An integrated molecular risk score early in life for subsequent childhood asthma risk

Böck A, Urner K, Eckert JK et al.  Clin Exp Allergy. 2024 Mar 31. doi: 10.1111/cea.14475. 

Abstract

Background

Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy).

Methods

Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5–11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO).

Results

Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68).

The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5–6 years).

Conclusion

Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers.

Graphical Abstract

For early prediction of childhood asthma, an integrated risk score combining established risk-factors with genome-wide molecular markers (genotype, DNA methylation, mRNA expression) at birth was defined, complemented by subsequent clinical symptoms/diagnoses (wheeze, atopic dermatitis, food allergy). While epidemiological predictors have moderate predictive power, molecular markers from birth improve prediction to a modest extent. Including allergic symptoms/diagnoses significantly increased predictive efficiency.

Key messages

• Epidemiological predictors exhibit moderate predictive efficacy for childhood asthma.
• Molecular markers from birth modestly enhance prediction.
• Inclusion of allergic symptoms/diagnoses significantly boosts predictive power, informing future study designs.

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