t DSPAP s 9. årsmøde Sachs Children s Hospital Karolinska Institutet

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1 Ef Erfaringer fra kohortestudier t DSPAP s 9. årsmøde Magnus Wickman Sachs Children s Hospital Karolinska Institutet Stockholm

2 Study design Cross sectional studies, recall bias reversed causation error - no cause relationships, only associations Cohort studies - hypothesis generating, - exposure data collected before onset of disease, - no problem with recall bias exp data collected before onset - nested case control study Case control studies - exposure data collected at time for onset of disease - recall bias -selection of controls Intervention studies: cause relationship can be proven (but if the disease is multi factorial?)

3 Birth cohorts Population based - prevalence, risk factors Enriched for heredity or selected for other exposures - risk factors, mechanisms

4 To start a birth cohort Inclusion of all women in early ypregnancy in a pre-defined area during a certain period of time (N>10,000) Small cohort of selected individuals id to study mechanisms (N<400) Data on nonresponders Biological markers > 75-70% inclusion rate < 70% inclusion rate Inclusion rate = select until you have the number needed according to power calculations

5 To start a birth cohort Large cohort (N>10,000) Phenotyping important Low follow up rate? Small selected cohort Cases and controls High follow up rate Natural course of disease/prevalence Early markers of inflammation Risk factors Prevention Early markers of inflammation Early events Prediction and onset of disease Gene-environment interaction Outcome needs to be common Genetics - Epigenetics Genetics - Epigenetics

6 To start a birth cohort of 10,000 75% of 75% of 75% of 75% of 75% Eligible 10,000 Study base 7, years follow up 5,625 4 years 4,218 8 years 3, years 2,372 <25%

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8 A large birth cohort Pro: Great opportunities Biological markers collected before, during and after onset of disease Exposure data collected before onset of disease Always new research questions Collaboration possible - pooling of data - replication Genetic material available if DNAE/RNA is sampled and sampled correctly Publication in major journals Con: When to start recruitment? Long period before harvest - difficult with funding Research questions may not be valid at the time for harvest What about sustainability within your group? Loss at follow ups Relative expensive Think twice before you start tougher than toughest endurance sport

9 Birth cohorts within GA 2 LEN Study Start N ECA BAMSE DARC ECA MAS LISA DARC GINI-B PIAMA-NHS GINI-B KOALA KOALA PIAMA-NHS CO.N.ER LISA GEPSII CO.N.ER AMICS-Barcelona AMICS-B AMICS-Menorca AMICS-M Ttl Total BAMSE MAS GEPSII

10 Examples of risk factors studied in relation to development of allergy related disease Furred pets SHSE (second hand tobacco smoke exposure) Food nutritions Mediterranean diet - Breast milk - early fish intake (omega-3, antioxidant idant vitamins/ minerals) - Fruit and vegetables

11 Esben Eller, Allergy 2008

12 Sensitization (to at least 1 aero-allergen) and sensitization, allergic asthma Cat only vs. no pet ownership: Sensitization Allergic Asthma OR 1.09 ( ) OR 0.87 ( ) Lödrup Carlsen K.C. and the GA 2 LEN WP birth cohort consortium, submitted

13 Effect of allergen exposure and sensitisation at <3 years on lung function at 7 years NS= not sens S/LE= sensitised and low exp S/HE= sensitised and high exposure Illi S et al, The Lancet 2006

14 Second hand tobacco smoke exposure (asthma, eczema, sensitization, lung function) SHSE during pregnancy (foetal exposure) Early SHSE of the infant No controversies N Engl J Med 2010;363:

15 0.34 tpef F/tE No P Occ 1-9 >10 A+P Reduced t PTEF /t E <0.20 measured within the first week of life as well as maternal daily smoking during pregnancy are significant risk factors (independent) for developing persistent bronchial obstr within the first 2 years of life Lodrup Carlssen KC et al ERJ 1997 Lødrup Carlsen KC et al, PAI 1999

16 Foetal SHSE S and asthma a up to 4 years of age - children exposed to both prenatal and postnatal excluded 6 5 OR R, 95% CI Transient Late onset Persistent t Lannerö et al, Respiratory Research 2005

17 Foetal SHS exp, but not postnatal SHS exp and risk of asthma according to definition in 6 European birth cohorts Neuman Å, in manuscript

18 Effect of regular pre- and postnatal maternal smoking at the age of Sensitisation UCI 26.7 Wheezing UCI Odds ratio and 95% CI Sensitization Wheezing Sensitization Wheezing 1 0 No atopic parent 1 atopic parent 2 atopic parents

19 Increased risk of specific sensitisation and pre- and postnatal tobacco smoke exposure At age 3: food allergens Kulig M et al. Allergy 1999 At age 4 (postnatal only): sens birch (OR 2.90) sens cat (OR 2.68) Lannerö et al., Thorax 2008

