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Life Course Approach to Disease Causation
울산의대 예방의학교실 강 영 호
질문 : 역학 연구의 성과는 있는가?
기존의 역학 연구 결과들은 질병 발생을 잘 예측하는가?
기존 역학 연구 결과를 이용한 intervention은 효과를
거두었는가?
Screening and Predictability
Review of RCT of Multiple Risk Factor Intervention
0.98 (0.90-1.06)0.99 (0.94-1.04)All study without 6, 7 study
0.96 (0.89-1.04)0.97 (0.92-1.02)All study
1.33 (0.73-2.46)1.22 (0.86-1.74)48307/2783Oxcheck study9
1.89 (0.20-21.0)1.89 (0.20-21.0)1.5339/320Cost effectiveness of lipid lowering study
8
0.37 (0.16-0.88)0.39 (0.18-0.84)5350/50Johns Hopkins hypertension study
7
0.88 (0.69-1.11)0.82 (0.71-0.95)55485/5455Hypertension detection and follow up programme
6
4.01 (0.45-35.95)2.36 (0.90-6.17)5612/610Finnish businessmen study5
0.93 (0.72-1.20)1.02 (0.86-1.22)76428/6438Multiple risk factor intervention trial
4
0.44 (0.17-1.15)0.69 (0.36-1.32)5604/629Oslo study3
1.00 (0.89-1.12)0.98 (0.91-1.05)11.810 004/20 018Gotheburg study2
0.95 (0.83-1.09)0.99 (0.91-1.07)630 489/26 971WHO factory study1
CHD mortality (OR, 95% CI)
All-cause mortality (OR, 95% CI)
Duration of follow
up
No. of participation
Study
기존의 역학 연구로부터의 교훈
• 성인기의 생활양식이나 전통적인 위험요인으로는 서구 사회의
주된 질병인 coronary heart disease의 발생과 이로 인한
사망을 잘 설명하지 못한다.
• 운동, 체중 조절, 금연, 식생활 개선 등 성인을 대상으로 한
lifestyle intervention으로는 주요 질병(예 : coronary
heart disease)의 발생을 막는 효과가 없거나 매우 미미한
효과만이 기대된다.
질병의 인과론에 대한 현재의 의학 지식
• 대부분 우리가 알고 있는 의학(특히, 역학) 지식은 개인 수준에서
이뤄진 단면연구 또는 비교적 짧은 시간 동안 추적, 관찰한 코호트
연구들에 기반하고 있다.
• 특히 많은 수의 연구들은 성인기(주로 남성에서) 이후의 폭로와
건강현상 간의 관련성을 탐구하고 있다.
• 대부분의 의학연구에서는, 널리 알려져 있는 다원인 모형, 즉,
web of causation 에 따라 질병현상을 이해하고 있다.
“Web of Causation”
Adult Disease
Risk Factor Risk Factor
Risk Factor
Risk Factor
Risk FactorRisk FactorRisk Factor
Risk Factor Risk Factor
Risk Factor
Risk Factor
Risk FactorMcMahon (1960)
그런데,
• 보편적 질병 원인 모형으로서의 “web of causation”모형은 명시적으로 시간 개념을 포함하고 있지는 않다.
• 하지만, 수많은 건강/질병 현상들은 ‘자연사’(natural history)를 갖고 있으며, 폭로와 질병 발생간에 time lag를 두고 있다.
• 생애적 접근법은 질병 원인에 있어서 시간 개념(“과거의폭로가 미래의 건강에 영향을 미친다”)을 강조한 것이다.
정말로, 어릴 적의 폭로에 초점을 맞추는 것이
타당할까?
이를 입증할 간단한 관찰 결과가 어디 없을까?
한국전쟁과 베트남전쟁에서 사망한 미국 병사들의
관상동맥은?
?
Davey Smith, Ben-Shlomo, Lynch (2002)
들어보셨나요?
