Associations of Breathing Pattern Disorder and Nijmegen Score With Clinical Outcomes in Difficult-to-Treat Asthma.

BACKGROUND: Breathing pattern disorder (BPD) reflects altered biomechanical patterns of breathing that drive breathing difficulty and commonly accompanies difficult-to-treat asthma. Diagnosis of BPD has no gold standard, but Nijmegen Questionnaire (NQ) >23 is commonly used. OBJECTIVES: We sought to advance clinical characterization of BPD and better understand the clinical utility of NQ in difficult asthma in patients from the Wessex AsThma CoHort of difficult asthma (WATCH) study. METHODS: Associations between demographic and clinical factors in difficult asthma and BPD, ascertained by clinical diagnosis (yes/no, n = 476), by NQ scores (≤23: normal [no suggestion of BPD] and >23: abnormal [suggested BPD], n = 372), as well as the continuous raw NQ scores were assessed in univariate models to identify significant risk factors associated with the 3 BPD outcomes. For the clinician-diagnosed and NQ-based BPD, associations of continuous factors were assessed using the independent samples t test or the Mann-Whitney U test as appropriate for the data distribution or by the Spearman correlation test. Dichotomous associations were evaluated using χ2 tests. Multivariable logistic (dichotomous outcomes) and linear regression models (continuous outcomes) were developed to identify predictive factors associated with clinician-diagnosed and NQ-based BPD, dichotomous and continuous. Patients with data on NQ scores were grouped into NQ quartiles (low, moderate, high, and very high). The patterns of association of the quartiles with 4 health-related questionnaire outcomes were assessed using linear regression analyses. RESULTS: Multivariable regression identified that clinically diagnosed BPD was associated with female sex (odds ratio [OR]: 1.85; 95% confidence interval [CI]: 1.07, 3.20), comorbidities (rhinitis [OR: 2.46; 95% CI: 1.45, 4.17], gastroesophageal reflux disease [GORD] [OR: 2.77; 95% CI: 1.58, 4.84], inducible laryngeal obstruction [OR: 4.37; 95% CI: 2.01, 9.50], and any psychological comorbidity [OR: 1.86; 95% CI: 1.13, 3.07]), and health care usage (exacerbations [OR: 1.07; 95% CI: 1.003, 1.14] and previous intensive care unit (ICU) admissions [OR: 2.03; 95% CI: 1.18, 3.47]). Abnormal NQ-based BPD diagnosis was associated with history of eczema (OR: 1.83; 95% CI: 1.07, 3.14), GORD (OR: 1.94; 95% CI: 1.15, 3.27), or any psychological comorbidity (OR: 4.29; 95% CI: 2.64, 6.95) at multivariable regression. Differences between clinical and NQ-based BPD traits were also found with 42% discordance in BPD state between these definitions. Multivariable linear regression analysis with NQ as a continuous outcome showed positive association with worse asthma outcomes (admission to ICU, P = .037), different phenotypic traits (female sex, P = .001; ever smoker, P = .025), and greater multimorbidity (GORD, P = .002; sleep apnea, P = .04; and any psychological comorbidity, P < .0001). CONCLUSION: BPD is associated with worse health outcomes and negative health impacts in difficult asthma within a multimorbidity disease model. It therefore merits better recognition and prompt treatment. Clinical diagnosis and NQ offer different perspectives on BPD, so this goal may be best addressed by considering clinical features alongside the magnitude of NQ.

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

The efficacy of the Dyson air purifier on asthma control: A single-center, investigator-led, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Air pollution is associated with poor asthma outcomes. High-efficiency particulate air air purifiers may reduce air pollution and thus improve asthma outcomes. However, the efficacy of such devices for this purpose remains inconclusive. OBJECTIVE: To investigate the effects of reducing the levels of pollutants on asthma outcomes in adults, using a novel Dyson high-efficiency particulate air air purifier. METHODS: In a single-center, double-blinded, randomized controlled trial, participants (N = 50) were randomized at a 1:1 ratio to active filters (intervention) or to dummy filters (placebo) for a total of 78 weeks. The primary outcomes were the changes in Asthma Control Questionnaire 6 (ACQ6) and Asthma-specific Quality of Life Questionnaire (AQLQ) scores from baseline. The secondary outcomes were changes in indoor air pollution and lung function measurements. The coronavirus disease 2019 pandemic limited spirometry measurements to 2 time points and assessment of fractional exhaled nitric oxide and bronchial hyperresponsiveness to baseline only. RESULTS: Air pollutant levels were significantly lower in the intervention group compared with the placebo group (P = .0003). Both groups had a significant improvement in their ACQ6 and AQLQ. However, there were no significant between-group differences in ACQ6, AQLQ, or spirometry, compared with baseline in multivariable repeated measures models. CONCLUSION: The Dyson air purifier significantly improved air quality. However, there were no significant improvements in asthma control, quality of life, or measures of lung function in the intervention group compared with the control group despite improvements in indoor air quality. Larger, extended studies are required to confirm or refute these findings, especially given that the coronavirus disease 2019 pandemic prevented the procurement of detailed objective data. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04729530; ttps://clinicaltrials.gov/ct2/show/NCT04729530.

