Gevoeligheid maakt het verschil. Risico s van milieu-blootstellingen in de bevolking

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1 Gevoeligheid maakt het verschil. Risico s van milieu-blootstellingen in de bevolking T I M N A W R O T, P h D. C E N T R E F O R E N V I R O N M E N T A L S C I E N C E S, H a s s e l t U n i v e r s i t y S e n i o r e n u n i v e r s i t e i t D i e p e n b e e k, 1 0 d e c e m b e r

2 Wat gaan we doen? De geschiedenis van de epidemiologie Study designs Gevoeligheid in de bevolking: acute vs chronische effecten, onderliggende aandoeningen Impact van het rookverbod in een gevoelige groep Een groot Limburgs geboortecohort

3 What is Epidemiology? Greek: EPI: upon DEMOS: people LOGOS: study The study of how disease is distributed in populations and the factors that influence or determine this distribution.

4 Dag allemaal, Epidemiologen leggen associaties dat doe ik ook heel de dag.

5 Waarom data bij mensen? Extrapolation from animals to humans risk estimates? differ by 100. Range of exposure of interest Complexity of exposure Epidemiological data include the genetic diversity inherent in human populations

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7 Molecular epidemiology Approach to incorporate molecular, cellular, and other biological measurements into epidemiologic research.

8 Geschiedenis van de epidemiologie: eerste klinische studie in 1747 Earliest clinical trial in 1747 Scurvy James Lind treated 12 scorbutic ship passengers on a British navy ship with cider, vinegar, sea water, oranges and lemon

9 Geschiedenis (2), 1854 John Snow 1854, when John Snow demonstrated the transmission of cholera from contaminated water The majority of people who got ill used the Broad Street Pump in London's Golden Square He removed the pump handle from the polluted well and the spread of the disease stopped.

10 John Snow

11 Broad street pump

12 Geschiedenis (3) Roken en longkanker 1954

13 ichard Doll ( ), who stopped smoking cigarettes at age 37, photographed aged 91 at the 2004 BMJ press conference on the 50-year results from his study of British doctors

14 DOLL R, HILL AB. The mortality of doctors in relation to their smoking habits; a preliminary report. Br Med J. 1954;1:

15 Mortality and smoking, first prospective evidence* *Doll R et al. BMJ 1954; 26:

16 Survival curve of male British doctors* *Doll R et al. BMJ 2004; 328:1519

17 What is the health benefit of quitting smoking at age 60? *Doll R et al. BMJ 2004; 328:1519

18 Epidemiologie en het mechanistisch denken Epidemiology contributes to a causal understanding which is needed in prevention and treatment of disease or in the assessment of risks. Epidemiology can indicate causality even in the absence of a mechanistic understanding. Treatment of scurvy far ahead of the knowledge of vitamin C (1747) Association between dirty water and cholera, 44 years before Vibrio cholera was identified (1854) Lung cancer and smoking (~1954)

19 Epidemiological Study Designs Unit of observation = group Ecological study: statistics within geographical area Community intervention trial Unit of observation = individual Experimental study Observational study Cohort study Case-control study Cross-sectional study

20 Deaths/10 6 /y Yearly Mean Mesothelioma Deaths Flanders 106/3x10 6 Lin et al. Lancet , Nawrot and Nemery. Lancet 2007, 369, BEL Belgium+Lux 53,790 T Yearly mean asbestos consumption (kg/head/year)

21 Ecological Fallacy Failure of ecological level associations to properly reflect individual level associations e.g. hats and lung cancer

22 Analytical Epidemiology Unit of observation = individual COHORT STUDY & CASE-CONTROL STUDY

23 Cohort Study Design D Exposed Population Participants without disease of interest Not exposed ND D ND Time

24 Case-Control Study Study group with disease Exposed Ratio diseased Not exposed O.R. Study group without disease Exposed Not exposed Ratio not-diseased

26 Hoe klein is fijn stof? FIJN STOF : verzamelnaam voor zeer kleine stofdeeltjes in de lucht, kleiner dan één honderdste van een millimeter. Uit: EPA, US Environment Protection Agency

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28 Brook R D et al. Circulation 2010;121:

29 Daily mortality according to temperature specific* PM10 quartiles Mean number of deaths / day <7 C 7-10 C C C >17.0 C PM 10 (µg/m 3 ) *temperature categories based on quintiles. Non-traumatic deaths (n = ) Nawrot, Torfs, Fierens et al. J Epidemiol Comm Health 2007, 61, 146-9

30 Severity Chronic vs acute effects and Event Age

31 Brook R D et al. Circulation 2010;121:

32 Cardiovascular death and PM exposure US ( ): 6 years, post-menopausal women free from CV disease Each increase of 10 ug/m³ PM 2,5 : 76% higher risk for death from CVD Miller et al. N Engl J Med. 2007