Barker’s Hypothesis
Fetal Origin Hypothesis
Fetal Programming
Barker Hypothesis in BMJ Collections
왜 태아기가 성인기의 건강을 결정한다고
생각하게 되었을까?
SMRs for CHD in England and Wales among Men aged 35-74 years during 1968-78
Barker(1998)
Infant Mortality Rates per 1000 Births in England and Wales during 1901-10
Barker(1998)
r=0.73SMRs for CHD in
Women in 1968-78 at
Ages 35-74 and Infant
Mortality per 1,000
Birth in 1921-25 in the
212 Areas of England and Wales
Barker & Osmond,Lancet (1986)
r=0.69SMRs for CHD in Men
in 1968-78 at Ages 35-
74 and Infant Mortality
per 1,000 Birth in
1921-25 in the 212
Areas of England and Wales
Barker & Osmond,Lancet (1986)
Programming, 즉, 성장과정의 critical point에서의
어떤 문제가 성인기의 건강에 결정적인 영향을 준다는
가설이 biologically plausible한가?
Animal Model 로부터의 Clue
• 신체의 sweet gland의 분화– 모든 사람은 동일한 sweet gland를 갖고 태어나지만, 첫 3년 동안의 외부 기온에따라 해당 기관의 기능이 결정된다.(Diamond, 1991)
• 쥐에서의 성호르몬 효과– 생후 5일째 testosterone propionate 를 맞은 암컷 쥐는 성장기까지는 아무런일이 없다가 배란기가 되었을 때 호르몬 분비에 이상이 나타난다.(Sonawane, 1988)
• 북미 악어와 온도– 북미 악어 알은 섭씨 30도에서 부화하였을 때는 암컷이 되지만 33도에서부화하였을 때는 수컷이 된다.(Deeming & Furguson, 1992)
• 쥐와 undernutrition (Widdowson & McCance, 1963)
Barker(1998)
Rat and Undernutrition
생후 3-6 주에 undernourished 생후 9-12 주에 undernourished
Barker,BMJ (1995)
Evidences for Barker’s Hypothesis
RR (95% CI) for Non-fatal Cardiovascular Disease (CHD and Stroke) by Birth Weight in the American Nurses Study
Rich-Edwards et al,BMJ (1997)
Adjusted for BMI, cigarette smoking, reported HT, reported cholesterol, parental history of MI under 60, diabetes, menopausal status, and use of postmenopausal hormones
SMRs among Men Born in Sheffield according to Birthweight and Head Circumference
Martyn et al,Lancet (1996)
Birthweight, BMI in Middle Age, and CHD Incidence in Caerphilly, South Wales
Frankel et al, Lancet (1996)
Odds Ratio for Breast Cancer by Birthweight in the USA Nurses Study
Ekbom, et al.Lancet (1992)
A Korean Study: Birthweight, Insulin Sensitivity, and Blood Pressure
Choi et al, Diabetes Res Clin Pract (2000)
태아기 발달 상의 문제를 나타내는 여러 가지
지표(birthweight, ponderal index, head circumference, etc)와 관련성을 보이는 질환들:
• CHD• Stroke• Diabetes - insulin action• Blood Pressure• Lung Function• Obesity• CHD risk factors - HDL, fibrinogen etc• Schizophrenia
Fetal Origin Hypothesis in the Viewpoint
of Life-course Approach
Lifecourse Approach vs. Fetal Origin Hypothesis
• Barker의 가설이나 생애적 접근법은 모두, 질병 원인에 있어서 시간
개념(“과거의 폭로가 미래의 건강에 영향을 미친다”)을 강조한다.
• 대체로 생애적 접근법의 연구자들은 fetal origin hypothesis도 생애적
접근법의 한 형태라고 생각한다.
• 다만, fetal origin hypothesis에서 설정하고 있는 critical period의결정력에 대해서는 비판적인 입장을 갖고 있다.