Multimorbidity in Difficult Asthma: The Need for Personalised and Non-Pharmacological Approaches to Address a Difficult Breathing Syndrome.

Three to ten percent of people living with asthma have difficult-to-treat asthma that remains poorly controlled despite maximum levels of guideline-based pharmacotherapy. This may result from a combination of multiple adverse health issues including aggravating comorbidities, inadequate treatment, suboptimal inhaler technique and/or poor adherence that may individually or collectively contribute to poor asthma control. Many of these are potentially "treatable traits" that can be pulmonary, extrapulmonary, behavioural or environmental factors. Whilst evidence-based guidelines lead clinicians in pharmacological treatment of pulmonary and many extrapulmonary traits, multiple comorbidities increase the burden of polypharmacy for the patient with asthma. Many of the treatable traits can be addressed with non-pharmacological approaches. In the current healthcare model, these are delivered by separate and often disjointed specialist services. This leaves the patients feeling lost in a fragmented healthcare system where clinical outcomes remain suboptimal even with the best current practice applied in each discipline. Our review aims to address this challenge calling for a paradigm change to conceptualise difficult-to-treat asthma as a multimorbid condition of a "Difficult Breathing Syndrome" that consequently needs a holistic personalised care attitude by combining pharmacotherapy with the non-pharmacological approaches. Therefore, we propose a roadmap for an evidence-based multi-disciplinary stepped care model to deliver this.

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.

BMI trajectory in childhood is associated with asthma incidence at young adulthood mediated by DNA methylation.

PURPOSE: Body mass index (BMI) is associated with asthma but associations of BMI temporal patterns with asthma incidence are unclear. Previous studies suggest that DNA methylation (DNAm) is associated with asthma status and variation in DNAm is a consequence of BMI changes. This study assessed the direct and indirect (via DNAm) effects of BMI trajectories in childhood on asthma incidence at young adulthood. METHODS: Data from the Isle of Wight (IoW) birth cohort were included in the analyses. Group-based trajectory modelling was applied to infer latent BMI trajectories from ages 1 to 10 years. An R package, ttscreening, was applied to identify differentially methylated CpGs at age 10 years associated with BMI trajectories, stratified for sex. Logistic regressions were used to further exclude CpGs with DNAm at age 10 years not associated with asthma incidence at 18 years. CpGs discovered via path analyses that mediated the association of BMI trajectories with asthma incidence in the IoW cohort were further tested in an independent cohort, the Avon Longitudinal Study of Children and Parents (ALSPAC). RESULTS: Two BMI trajectories (high vs. normal) were identified. Of the 442,474 CpG sites, DNAm at 159 CpGs in males and 212 in females were potentially associated with BMI trajectories. Assessment of their association with asthma incidence identified 9 CpGs in males and 6 CpGs in females. DNAm at 4 of these 15 CpGs showed statistically significant mediation effects (p-value < 0.05). At two of the 4 CpGs (cg23632109 and cg10817500), DNAm completely mediated the association (i.e., only statistically significant indirect effects were identified). In the ALSPAC cohort, at all four CpGs, the same direction of mediating effects were observed as those found in the IoW cohort, although statistically insignificant. CONCLUSION: The association of BMI trajectory in childhood with asthma incidence at young adulthood is possibly mediated by DNAm.