20 Plausible preventive mechanisms of certain nutrients Fatty acids long chain polyunsaturated Maturation of the foetal immunsystem: Proliferation and production of cytokines - elicit effector cell functions. Fatty acid composition of immune cells - affects phagocytosis, T-cell signaling and antigen presentation capability. Support epithelial barrier integrity and reduce IL-4 mediated permeability Anti-oxidants Reduce the neg effects of oxidative stress in the mucus membrane of the airways Human milk - fatty acids, anti-oxidants, prebiotics etc HM contains indigestible oligosaccharides, promote the growth mainly of bifidobacteria. Stimulates the development of the infant's own immune system Secretory IgA antibodies directed towards the microbes in the mother's gut and her food proteins. May enhance the infant's capacity to develop allergen tolerance

21 Maternal consumption during Apples Total fish Oily fish pregnancy / >4/ 1-4/ >4/ 1-4/ >4/ <1/ >1/ <1/ >1/ 1.4 w w w w w w w w w w OR, CI95% Outcome at 5 years 0 Ever wheeze Doctor Ever Doctor Doctor confirmed asthma confirmed confirmed asthma eczema hay fever Willers S et al, Thorax on line 2007

22 OR and 95%CI per unit increase for fish consumption OR, 95%CI Eczema Specific Specific SPT to Persistent t Atopic at 1 year IgE (mites, grass) at 4 years IgE to Hdm at 4 years Hdm at 6 years wheeze at 6 years wheeze at 6 years Romieu I et al, Clin Exp All 2007

23 Fish consumption at age 1 and longitudinal development of allergic diseases up to 8 yrs (GEE) after adjustment, N=3,265 Eczema 1 yrs Overall effect After excl* Asthma 1 yrs Overall effect After excl* Rhinitis 1 yrs Overall effect After excl* * exclusion of children with early symptoms Odds ratio (95% CI)

24 Why does fish intake reduces the risk of onset of allergy related disease and supplementation of omega 3 fatty acid not?

25 Breastfeeding - lots of controversies (asthma, eczema, sensitisation) Possible preventive effective duration is important Composition of human milk may vary In a population where the majority is breastfed for at least 3-4 months effect of human milk on development of allergic disease is minor

26 4 months excl breastfeeding or more and asthma up to 8 years of age in 3400 children GEE model Recurrent wheeze 1 yr 2 yrs 4 yrs 8 yrs Overall effect 0-8 yrs Overall effect after excl Asthma 1 yr 2 yrs 4 yrs 8 yrs Overall effect 0-8 yrs Overall effect after excl Adjusted odds ratios* *(95%C) CI) Kull I et al, JACI 2010

27 Joint project BAMSE/Stockholm and CAPS/Sydney on breastfeeding and allergy disease related outcomes Discrepancies i Northern Europe and Australia BAMSE population based cohort CAPS selected cohort with intervention Discrepancies are to 100% explained by difference in selection. When BAMSE is selected in the same manner effects less prevalent. Reversed causation can not be ruled out

28 Individual fruits and vegetables and allergic disease Cross-sectional analysis at age 8 years. Highest vs. lowest quartile (OR and 95% CI) ALL CHILDREN Apples/pears Allergic rhinitis Asthma Eczema Atopic sensitization Onions/leek Allergic rhinitis Asthma Eczema Atopic sensitization Carrots Allergic rhinitis Asthma Eczema Atopic sensitization Legumes Allergic rhinitis Asthma Eczema Atopic sensitization Rosenlund, JACI 2011 Odds ratio (95% CI) Adjusted for sex, socioeconomic status, maternal smoking during pregnancy and/or at baseline, iso-bmi, maternal age at baseline, and parental history of allergic disease.

29 Individual fruits and vegetables and allergic disease after exclusion Aples/pears Allergic rhinitis Asthma Eczema Atopic sensitization Onions/leek Allergic rhinitis Asthma Eczema Atopic sensitization Carrots Allergic rhinitis Asthma Eczema Atopic sensitization Legumes Allergic rhinitis Asthma Eczema Atopic sensitization AFTER EXCLUSION Odds ratio (95% CI) Rosenlund, JACI 2011 Adjusted for sex, socioeconomic status, maternal smoking during pregnancy and/or at baseline, iso-bmi, maternal age at baseline, and parental history of allergic disease.