• 그러나, fetal origin hypothesis가 생애적 접근법의 중요성을 부각시키는
데에 공헌한 것은 분명한 사실이다.
생애에 걸친위험 요인의 폭로
In-utero
Childhood
Adolescence
Adulthood
Older Age
Fetal nutrition, Infection, Pre-natal Care
Breast Feeding, Child Diet, Safety
Physical Activity
Substance Abuse, Violence
Social Relationships
Work Environments
생애에 걸친 위험요인의 폭로 수준 변화와 건강 영향
Childhood Adolescence Adulthood Old Age
HI
LO
RiskExposure
HealthStatus
HI
LO
RiskExposure
HI
LO
RiskExposure
그러면, 이러한 어릴 적의 폭로가 성인기 건강에 어떻게 영향을 줄 것인가?
1. 어릴 적 폭로가 성인기 이후의 건강에
독립적 영향(independent effects)이 있는가?
2. 어릴 적의 폭로가 성인기의 폭로와 함께
누적적인 효과(cumulative effects)가 있는가?
3. 어릴 적의 폭로와 성인기의 폭로가 교호 효과 또는,상승 효과(interactive or synergistic effects)가 있는가?
0.5
0.7
0.9
1.1
1.3
1.5
1.7
1.9
2.1
2.3
CHD Stroke LungCancer
StomachCancer
OtherCancer
Respiratory External
Mortality of Men with Father’s Manual Social Class
Davey Smith et al. BMJ (1998)
Age + Adult SC, Car, Deprivation + Risk Factors
RH
Infant mortality 1921-23 against stomach cancer mortality 1991-93for men aged 65-74 in 27 countries
0 50 100 150 200 2500
50
100
150
200
250
CANADA
CHILE
USA
JAPAN
AUSTRIA
BELGIUM
BULGARIACZECHOSL
DEN
FINLAND
FRAGREECE
HUNGARY
IRELANDITALY
NETHLANDSNORWAY
POLANDPORTUGAL
ROMANIA
RUSSIA
SPAIN
SWESWITZ
UK
AUSTRALIANZ
Stom
ach
canc
er m
orta
lity
rate
per
100
K, 1
991-
93
Infant mortality rate per 1000, 1921-23 Leon & DaveySmith, BMJ (2000)
Stomach cancer Hemorrhagic stroke
Helicobacter Pylori Salt
Physical Functioning in 1994
1
1.5
2
2.5
3
3.5
4IADL ADL Nagi scale
1 2 3 1 2 3 1 2 3Number of Times Income less than 200% Poverty 1965-1983
Lynch, et al. NEJM (1997)
OR
Psychological Functioning in 1994
1
2
3
4
5
6OR
1 2 3 1 2 3 1 2 3 1 2 3
DSM-III DepressiveSymptoms
Cynicism Lack ofOptimism
Number of Times Income less than 200% Poverty 1965-1983Lynch, et al. NEJM (1997)
Cognitive and Social Functioning in 1994
1
2
3
4
5OR
CognitiveFunction
Social Isolation
1 2 3 1 2 3 Number of Times Income less than 200% Poverty 1965-1983
Lynch, et al. NEJM (1997)
Serial Changes in Childhood BMI to Impaired Glucose Tolerance in Young Adulthood
Bhargava et al, NEJM (2004)
Life Course Effect를 어떻게 연구할 것인가?
Life Course Approach를 정리하면,
Latent ApproachesTS+1
1. “Sensitive Period”TS
E D
TC+1
2. “Critical Period”TC
E
e.g., fetal origins
D
두 모형 모두, 특정 시기에서의 폭로가 필요
Latent Approaches
e.g., unprotected sex
3. “Unspecified Effect”
TE1
E
TE2
E
TE0
E
TE+1
D
폭로 여부와 폭로시기에는 관련성이 없음.