The Efficacy of the Dyson Air Purifier in Improving Asthma Control: Protocol for a Single-Center, Investigator-Led, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Indoor air quality has been shown to influence asthma control and outcomes. Air purifiers and high-efficiency particulate air filtration devices can improve indoor air quality by reducing the indoor levels of air pollution and allergens. However, the influence of this improved indoor air quality on asthma control remains unclear; hence, randomized controlled trials are needed to further elucidate this phenomenon. OBJECTIVE: This study aims to investigate the effect of reducing the levels of allergens and pollutants in the bedroom and living room through the use of Dyson air purifiers (Dyson Pure Cool) on asthma control. METHODS: This is an 18-month long, investigator-led, randomized, double-blinded, placebo-controlled, single-center trial. Subjects will be randomized in a 1:1 ratio to active or placebo Dyson filters. The primary outcome is the change in the scores of Asthma Control Questionnaire 6 and Asthma-specific Quality of Life Questionnaire from baseline. Secondary outcomes include changes in lung function (forced expiratory volume in one second, forced expiratory volume in one second/forced vital capacity ratio, and midexpiratory flows), peak expiratory flow measurements, airway hyperresponsiveness (assessed by methacholine bronchial challenge), fractional exhaled nitric oxide, and indoor air pollutant levels. The sample size will be 50 subjects, and all subjects will have a confirmed diagnosis of mild persistent to moderate persistent asthma along with an Asthma Control Questionnaire 6 score of >1.5. RESULTS: This study was approved by the West Midlands Research Ethics Committee (18/WM/0277). The study results will be published in peer-reviewed scientific journals; presented at relevant scientific conferences; and shared in plain English with participants in our newsletters, in our clinics, and via the David Hide Asthma and Allergy Research Centre website. Our trial began in September 2019 and is expected to end in August 2021. CONCLUSIONS: This is a double-blinded, placebo-controlled, randomized, investigator-led study to investigate the efficacy of a novel air purifier in improving asthma control in adults. The trial period of 18 months will facilitate the collection of robust data and will therefore generate clear signals. However, this extended trial duration may lead to patient withdrawal. Furthermore, this trial is conducted at a single center and in a location with a homogenous cohort of people, which may affect translatability. Nonetheless, it is hoped that the findings of this trial may help further inform clinicians regarding the utility of this novel device as an adjunct in asthma care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04729530; https://clinicaltrials.gov/ct2/show/NCT04729530. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/28624.

Sex-specific longitudinal association of DNA methylation with lung function.

Investigating whether DNA methylation (DNA-M) at an earlier age is associated with lung function at a later age and whether this relationship differs by sex could enable prediction of future lung function deficit. A training/testing-based technique was used to screen 402 714 cytosine-phosphate-guanine dinucleotide sites (CpGs) to assess the longitudinal association of blood-based DNA-M at ages 10 and 18 years with lung function at 18 and 26 years, respectively, in the Isle of Wight birth cohort (IOWBC). Multivariable linear mixed models were applied to the CpGs that passed screening. To detect differentially methylated regions (DMRs), DMR enrichment analysis was conducted. Findings were further examined in the Avon Longitudinal Study of Parents and Children (ALSPAC). Biological relevance of the identified CpGs was assessed using gene expression data. DNA-M at eight CpGs (five CpGs with forced expiratory volume in 1 s (FEV1) and three CpGs with FEV1/forced vital capacity (FVC)) at an earlier age was associated with lung function at a later age regardless of sex, while at 13 CpGs (five CpGs with FVC, three with FEV1 and five with FEV1/FVC), the associations were sex-specific (p FDR <0.05) in IOWBC, with consistent directions of association in ALSPAC (IOWBC-ALSPAC consistent CpGs). cg16582803 (WNT10A) and cg14083603 (ZGPAT) were replicated in ALSPAC for main and sex-specific effects, respectively. Among IOWBC-ALSPAC consistent CpGs, DNA-M at cg01376079 (SSH3) and cg07557690 (TGFBR3) was associated with gene expression both longitudinally and cross-sectionally. In total, 57 and 170 DMRs were linked to lung function longitudinally in males and females, respectively. CpGs showing longitudinal associations with lung function have the potential to serve as candidate markers in future studies on lung function deficit prediction.

Preconceptional smoking alters spermatozoal miRNAs of murine fathers and affects offspring's body weight.

BACKGROUND: Active smoking has been reported among 7% of teenagers worldwide, with ages ranging from 13 to 15 years. An epidemiological study suggested that preconceptional paternal smoking is associated with adolescent obesity in boys. We developed a murine adolescent smoking model before conception to investigate the paternal molecular causes of changes in offspring's phenotype. METHOD: Male and female C57BL/6J mice were exposed to increasing doses of mainstream cigarette smoke (CS) from onset of puberty for 6 weeks and mated with room air (RA) controls. RESULTS: Thirteen miRNAs were upregulated and 32 downregulated in the spermatozoa of CS-exposed fathers, while there were no significant differences in the count and morphological integrity of spermatozoa, as well as the proliferation of spermatogonia between CS- and RA-exposed fathers. Offspring from preconceptional CS-exposed mothers had lower body weights (p = 0.007). Moreover, data from offspring from CS-exposed fathers suggested a potential increase in body weight (p = 0.062). CONCLUSION: We showed that preconceptional paternal CS exposure regulates spermatozoal miRNAs, and possibly influences the body weight of F1 progeny in early life. The regulated miRNAs may modulate transmittable epigenetic changes to offspring, thus influence the development of respiratory- and metabolic-related diseases such as obesity, a mechanism that warrants further studies for elaborate explanations.