33 Oxidized LDL, U/L Oxidized LDL, U/L Atherosclerosis and particulate exposure Sun Q. et al. JAMA r=0.28 p= r=-0.20 p= Carbon load, µm² Distance to major road, m (Log scale) Analysis adjusted for sex, age, socioeconomic status, LDL and HDL cholesterol, BMI, type of diabetes, glycated haemoglobin, statin use and blood leukocyte counts. Jacobs L. et al. Plos One 2011

34 Prospective study, 3 year folluw-up of 329 men Outcome: Change in carotid intima-media thickness (CIMT) Plaque status (number and size of plaques)

35 Severity Chronic vs acute effects and Event Age

36 Case-crossover desing as trigger Case only designs Usual frequency of exposure during past comparison Exposure in hazard period immediately before acute event Maclure Am J Epidemiol 1991 reference interval time index interval index event

37 Community vs. Individual thinking Baccarelli A et al. Lancet 2011

38 Nawrot T et al. Lancet 2011

39 Nawrot T et al. Lancet 2011

40 Agonist Collagen Platelets Bloodvessel PFA cartridge Jacobs L et al. Environ Health Perspect 2011

41 Jacobs L et al. Environ Res 2012

42 Microvascular responses to short-term changes in particulate air pollution in healthy persons CRAE, µm Exposure Time (lags) Model 1 (n=84) Model 2 (n=59) PM 10 (per 10 µg/m³ increase) 2 hours (-1.13; -0.11) a (-0.68; 0.17) 4 hours (-1.22; -0.13) a (-0.75; 0.16) 6 hours (-1.31; -0.18) a (-0.79; 0.15) 24 hours (-1.42; -0.45) c (-0.92; -0.08) a 1 day (-1.27; -0.48) c (-0.89; -0.18) b 2 days (-1.18; -0.02) a (-0.95; 0.15) BC (per 1 µg/m³ increase) 2 hours 0.24 (-0.57; 1.05) 0.15 (-0.54; 0.84) 4 hours 0.38 (-0.49; 1.26) 0.20 (-0.55; 0.96) 6 hours 0.52 (-0.47; 1.51) 0.29 (-0.58; 1.16) 24 hours (-3.18; -0.51) (-2.21; 0.04) 1 day (-2.57; -0.97) c (-1.19; -0.47) b 2 days (-1.13; 0.71) (-1.24; 0.57) In model 1, estimates were adjusted for: gender, age, BMI, smoking habits of study participants, alcohol and coffee consumption 24 hours prior to examination, time of the day and day of the week, outdoor temperature and barometric pressure. Model 2 also includes, in addition to covariates in model 1, adjustment for systolic and diastolic blood pressure and central retinal venular equivalent. Louwies T, Int Panis L et al. submitted

43 Gevoeligheid in de bevolking V O O R B E E L D E N V A N O N D E R L I G G E N D E A A N D O E N I N G E N

44 Patient groups (1): cystic fibrosis 215 CF patients A pulmonary exacerbation = use of intravenous / oral antibiotics at home or in hospital. [Bilton D et al. Journal of Cystic Fibrosis 2011;10: S79 S81] Goeminne P, Kicinski M et al. Chest in press

45 Patientgroup (2): lung transplant patients Aim: Association between proximity of the home to major roads and incidence of chronic rejection and mortality in a cohort of lung transplants. Methods Follow-up (median 2.7 y) of 288 lung transplant patients. Geocoding. Cox regression

46 Incidence of BOS and % survival in association with residential distance to a major road (1) Red line represents those living within 171 m (lowest tertile) of a major road Nawrot T, De Vos R et al. Thorax 2011

47 Incidence of BOS and % survival in association with residential distance to a major road (1) Adjustements applied for sex, age, type of transpalntation (single or double lung), infections, acute rejections, SES, time trend. Nawrot T, De Vos R et al. Thorax 2011

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49 Air pollution and infant mortality in an affluent society: a case crossover design Scheers H et al. Environ Health Perspect 2011

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51 The Barker Hypothesis Or :- Fetal origins of adult disease hypothesis Fetal programming hypothesis Adverse environments in fetal life and early childhood establish increased risk of disease in adult life

52 The early Barker studies Dark areas high infant mortality rate ( ) and high death rate from coronary artery disease ( )

53 Evidence of Programming in Human Populations Hertfordshire population SBP (mm Hg) ,5-6,5-7,5-8, Birthweight

54 Low Birthweight/Disproportionate size at Birth associated with: Coronary artery disease Raised cholesterol Hypertension Raised cortisol Glucose intolerance Raised fibrinogen Asthma in childhood Immune dysfunction Chronic renal failure

