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Mechanisms of Asthma and Allergy (MeDALL): from population based birth cohorts to systems biology

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Mechanisms of Asthma and Allergy (MeDALL): from population based birth cohorts to systems biology

  1. 1. Mechanisms of Asthma and Allergy (MeDALL): from population based birth cohorts to systems biology Josep M. AntóCentre de Recerca en Epidemiologia Ambiental (CREAL) IMIM, UPF, CIBERESP
  2. 2. Outline•  Background.•  MeDALL Phenotypes.•  Harmonisation.•  Experimental Studies.•  Integration.
  3. 3. COPD SubtypesGarcia-Aymerich J et al Thorax 2011
  4. 4. Epidemiology of allergy
  5. 5. Understanding the asthma epidemicQuestion: Why environmental changes have induced anepidemic increase of IgE-mediated allergic diseases withoutmajor changes in hereditary genetic background?Risk factors: hundreds? Causal mechanisms poorly known.Disease mechanisms: allergic and non allergic; not greatprogressTreatment: symptoms well controlled by inhaled steroidsexcept in severe asthmaPrevention: not available (except occupational and soybean)
  6. 6. Coordination J Bousquet/ JM Antó (INSERM-Paris/CREAL-Barcelona)
  7. 7. Classical  approach   Novel  approach  Defini4on  by   Birth  cohorts   Mathema4cal   Experts   IgE  arrays   modelling   Classical  phenotypes   Novel  clusters  of  phenotypes   Analysis  of   risk  factors   Selec4on  of  2  extreme  phenotypes   and  GxE   Selec4on  of  extreme  phenotypes   IgG  arrays   Karelia  cross-­‐   IgG  arrays   Targe7ed   sec;onal   Targe7ed        proteomics        proteomics   Transcriptomics   Transcriptomics   Gene;cs   Gene;cs   Birth  cohort   Epigene;cs   Follow-­‐up   Epigene;cs   Mathema4cal   modelling   Iden4fica4on  of  classical  fingerprints   Iden4fica4on  of  novel  fingerprints  
  8. 8. MeDALL Cohorts
  9. 9. Birth cohorts in MeDALL§  Younger birth cohorts: o  Recruited: 12,500 o  Follow up: 6,000 at ages 4y – 8y§  Older birth cohorts: o  Recruited >20,000 o  Follow-up 13,000 at ages 14y - 18y
  10. 10. Classical  approach   Novel  approach  Defini4on  by   Birth  cohorts   Mathema4cal   Experts   IgE  arrays   modelling   Classical  phenotypes   Novel  clusters  of  phenotypes   Analysis  of   risk  factors   Selec4on  of  2  extreme  phenotypes   and  GxE   Selec4on  of  extreme  phenotypes   IgG  arrays   Karelia  cross-­‐   IgG  arrays   Targe7ed   sec;onal   Targe7ed        proteomics        proteomics   Transcriptomics   Transcriptomics   Gene;cs   Gene;cs   Birth  cohort   Epigene;cs   Follow-­‐up   Epigene;cs   Mathema4cal   modelling   Iden4fica4on  of  classical  fingerprints   Iden4fica4on  of  novel  fingerprints   Integrative knowledge Valida;on  in  birth  cohorts  samples                         Valida4on  in  birth  cohorts  samples                         management Replica;on  in  in  birth  cohort  follow-­‐up       Replica4on  in  birth  cohort  follow-­‐up       Confirma;on  in  animal  models   Analysis  of   risk  factors   Confirma;on  by  in  vitro  immunology   and  GxE   Mathema;cal   modelling   Integra;on  of  all  data  for  determina;on  of  biomarkers  for  early  diagnosis,     preven;on  and  iden;fica;on  of  targets  for  therapy  of  allergy  
  11. 11. MeDALL Work Packages and partners1. Coordination J Bousquet/ JM Antó (INSERM-Paris / CREAL-Barcelona)2. Phenotypes identification: classical and novel JM Antó (CREAL)3. Birth cohorts: infancy and childhood J Sunyer (CREAL)4. Birth cohorts: children and adolescents T Kiel (Charité-Berlin)5. Characterization of inhalant and food allergens R Valenta (MUW, Vienna)6. Epigenetics (D Postma, UMMG Groningen) and Proteomics (S Guerra-CREAL)7. Systems biology (C Auffrey, CNRS, Paris)8. Confirmatory animal models (B Lambretch, Unv Gent, Gent)9. In vitro human immunology (M Adkis, SIAK, Davos)10. Translational integration into health care (T Haathela, HUCH, Helsinki)11. Training and disemination (T Zuberbier, Charité)12. Ethical Issues (A Cambo, Inserm, Paris)
  12. 12. Barabasi A. NEJM 2007
  13. 13. HOW  TO  INTEGRATE  THE  ANALYSIS  •  Hawkins  RD  et  al.  Nat  Rev  Genet  2010  •  Unsupervised  integra4on:     –  paMern  discovery  •  Supervised  integra4on:     –  tes4ng  predic4ons  
  14. 14. How to integrate the analysis•  Unsupervised integration: pattern discovery –  Cluster, LCA, network analysis .. –  No prior hypothesis,… –  Generated hypothesis tested by supervised integration and experimental models.•  Supervised integration: testing predictions –  Research questions are crucial. –  Methods are question dependent.
  15. 15. MeDALL papers•  Bousquet  J,  Anto  J,  Sunyer  J,  Nieuwenhuijsen  M,  Vrijheid  M,  Keil  T.  Pooling   Birth  Cohorts  in  Allergy  and  Asthma:  European  Union-­‐Funded  Ini4a4ves  -­‐   A  MeDALL,  CHICOS,  ENRIECO,  and  GALEN  Joint  Paper.  Int  Arch  Allergy   Immunol.  2012  Dec  13;161(1):1-­‐10.  [Epub  ahead  of  print]  •  Antó  JM  et  al.  Understanding  the  complexity  of  IgE-­‐related  phenotypes   from  childhood  to  young  adulthood:  a  Mechanisms  of  the  Development  of   Allergy  (MeDALL)  seminar.  J  Allergy  Clin  Immunol.  2012  Apr;129(4): 943-­‐54.  •  Bousquet  J  et  al.  MeDALL  (Mechanisms  of  the  Development  of  ALLergy):   an  integrated  approach  from  phenotypes  to  systems  medicine.  Allergy.   2011  May;66(5):596-­‐604.  
  16. 16. Dieter Maier Biomax Informatics AGMariona Pinart Marta Benet Xavi Basagaña Judith Garcia Josep M. Antó

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