. 2024 May;54(5):314-328.

doi: 10.1111/cea.14475. Epub 2024 Mar 31.

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

Andreas Böck^{1

2}, Kathrin Urner^{1

2}, Jana Kristin Eckert^{1

2}, Michael Salvermoser^{1

2}, Kristina Laubhahn^{1

3}, Sonja Kunze^{4

5}, Jörg Kumbrink⁶, Marc P Hoeppner⁷, Kathrin Kalkbrenner^{1

2}, Simone Kreimeier^{2

8}, Kirsten Beyer^{2

9}, Eckard Hamelmann^{2

10}, Michael Kabesch^{2

11}, Martin Depner^{2

12}, Gesine Hansen^{2

13

14

15}, Josef Riedler¹⁶, Marjut Roponen¹⁷, Elisabeth Schmausser-Hechfellner¹², Cindy Barnig^{18

19}, Amandine Divaret-Chauveau^{20

21

22}, Anne M Karvonen²³, Juha Pekkanen^{23

24}, Remo Frei^{25

26}, Caroline Roduit^{25

26

27

28}, Roger Lauener^{25

27}, Bianca Schaub^{1

2

3}; CHAMP study group; PASTURE study group

Collaborators, Affiliations

Collaborators

Affiliations

¹ Pediatric Allergology, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
² Member of the CHildhood Allergy and Tolerance Consortium (CHAMP), LMU Munich, Munich, Germany.
³ Comprehensive Pneumology Center - Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany.
⁴ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶ Institute of Pathology, Medical Faculty, LMU Munich, Munich, Germany.
⁷ Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
⁸ Department of Health Economics and Health Care Management, School of Public Health, Bielefeld University, Bielefeld, Germany.
⁹ Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
¹⁰ Department for Pediatrics, Children's Center Bethel, University Hospital OWL, Bielefeld University, Bielefeld, Germany.
¹¹ University Children's Hospital Regensburg (KUNO), St. Hedwig's Hospital of the Order of St. John and the University of Regensburg, Regensburg, Germany.
¹² Institute of Asthma and Allergy Prevention, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
¹³ Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
¹⁴ Biomedical Research in Endstage and Obstructive Lung Disease Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.
¹⁵ Excellence Cluster Resolving Infection Susceptibility RESIST (EXC 2155), Deutsche Forschungsgemeinschaft, Hannover Medical School, Hannover, Germany.
¹⁶ Children's Hospital Schwarzach, Schwarzach, Austria.
¹⁷ Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio, Finland.
¹⁸ Department of Respiratory Disease, University Hospital, Besanҫon, France.
¹⁹ INSERM, EFS BFC, LabEx LipSTIC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Univ. Bourgogne Franche-Comté, Besançon, France.
²⁰ Pediatric Allergy Department, Children's Hospital, University Hospital of Nancy, Vandoeuvre les Nancy, France.
²¹ EA3450 Development, Adaptation and Handicap (devah), Pediatric Allergy Department, University of Lorraine, Nancy, France.
²² UMR/CNRS 6249 Chrono-environment, University of Franche Comté, Besançon, France.
²³ Department of Health Security, Finnish Institute for Health and Welfare, Kuopio, Finland.
²⁴ Department of Public Health, University of Helsinki, Helsinki, Finland.
²⁵ Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
²⁶ Division of Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, University of Bern, Bern, Switzerland.
²⁷ Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland.
²⁸ Children's Hospital, University of Zürich, Zürich, Switzerland.

PMID: 38556721
DOI: 10.1111/cea.14475

Free article

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

Andreas Böck et al. Clin Exp Allergy. 2024 May.

Free article

. 2024 May;54(5):314-328.

doi: 10.1111/cea.14475. Epub 2024 Mar 31.

Authors

Collaborators

Affiliations

¹ Pediatric Allergology, Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
² Member of the CHildhood Allergy and Tolerance Consortium (CHAMP), LMU Munich, Munich, Germany.
³ Comprehensive Pneumology Center - Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany.
⁴ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁵ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶ Institute of Pathology, Medical Faculty, LMU Munich, Munich, Germany.
⁷ Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
⁸ Department of Health Economics and Health Care Management, School of Public Health, Bielefeld University, Bielefeld, Germany.
⁹ Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
¹⁰ Department for Pediatrics, Children's Center Bethel, University Hospital OWL, Bielefeld University, Bielefeld, Germany.
¹¹ University Children's Hospital Regensburg (KUNO), St. Hedwig's Hospital of the Order of St. John and the University of Regensburg, Regensburg, Germany.
¹² Institute of Asthma and Allergy Prevention, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
¹³ Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
¹⁴ Biomedical Research in Endstage and Obstructive Lung Disease Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.
¹⁵ Excellence Cluster Resolving Infection Susceptibility RESIST (EXC 2155), Deutsche Forschungsgemeinschaft, Hannover Medical School, Hannover, Germany.
¹⁶ Children's Hospital Schwarzach, Schwarzach, Austria.
¹⁷ Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio, Finland.
¹⁸ Department of Respiratory Disease, University Hospital, Besanҫon, France.
¹⁹ INSERM, EFS BFC, LabEx LipSTIC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Univ. Bourgogne Franche-Comté, Besançon, France.
²⁰ Pediatric Allergy Department, Children's Hospital, University Hospital of Nancy, Vandoeuvre les Nancy, France.
²¹ EA3450 Development, Adaptation and Handicap (devah), Pediatric Allergy Department, University of Lorraine, Nancy, France.
²² UMR/CNRS 6249 Chrono-environment, University of Franche Comté, Besançon, France.
²³ Department of Health Security, Finnish Institute for Health and Welfare, Kuopio, Finland.
²⁴ Department of Public Health, University of Helsinki, Helsinki, Finland.
²⁵ Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
²⁶ Division of Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, University of Bern, Bern, Switzerland.
²⁷ Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland.
²⁸ Children's Hospital, University of Zürich, Zürich, Switzerland.

PMID: 38556721
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.

Keywords: asthma; epidemiology; genetics; paediatrics; prevention.

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References

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical