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Data from three UK birth cohorts were used in this study: the IOWBC, Manchester Asthma and Allergy Study (MAAS), and The Avon Longitudinal Study of Parents and Children (ALSPAC) (see Supplementary Methods for cohort details, Table S1). All analyses in the IOWBC (and where data were available in MAAS and ALSPAC at their respective time points, Table S1) were adjusted for gender, maternal asthma, paternal asthma, and sibling asthma. Keywords: ALSPAC; childhood asthma; meta-analysis; parental smoking; polygenic risk score; PRS-by-environment interactions EN ALSPAC childhood asthma meta-analysis parental smoking polygenic risk score PRS-by-environment interactions 1 4 4 04/28/22 20220401 NES 220401 AUTHOR CONTRIBUTIONS B Dilini M. Kothalawala: b Conceptualization (equal); Data curation (equal); Formal analysis (equal); Investigation (equal); Methodology (lead); Project administration (lead); Software (equal); Validation (equal); Visualization (lead); Writing - original draft (lead); Writing - review & editing (lead). Covariates are gender, maternal asthma, paternal asthma, and sibling asthma. [Extracted from the article]

Background: Respiratory symptoms are common in early life and often transient. It is difficult to identify in which children these will persist and result in asthma. Machine learning (ML) approaches have the potential for better predictive performance and generalisability over existing childhood asthma prediction models. This study applied ML approaches to predict school‐age asthma (age 10) in early life (Childhood Asthma Prediction in Early life, CAPE model) and at preschool age (Childhood Asthma Prediction at Preschool age, CAPP model). Methods: Clinical and environmental exposure data was collected from children enrolled in the Isle of Wight Birth Cohort (N = 1368, ∼15% asthma prevalence). Recursive Feature Elimination (RFE) identified an optimal subset of features predictive of school‐age asthma for each model. Seven state‐of‐the‐art ML classification algorithms were used to develop prognostic models. Training was performed by applying fivefold cross‐validation, imputation, and resampling. Predictive performance was evaluated on the test set. Models were further externally validated in the Manchester Asthma and Allergy Study (MAAS) cohort. Results: RFE identified eight and twelve predictors for the CAPE and CAPP models, respectively. Support Vector Machine (SVM) algorithms provided the best performance for both the CAPE (area under the receiver operating characteristic curve, AUC = 0.71) and CAPP (AUC = 0.82) models. Both models demonstrated good generalisability in MAAS (CAPE 8‐year = 0.71, 11‐year = 0.71, CAPP 8‐year = 0.83, 11‐year = 0.79) and excellent sensitivity to predict a subgroup of persistent wheezers. Conclusion: Using ML approaches improved upon the predictive performance of existing regression‐based models, with good generalisability and ability to rule in asthma and predict persistent wheeze. [ABSTRACT FROM AUTHOR]

To the Editor, We would like to thank Owora et al1 for their interest in our systematic review of childhood asthma prediction models and welcome their subsequent analyses and recommendations for future research in this field. To provide an illustrative example of the potential insight offered by reclassification tables, we compared two existing asthma prediction models for which data were available in the Isle of Wight Birth Cohort (IOWBC).5 The two models we compared were the updated PIAMA6 and PARS7 models. For example, although not evident from the receiver operating characteristic (ROC) plot, the reclassification table suggests that predictions made by the updated PIAMA model are skewed towards underestimating asthma risk in the IOWBC when compared against the PARS model. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]