30 Utility of risk assessment data from birth cohorts Can be used in national guidelines on prevention since we lack good intervention ti studies on the effect of: SHSE Pet keeping Maternal diet during pregnancy, lactation Diet of the baby the first year of life

31 Development of allergy related diseases over time

32 Prevalence of allergic diseases in the BAMSE cohort shown as mean with 95%CI % 25 Asthma Eczema % 25 % 25 All rhinitis Age in years

33 Trends in eczema in the first 18 years of life: results from the Isle of Wight 1989 birth cohort study Boys Girls 9.4 % Age in years Ali Ziyab, Graham Roberts et al, Clin Exp 2010

34 Early co-morbidity and the allergic march

35 Infant wheeze and outcome of any allergy related disease at 8 years of age, N=3279 Between 1 Infants with wheeze, Non infant wheezers, and 2 years N= 830 (25 %) N=2449 (75 %) At 8 years Complete remission i N=505/817 (62%) Allergic disease among early wheezers N=312/817 Asthma N=116/824 (14%) (38%) Eczema N=181/812 (22%) Rhinitis N=156/828 (19%) Allergic disease among non early wheezers N=598/2391 Asthma N=91/2436 (4%) (25%) Eczema N=413/2396 (17%) Rhinitis N=288/2443 (12%) Åsa Neuman, in manuscript

36 Prognostic value of IgE sensitization in some of the GA 2 LEN Birth Cohorts

37 Prevalence of asthma, wheeze up to age 7 and increased BHR in relation to age at onset of allergic sensitisation over time Prevale ence in % at age 7 years 50 No sensitisation, n=342, 54% Transient sensitisation (0-2 yrs), n=82, 13% Late sensitisation, n=117, 18% 40 Persistent sensitisation, n=99, 15% ** ** ** 5 * ** ** ** 0 Asthma ever Current wheeze Current asthma Current BHR Any of cow s milk, egg white, soy bean, wheat, dust mite, cat, dog, grass mix, birch, >0.35 ku/l Sabina Illi et al, JACI 2001 and 2004

38 The prevalence of allergic diseases and sensitization in 6-year-old children Follow-up of the DARC birth cohort Kjaer HF et al PAI 2009

39 The prevalence of allergic diseases and sensitization in 6-year-old children Follow-up of the DARC birth cohort Kjaer HF et al PAI 2009

40 Early sensitisation is a risk factor for allergy related disease later in childhood or even in teenage Screen for atopic constitution early when symptoms of moderate or severe eczema or wheeze in particular if parental allergy

41 Clinical interpretation of s-ige levels ic diagnosis s/symptoms s Inhalant allergens Foods Probab bility of aller rgen-specif IgE antibody concentration (ku A /L)

42 lity of symptoms s to milk (%) Probabil Sensitisation and probability of symptoms to the same food at 4 years, N=2,614 n=195* n=111* n= (%)100 ity of symptoms s to egg 80 Milk Egg Fish Probabil ility of symptom ms to fish (%) Probab IgE ab levels (ku A /L) IgE ab levels (ku A /L) IgE ab levels (ku A /L) robability of sym mptoms to peanu ut (%) Pr Peanut n=112* IgE ab levels (ku A /L) ptoms to soy be ean (%) Pro obability of sym Soy OR=1.8 CI 95% n= 68* IgE ab levels (ku A /L) robability of sym mptoms to whea at (%) Pr Wheat n= IgE ab levels (ku A /L) Östblom E, Allergy 2008

43 Proportion of children who reacts to peanuts among those sensitised to peanuts only or to peanuts and birch among 8 year olds (N=2,405) 100 rtion with symptom ms to peanu ut (%) Propo Ara h 8 but also some with Ara h 2 Ara h Peanut, but also birch Peanut, but not birch Allergen spec IgE >0.35 ku/l

44 Comparison between studies of probability of symptoms to peanut in relation to increased levels of peanut specific IgE antibodies Proba ability Prospective Sampson H Retrospective Sampson H Asarnoj, BAMSE 8 yrs, peanut, not birch Asarnoj, BAMSE 8 yrs, peanut and birch

45 Sens peanut not birch Sens peanut and birch Sens birch, not peanut No sens Peanut, no birch Semi-quantitative micro array 74% 43% 8% 0% N=50 N=50 N=50 N=50 technique Ara h 1 Ara h 2 Ara h 3 Ara h 8 Bet v 1 Symptoms peanut Ara h 1 Ara h 2 Ara h 3 Ara h 8 Bet v 1 Symptoms peanut Ara h 1 Ara h 2 Ara h 3 Ara h 8 Bet v 1 Symptoms peanut Ara h 1 Ara h 2 Ara h 3 Ara h 8 Bet v 1 Symptoms peanut Ara h 2 and 1 and 3 97% report reaction If all three: 50% report lower respiratory reactions If only Ara h 8 = 15% Asarnoj A et al. Allergy 2010

46 Quantitative IgE and analysis of allergen components are useful diagnostic tool to better understand underlying allergic disease

47 Large national cohorts in Scandinavia future in birth cohort research? The Nordic countries are well suited for this kind of research because of their population-based registers on diseases, demography and social conditions, linkable at the individual level by means of the unique ID-number given to all citizens. The Danish National Birth Cohort pregnant women The Norwegian Mother and Child Cohort Study newborns LifeGene Sweden LifeGene, Sweden Pilot 2009, Aim: individuals all ages Born into a cohort recruited through women years

48 Next generation of birth cohort studies: Time window recruitment early in pregnancy or even before Better characterisation of phenotypes Better characterisation of environment to study interactions Gene environment interaction studies