DNA Methylation at Birth is Associated with Childhood Serum Immunoglobulin E Levels.

Immunoglobulin E (IgE) is known to play an important role in allergic diseases. Epigenetic traits acquired due to modification of deoxyribonucleic acid (DNA) methylation (DNAm) in early life may have phenotypic consequences through their role in transcriptional regulation with relevance to the developmental origins of diseases including allergy. However, epigenome-scale studies on the longitudinal association of cord blood DNAm with IgE over time are lacking. Our study aimed to examine the association of DNAm at birth with childhood serum IgE levels during early life. Genome-scale DNAm and total serum IgE measured at birth, 5, 8, and 11 years of children in the Taiwan Maternal and Infant Cohort Study were included in the study in the discovery stage. Linear mixed models were implemented to assess the association between cord blood DNAm at ~310K 5'-cytosine-phosphate-guanine-3' (CpG) sites with repeated IgE measurements, adjusting for cord blood IgE. Identified statistically significant CpGs (at a false discovery rate, FDR, of 0.05) were further tested in an independent replication cohort, the Isle of Wight (IoW) birth cohort. We mapped replicated CpGs to genes and conducted gene ontology analysis using ToppFun to identify significantly enriched pathways and biological processes of the genes. Cord blood DNAm of 273 CpG sites were significantly (FDR = 0.05) associated with IgE levels longitudinally. Among the identified CpGs available in both cohorts (184 CpGs), 92 CpGs (50%) were replicated in the IoW in terms of consistency in direction of associations between DNA methylation and IgE levels later in life, and 16 of the 92 CpGs showed statistically significant associations (P < .05). Gene ontology analysis identified 4 pathways (FDR = 0.05). The identified 16 CpG sites had the potential to serve as epigenetic markers associated with later IgE production, beneficial to allergic disease prevention and intervention.

Epigenome-scale comparison of DNA methylation between blood leukocytes and bronchial epithelial cells.

Aim: Agreement in DNA methylation (DNAm) at the genome scale between blood leukocytes (BL) and bronchial epithelial cells (BEC) is unknown. We examine as to what extent DNAm in BL is comparable with that in BEC and serves as a surrogate for BEC. Materials & methods: Overall agreement (paired t-tests with false discovery rate adjusted p > 0.05) and consistency (Pearson's correlation coefficients >0.5) between two tissues, at each of the 767,412 CpGs, were evaluated. Results: We identified 247,721 CpGs showing overall agreement and 47,371 CpGs showing consistency in DNAm. Identified CpGs are involved in certain immune pathways, indicating the potential of using blood as a biomarker for BEC at those CpGs in lower airway-related diseases. Conclusion: CpGs showing overall agreement and those without overall agreement are distributed differently on the genome.

Sex-specific associations of asthma acquisition with changes in DNA methylation during adolescence.

BACKGROUND: Underlying biological mechanisms involved in sex differences in asthma status changes from pre- to post-adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma. OBJECTIVE: We hypothesized that asthma acquisition from pre- to post-adolescence was associated with changes in DNAm during this period at asthma-associated cytosine-phosphate-guanine (CpG) sites and such an association was sex-specific. METHODS: Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n = 124 females, 151 males) were studied. Using a training-testing approach, epigenome-wide CpGs associated with asthma were identified. Logistic regression was used to examine sex-specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma-associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed. RESULTS: We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (P-values <1.0 × 10-3 ). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex-specific effects on asthma transition (P-values <.01 in both cohorts). CONCLUSION AND CLINICAL RELEVANCE: Gender reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre- to post-adolescence at asthma-associated CpGs. These CpGs are potential biomarkers of sex-specific asthma acquisition in adolescence.

Epigenome-Wide Association Study Reveals Duration of Breastfeeding Is Associated with Epigenetic Differences in Children.