55 Epigenetica, de orkestleider van het DNA genotype fenotype

56 Epigenetica, de orkestleider van het DNA genotype fenotype

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58 Nederlandse hongerwinter VZCjo&list=PLP- 1fwOF25btswCjADmXq6ZMZpQYDJVWP &index=2

59 Heijmans B et al. PNAS 2008

60 Early life exposures (1) BACKGROUND: There is evidence that altered DNA methylation is an important epigenetic mechanism in prenatal programming and that developmental periods are sensitive to environmental stressors. OBJECTIVE: We hypothesized that exposure to fine particles (PM 2.5 ) during pregnancy could influence DNA methylation patterns of the placenta. Janssen B, Godderis L, et al. Submitted

61 Janssen B et al. Environ Health Perspect 2012 Early life exposures (2)

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64 Crystal E, et. al. Circulation 2012

65 Rookverbod en myocardinfarct Tabel: Vermeden sterfte door acuut myocardinfarct (AMI) in 2006 relatieve impact na invoering sterfte aan AMI in 2005 Aantal overlijdens door AMI vermeden in 2006 man <60-10,80% vrouw <60-34,80% man >60-8,20% vrouw >60-7,80%

66 Triggers of preterm birth

67 Crump C et al. JAMA 2011

68 Triggers identified for preterm birth Cox B, et. al. submitted

69 Rate of preterm births and smoke free legislation n= Cox B, et. al. BMJ in press

70 Methods The immediate effect of smoke-free legislation was modelled as a step function (step change), while the gradual effects were studied with an interaction term between the indicator variable and time (trend or slope change). The models allowed for an underlying trend throughout the study period and were adjusted for infant sex, maternal age, parity, socio-economic status [municipality level / individual level (in sensitivity analysis)], national origin, level of urbanization of maternal residence, month of the year, day of the week, public holidays, apparent temperature, and PM 10. Both for apparent temperature and for PM 10 we calculated the average exposure on the day of delivery and the day before, and we allowed for non-linear associations with preterm birth by using natural cubic splines.

71 Preterm birth and stepwise introduction of smoking ban Model Spontaneous preterm delivery 2006 Legislation 2006 Legislation 2007 Legislation 2010 Step change Slope change Step change Slope change Step change Slope change -3.24% -1.85% (-4.40; -2.07)** (-2.42; -1.28)** 2007 n/a n/a n/a n/a n/a n/a -3.69% -2.16% (-4.81; -2.55)** (-2.85; -1.46)** 2010 n/a n/a n/a n/a Final - - n= n/a n/a -3.36% -5.17% (-4.73; -1.98)** (-7.36; -2.94)** -3.13% % (-4.37; -1.87)** (-5.11; -0.13)** Adjusted for underlying trend, newborn sex, maternal age, parity, socio-economic status, urbanization, month of the year, day of the week, public holidays, and short-term changes in apparent temperature and particulate air pollution (PM 10 ). To put the relative changes in perspective, these changes correspond to a reduction of 6 preterm births per 1000 deliveries over the 5 study years (after 2007). Cox B, et. al. BMJ in press

72 Mackay DF, et. al. PlosMed % (95% CI: 17.2 to 5.1) p = 0.001

73 Pueblo El Paso Page RL, et. al. J of womens s Health. 2012

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75 Wat gaan wij nog doen Een gezondheidsstudie bij honderden Limburgse kinderen die we opvolgen van bij de geboorte tot jongvolwassenen.

76 Human Life: John Wallis, To study chronic disease risk, traditionally recruited middle-aged subjects. Inter generational study design: including exposure early in life and during critical life stages. Risk: Exposures, inflammation, oxidative stress, disease suscpetibility, behavioral and socioeconomic determinants, : DURING ALL STAGES OF LIFE

77 Recruteren van pasgeborenen Placenta Moeder Navelstreng bloed

78 Placenta biopsies

79 Meten van Biomerkers in Bloed en Weefsel Telomeren Mitochondrial DNA inhoud als een potentiële biomerker van mitochondriale dysfunctie DNA methylatie: Veranderingen aan DNA die de expressie van genen beïnvloeden

80 Gezondheidsstudie bij jonge kinderen Bloeddruk

81 Gezondheidsstudie bij jonge kinderen Halsslagader

82 Gezondheidsstudie bij jonge kinderen Microvasculatuur

83 Gezondheidsstudie bij jonge kinderen Speeksel

84 Gezondheidsstudie bij jonge kinderen Lengte Gewicht Buikomtrek

85 Wat onthouden we Risico s moeten we niet alleen interpreteren op het individueel niveau maar ook op het niveau van de bevolking. De effecten van luchtvervuiling zijn veel sterker bij mensen met onderliggende aandoeningen. Met meer en meer zekerheid kunnen we stellen dat vroeg in het leven een kritische periode is voor het ontwikkelen van ziekten later in het leven. Het rookverbod heeft gunstige effecten vroeg in het leven.