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 0 1 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
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.
Dag allemaal,
Epidemiologen leggen associaties dat doe ik ook heel de dag.
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
“Molecular epidemiology”
Approach to incorporate molecular, cellular, and other biological measurements into epidemiologic research.
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
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.
John Snow
Broad street pump
Geschiedenis (3) Roken en longkanker 1954
Richard Doll (1912-2005), 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
DOLL R, HILL AB. The mortality of doctors in relation to their smoking habits; a preliminary report.
Br Med J. 1954;1:1451-5.
Mortality and smoking, first prospective evidence*
*Doll R et al. BMJ 1954; 26:1451-1455.
Survival curve of 34 469 male British doctors*
*Doll R et al. BMJ 2004; 328:1519
What is the health benefit of quitting smoking at age 60?
*Doll R et al. BMJ 2004; 328:1519
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)
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
Yearly Mean Mesothelioma Deaths 2000-2004
0 1 2 3 4 5 6
Death
s/1
06/y
Yearly mean asbestos consumption 1960-1969 (kg/head/year)
5.5
20 BEL
Flanders
106/3x106 Lin et al. Lancet 2007 369, 844-9
Belgium+Lux
53,790 T
Nawrot and Nemery. Lancet 2007, 369, 1692
Ecological Fallacy
• Failure of ecological level associations to properly
reflect individual level associations
• e.g. hats and lung cancer
Analytical Epidemiology
COHORT STUDY & CASE-CONTROL
STUDY
Unit of observation = individual
Cohort Study Design
Population
Participants
without
disease of
interest
Exposed
Not
exposed
D
ND
D
ND
Time
Case-Control Study
Study group
with disease
Exposed
Study group
without
disease
Exposed
Ratio diseased
Ratio not-diseased
O.R.
Not
exposed
Not
exposed
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
Hoe klein is fijn stof?
Uit: EPA, US Environment Protection Agency
“FIJN STOF”: verzamelnaam voor zeer kleine stofdeeltjes in de
lucht, kleiner dan één honderdste van een millimeter.
Brook R D et al. Circulation 2010;121:2331-2378
Daily mortality according to temperature specific* PM10 quartiles
*temperature categories based on quintiles.
Non-traumatic deaths (n = 354 357)
0 20 40 60 80
<7°C
7-10°C
10-14°C
14-17°C
>17.0°C
130
140
150
160
170
PM10 (µg/m3)
Mean
nu
mb
er
of
death
s /
day
Nawrot, Torfs, Fierens et al. J Epidemiol Comm Health 2007, 61, 146-9
Chronic vs acute effects and
Age
Severity
Event
Brook R D et al. Circulation 2010;121:2331-2378
Cardiovascular death and PM exposure
US (1994-1998): 6 years, 65.000 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
Atherosclerosis and particulate exposure
Jacobs L. et al. Plos One 2011
Sun Q. et al. JAMA 2005.
0.0 0.5 1.0 1.5
0
50
100
150
200 r=0.28
p=0.01
Carbon load, µm²
Oxid
ized
LD
L,
U/L
0
50
100
150
200 r=-0.20
p=0.08
1 10 100 1000 10000
Distance to major road, m(Log scale)
Oxid
ized
LD
L,
U/L
Analysis adjusted for sex, age, socioeconomic status, LDL and
HDL cholesterol, BMI, type of diabetes, glycated haemoglobin,
statin use and blood leukocyte counts.
Prospective study, 3 year folluw-up of 329 men
Outcome: Change in carotid intima-media thickness (CIMT)
Plaque status (number and size of plaques)
Chronic vs acute effects and
Age
Severity
Event
Case-crossover desing as trigger
Case only designs
comparison
reference
interval
index
interval
index
event
time
Usual frequency of exposure during past
Exposure in hazard period immediately before acute event
Maclure Am J Epidemiol 1991
Baccarelli A et al. Lancet 2011
Community vs. Individual thinking
Nawrot T et al. Lancet 2011
Nawrot T et al. Lancet 2011
Bloodvessel PFA cartridge
Agonist
Platelets
Collagen
Jacobs L et al. Environ Health Perspect 2011
Jacobs L et al. Environ Res 2012
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) PM10 (per 10 µg/m³
increase)
2 hours -0.62 (-1.13; -0.11) a -0.25 (-0.68; 0.17)
4 hours -0.67 (-1.22; -0.13) a -0.30 (-0.75; 0.16)
6 hours -0.75 (-1.31; -0.18) a -0.32 (-0.79; 0.15)
24 hours -0.93 (-1.42; -0.45)c -0.50 (-0.92; -0.08)a
1 day -0.88 (-1.27; -0.48)c -0.54 (-0.89; -0.18)b
2 days -0.60 (-1.18; -0.02)a -0.40 (-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 -1.84 (-3.18; -0.51) -1.08 (-2.21; 0.04)
1 day -1.77 (-2.57; -0.97)c -1.18 (-1.19; -0.47)b
2 days -0.21 (-1.13; 0.71) -0.33 (-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
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
Gevoeligheid in de bevolking
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]
Patient groups (1): cystic fibrosis
Goeminne P, Kicinski M et al. Chest in press
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
Incidence of BOS and % survival in association with residential distance to a major road (1)
Nawrot T, De Vos R et al. Thorax 2011
Red line represents those living within 171 m (lowest tertile) of a major road
Incidence of BOS and % survival in association with residential distance to a major road (1)
Nawrot T, De Vos R et al. Thorax 2011
Adjustements applied for sex, age, type of transpalntation (single or double
lung), infections, acute rejections, SES, time trend.
