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.