asthma diagnosis/medication and allergic sensitisation were associated with trajectories with diminished lung function in all cohorts. We found evidence of an increase in cardiovascular risk markers ascertained by echocardiography (including left ventricular mass indexed to height and carotid intima-media thickness) with decreasing FEV1/FVC (with p values for the mean crude effects per-trajectory ranging from 0.10 to p&lt;0.001). In this analysis, we considered trajectories as a pseudo-continuous variable; we confirmed the assumption of linearity in all the regression models. Conclusions: Childhood lung function trajectories may serve as predictors in the development of not only future lung disease, but also the cardiovascular disease and multimorbidity in adulthood.</p