Air pollution and infant mortality in an affluent society: a case crossover design
Scheers H et al. Environ Health Perspect 2011
“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
Dark areas
high infant mortality
rate (1901-1910)
and high death
rate from
coronary artery
disease (1959-78)
The early ‘Barker ‘studies
Evidence of Programming in Human Populations Hertfordshire population
158
160
162
164
166
168
170
172
-5,5 -6,5 -7,5 -8,5 8.5+
Birthweight
SBP (mm Hg)
Low Birthweight/Disproportionate size at Birth associated with:
Coronary artery disease
Hypertension
Glucose intolerance
Asthma in childhood
Immune dysfunction
Chronic renal failure
Raised cholesterol
Raised cortisol
Raised fibrinogen
Epigenetica, de orkestleider van het DNA
genotype fenotype
Epigenetica, de orkestleider van het DNA
genotype fenotype
Nederlandse hongerwinter
http://www.youtube.com/watch?v=le4HYO
VZCjo&list=PLP-
1fwOF25btswCjADmXq6ZMZpQYDJVWP
&index=2
Heijmans B et al. PNAS 2008
Early life exposures (1)
Janssen B, Godderis L, et al. Submitted
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 (PM2.5) during pregnancy could influence DNA methylation patterns of the placenta.
Early life exposures (2)
Janssen B et al. Environ Health Perspect 2012
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
Crystal E, et. al. Circulation 2012
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% 362 39
vrouw <60 -34,80% 89 31
man >60 -8,20% 1970 162
vrouw >60 -7,80% 1572 123
Triggers of preterm birth
Crump C et al. JAMA 2011
Triggers identified for preterm birth
Cox B, et. al. submitted
Rate of preterm births and smoke free legislation
n=606 877
Cox B, et. al. BMJ in press
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 PM10. Both for apparent temperature and for PM10 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.
Preterm birth and stepwise introduction of smoking ban
Model Legislation 2006 Legislation 2007 Legislation 2010
Step change Slope change Step change Slope change Step change Slope change
Spontaneous preterm delivery
2006 -3.24% -1.85%
n/a n/a n/a n/a (-4.40; -2.07)** (-2.42; -1.28)**
2007 n/a n/a -3.69% -2.16%
n/a n/a (-4.81; -2.55)** (-2.85; -1.46)**
2010 n/a n/a n/a n/a -3.36% -5.17%
(-4.73; -1.98)** (-7.36; -2.94)**
Final - - -3.13%
- - -2.65%
(-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 (PM10). 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).
n=606 877
Cox B, et. al. BMJ in press
-11.0 % (95% CI: −17.2 to −5.1) p = 0.001
Mackay DF, et. al. PlosMed. 2012
El Paso
Pueblo
Page RL, et. al. J of womens’s Health. 2012
Wat gaan wij nog doen
Een gezondheidsstudie bij honderden Limburgse kinderen die we opvolgen van bij de geboorte tot jongvolwassenen.
Human Life: John Wallis, 1790.
Risk: Exposures, inflammation,
oxidative stress, disease
suscpetibility, behavioral and socio-
economic determinants,…:
DURING ALL STAGES OF LIFE
To study chronic disease risk, traditionally recruited middle-aged subjects.
Inter generational study design: including exposure early in life and during critical life stages.
Moeder
Placenta
Navelstrengbloed
Recruteren van pasgeborenen
Placenta biopsies
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
Gezondheidsstudie bij jonge kinderen
Bloeddruk
Gezondheidsstudie bij jonge kinderen
Halsslagader
Gezondheidsstudie bij jonge kinderen
Microvasculatuur
Gezondheidsstudie bij jonge kinderen
Speeksel
Gezondheidsstudie bij jonge kinderen
Lengte
Gewicht
Buikomtrek
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.