Several small studies have shown associations between breastfeeding and genome-wide DNA methylation (DNAm). We performed a comprehensive Epigenome-Wide Association Study (EWAS) to identify associations between breastfeeding and DNAm patterns in childhood. We analysed DNAm data from the Isle of Wight Birth Cohort at birth, 10, 18 and 26 years. The feeding method was categorized as breastfeeding duration >3 months and >6 months, and exclusive breastfeeding duration >3 months. EWASs using robust linear regression were performed to identify differentially methylated positions (DMPs) in breastfed and non-breastfed children at age 10 (false discovery rate of 5%). Differentially methylated regions (DMRs) were identified using comb-p. The persistence of significant associations was evaluated in neonates and individuals at 18 and 26 years. Two DMPs, in genes SNX25 and LINC00840, were significantly associated with breastfeeding duration >6 months at 10 years and was replicated for >3 months of exclusive breastfeeding. Additionally, a significant DMR spanning the gene FDFT1 was identified in 10-year-old children who were exposed to a breastfeeding duration >3 months. None of these signals persisted to 18 or 26 years. This study lends further support for a suggestive role of DNAm in the known benefits of breastfeeding on a child's future health.

Prediction models for childhood asthma: A systematic review.

BACKGROUND: The inability to objectively diagnose childhood asthma before age five often results in both under-treatment and over-treatment of asthma in preschool children. Prediction tools for estimating a child's risk of developing asthma by school-age could assist physicians in early asthma care for preschool children. This review aimed to systematically identify and critically appraise studies which either developed novel or updated existing prediction models for predicting school-age asthma. METHODS: Three databases (MEDLINE, Embase and Web of Science Core Collection) were searched up to July 2019 to identify studies utilizing information from children ≤5 years of age to predict asthma in school-age children (6-13 years). Validation studies were evaluated as a secondary objective. RESULTS: Twenty-four studies describing the development of 26 predictive models published between 2000 and 2019 were identified. Models were either regression-based (n = 21) or utilized machine learning approaches (n = 5). Nine studies conducted validations of six regression-based models. Fifteen (out of 21) models required additional clinical tests. Overall model performance, assessed by area under the receiver operating curve (AUC), ranged between 0.66 and 0.87. Models demonstrated moderate ability to either rule in or rule out asthma development, but not both. Where external validation was performed, models demonstrated modest generalizability (AUC range: 0.62-0.83). CONCLUSION: Existing prediction models demonstrated moderate predictive performance, often with modest generalizability when independently validated. Limitations of traditional methods have shown to impair predictive accuracy and resolution. Exploration of novel methods such as machine learning approaches may address these limitations for future school-age asthma prediction.

Changes in DNA methylation from pre- to post-adolescence are associated with pubertal exposures.

BACKGROUND: Adolescence is a period characterized by major biological development, which may be associated with changes in DNA methylation (DNA-M). However, it is unknown to what extent DNA-M varies from pre- to post-adolescence, whether the pattern of changes is different between females and males, and how adolescence-related factors are associated with changes in DNA-M. METHODS: Genome-scale DNA-M at ages 10 and 18 years in whole blood of 325 subjects (n = 140 females) in the Isle of Wight (IOW) birth cohort was analyzed using Illumina Infinium arrays (450K and EPIC). Linear mixed models were used to examine DNA-M changes between pre- and post-adolescence and whether the changes were gender-specific. Adolescence-related factors and environmental exposure factors were assessed on their association with DNA-M changes. Replication of findings was attempted in the comparable Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. RESULTS: In the IOW cohort, after controlling for technical variation and cell compositions at both pre- and post-adolescence, 15,532 cytosine-phosphate-guanine (CpG) sites (of 400,825 CpGs, 3.88%) showed statistically significant DNA-M changes from pre-adolescence to post-adolescence invariant to gender (false discovery rate (FDR) = 0.05). Of these 15,532 CpGs, 10,212 CpGs (66%) were replicated in the ALSPAC cohort. Pathway analysis using Ingenuity Pathway Analysis (IPA) identified significant biological pathways related to growth and development of the reproductive system, emphasizing the importance of this period of transition on epigenetic state of genes. In addition, in IOW, we identified 1179 CpGs with gender-specific DNA-M changes. In the IOW cohort, body mass index (BMI) at age 10 years, age of growth spurt, nonsteroidal drugs use, and current smoking status showed statistically significant associations with DNA-M changes at 15 CpGs on 14 genes such as the AHRR gene. For BMI at age 10 years, the association was gender-specific. Findings on current smoking status were replicated in the ALSPAC cohort. CONCLUSION: Adolescent transition is associated with changes in DNA-M at more than 15K CpGs. Identified pathways emphasize the importance of this period of transition on epigenetic state of genes relevant to cell growth and immune system development.