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Böck, A.* ; Urner, K.* ; Eckert, J.K.* ; Salvermoser, M.* ; Laubhahn, K.* ; Kunze, S. ; Kumbrink, J.* ; Hoeppner, M.P.* ; Kalkbrenner, K.* ; Kreimeier, S.* ; Beyer, K.* ; Hamelmann, E.* ; Kabesch, M.* ; Depner, M. ; Hansen, G.* ; Riedler, J.* ; Roponen, M.* ; Schmaußer-Hechfellner, E. ; Barnig, C.* ; Divaret-Chauveau, A.* ; Karvonen, A.M.* ; Pekkanen, J.* ; Frei, R.* ; Roduit, C.* ; Lauener, R.* ; Schaub, B.* ; PASTURE Study Group (Illi, S. ; Pechlivanis, S. ; Pagani, G. ; Ege, M.J.)

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

Clin. Exp. Allergy 54, 314-328 (2024)

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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.

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