Gevoeligheid maakt het verschil.

Gevoeligheid maakt het verschil.
Risico’s van milieu-blootstellingen in de bevolking
TIM NAWROT, PhD.
CENTRE FOR ENVIRONMENTAL SCIENCES, Hasselt University
Seniorenuniversiteit
Diepenbeek, 10 december 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
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
Flanders
106/3x106
Lin et al. Lancet 2007 369, 844-9
Nawrot and Nemery. Lancet 2007, 369, 1692
20
Deaths/106/y
BEL
Belgium+Lux
53,790 T
5.5 6
Yearly mean asbestos consumption 1960-1969 (kg/head/year)
0
1
2
3
4
5
Ecological Fallacy
• Failure of ecological level associations to properly
reflect individual level associations
• e.g. hats and lung cancer
Analytical Epidemiology
Unit of observation = individual
COHORT STUDY & CASE-CONTROL
STUDY
Cohort Study Design
D
Exposed
ND
Population
Participants
without
disease of
interest
D
Not
exposed
ND
Time
Case-Control Study
Study group
with disease
Exposed
Ratio diseased
Not
exposed
O.R.
Study group
without
disease
Exposed
Ratio not-diseased
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?
“FIJN STOF”: verzamelnaam voor zeer kleine stofdeeltjes in de
lucht, kleiner dan één honderdste van een millimeter.
Uit: EPA, US Environment Protection Agency
Brook R D et al. Circulation 2010;121:2331-2378
Daily mortality according to temperature
specific* PM10 quartiles
170
<7°C
7-10°C
10-14°C
14-17°C
>17.0°C
Mean number
of deaths / day
160
150
140
130
0
20
40
60
80
PM10 (µg/m3)
*temperature categories based on quintiles.
Non-traumatic deaths (n = 354 357)
Nawrot, Torfs, Fierens et al. J Epidemiol Comm Health 2007, 61, 146-9
Chronic vs acute effects and
Severity
Event
Age
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
Sun Q. et al. JAMA 2005.
r=0.28
p=0.01
200
150
150
Oxidized LDL, U/L
Oxidized LDL, U/L
r=-0.20
p=0.08
200
100
50
100
50
0
0
0.0
0.5
1.0
Carbon load, µm²
1.5
1
10
100
1000
10000
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
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
Severity
Event
Age
Case-crossover desing as trigger
 Case only designs
Usual frequency of exposure
during past
reference
interval
time
Maclure Am J Epidemiol 1991
comparison
Exposure in hazard
period immediately
before acute event
index
interval
index
event
Community vs.
Individual
thinking
Baccarelli A et al. Lancet 2011
Nawrot T et al. Lancet 2011
Nawrot T et al. Lancet 2011
Agonist
Collagen
Platelets
Bloodvessel
Jacobs L et al. Environ Health Perspect 2011
PFA cartridge
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)
-0.62 (-1.13; -0.11) a
-0.67 (-1.22; -0.13) a
-0.75 (-1.31; -0.18) a
-0.93 (-1.42; -0.45)c
-0.88 (-1.27; -0.48)c
-0.60 (-1.18; -0.02)a
-0.25 (-0.68; 0.17)
-0.30 (-0.75; 0.16)
-0.32 (-0.79; 0.15)
-0.50 (-0.92; -0.08)a
-0.54 (-0.89; -0.18)b
-0.40 (-0.95; 0.15)
0.24 (-0.57; 1.05)
0.38 (-0.49; 1.26)
0.52 (-0.47; 1.51)
-1.84 (-3.18; -0.51)
-1.77 (-2.57; -0.97)c
-0.21 (-1.13; 0.71)
0.15 (-0.54; 0.84)
0.20 (-0.55; 0.96)
0.29 (-0.58; 1.16)
-1.08 (-2.21; 0.04)
-1.18 (-1.19; -0.47)b
-0.33 (-1.24; 0.57)
PM10 (per 10 µg/m³
increase)
2 hours
4 hours
6 hours
24 hours
1 day
2 days
BC (per 1 µg/m³ increase)
2 hours
4 hours
6 hours
24 hours
1 day
2 days
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
Gevoeligheid in de bevolking
VOORBEELDEN VAN ONDERLIGGENDE
AANDOENINGEN
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
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)
Red line represents those living within 171 m (lowest tertile) of a major road
Nawrot T, De Vos R et al. Thorax 2011
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
.
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
The early ‘Barker ‘studies
Dark areas
high infant mortality
rate (1901-1910)
and high death
rate from
coronary artery
disease (1959-78)
Evidence of Programming in Human Populations
Hertfordshire population
172
170
168
SBP
166
(mm Hg)
164
162
160
158
-5,5
-6,5
-7,5
Birthweight
-8,5
8.5+
Low Birthweight/Disproportionate size at Birth associated
with:
 Coronary artery disease Raised cholesterol
 Raised cortisol
 Hypertension
 Glucose intolerance  Raised fibrinogen
 Asthma in childhood
 Immune dysfunction
Chronic renal failure
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=PLP1fwOF25btswCjADmXq6ZMZpQYDJVWP
&index=2
Heijmans B et al. PNAS 2008
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 (PM2.5) during pregnancy could
influence DNA methylation patterns of the placenta.
Janssen B, Godderis L, et al. Submitted
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
man
vrouw
<60
<60
relatieve impact na invoering
-10,80%
-34,80%
man
vrouw
>60
>60
-8,20%
-7,80%
Aantal
overlijdens door
sterfte aan AMI AMI vermeden
in 2005
in 2006
362
39
89
31
1970
1572
162
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
Legislation 2006
Model
Step change
Slope change
Legislation 2007
Step change
Legislation 2010
Slope change
Step change
Slope change
Spontaneous preterm delivery
2006
-3.24%
-1.85%
n/a
n/a
-3.69%
-2.16%
n/a
n/a
n/a
n/a
-3.36%
-5.17%
(-4.40; -2.07)** (-2.42; -1.28)**
2007
n/a
n/a
(-4.81; -2.55)** (-2.85; -1.46)**
2010
n/a
n/a
n/a
n/a
(-4.73; -1.98)** (-7.36; -2.94)**
Final
-
-
-3.13%
(-4.37; -1.87)**
-
-
-2.65%
(-5.11; -0.13)**
n=606 877
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).
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
Pueblo
El Paso
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.
 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
Recruteren van pasgeborenen
Placenta
Moeder
Navelstreng
bloed
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.