Accumulation Approaches
e.g., social pathways + respiratory infection1. “Pathways”“Chains of risk” TDT1
E1 E2
T2
E3
T3
E4
T4
D
각각의 폭로들이 연계되어 질병을 발생시킴.
Accumulation Approaches
e.g., smoking duration
2. Dose-Response TDT1
E1 E1
T2
E1
T3
E1
T4
D
폭로의 시기와는 독립적으로 폭로의 기간이 문제
Accumulation Approaches
e.g., child poverty + parental divorce + child abuse = “ecological niche”
3. “Clustering” T1 T2 TDT3
E1
E2
E3
E6
E2
E7
E1
E4
E5
D
특정한 하나의 시기에 특정 폭로들의 조합이 질병 발생과 연관
Accumulation Approaches
4. “Uncorrelated” T1 T2 T3 TD
E1
E4
E5
E6
E2
E7
E1
E2
E3
D
E1 + E4 + E7 = D
서로 다른 시기에 발생한 특정 폭로들의 조합이 질병 발생과 연관
Interaction Approachese.g., LBW + BMI
Poor childhood + education
“Interaction”T1
E1 E2
T2 TD
DE1
Lo E2
Hi E2
Poor adult socioeconomic position
Poor childhood Poor education
Air pollutionPassive smoking
Poor diet
Rapid decline in lung function
and onset of adult respiratory disease
Kuh and Ben-Shlomo (1997)
Air pollutionsmoking
Poor adult diet
Occupational hazards
Infant respiratory infections
Poor growth Poor lung in- utero development
Childhood respiratory
illness
Genetic predisposition
Lifecourse Effect를 보기 위한 자료는 있는가?
The Logic for a Conception-to-Death Cohort StudyWhen do disease begin? How do genes and environment interact over
the life course to influence the occurrence of disease? How do
diseases, and the etiologic processes underlying them, affect one
another? How do we study these questions when the causal period is
approaching that of the human life span itself? Reviewing these
questions, it seems curious or even paradoxical that we have not
already begun such a study. We have studied thousands of
generations of fruit flies, for example: and hundreds of generations of
rodents: but, it seems, not a single intensive study of even one
generation of humans. It could be that the prospects of our own
mortality blinds us to the value of such a study, since its conclusion would not occur in our own lifetimes.
Eaton, Ann Epidemiol. (2002)
Examples: The Danish National Birth Cohort
• The planning started in 1992 and the first grant was given to the project from the Medical Research Council in 1993.
• With collaboration with the about 3,500 GPs, women in weeks 6-12 of pregnancy is being included as study subjects.
• Blood bank, follow-up by unique ID numbers, computer-assisted telephone interviews and self-administered questionnaires.
• By August 2000, a total of 60,000 pregnant women had been recruited to the study. (aim: 100,000)
Olsen et al, Scand J Public Health (2001)
Examples: The Generation R Study in Rotterdam, the Netherlands
• Ten thousands children will be examined from early fetal life until young adulthood.
– 12, 20, 30 weeks of gestation, birth, 1-2 times/year until 20 years
• Physical examinations, questionnaires, interviews, ultrasound and biological samples (mother, mother’s partner, cord blood)
• Full participant recruitment and complete data collection started in 2002.
Hofman et al, Paediat Perinat Epidemiol (2004)
Examples: ALSPAC, The Avon Longitudinal Study of Parents and Children
• Avon county 120 miles west of London
• Approximately 10,000 children and their parents from early pregnancy until the children are aged between 8 and 9.
• Children in Focus (CiF): 10% sub-sample of children.– Validation for self-completion questionnaires
– Physical examination
– Biologic sample from mother, mother’s partner, and child
Golding et al, Paediat Perinat Epidemiol (2001)
우리 나라에서의 Lifecourse Approach
Relation btw Height and All-cause Mortality, Civil Servants Data of Korea
1.093 (1.031-1.158)1.045 (0.986-1.107)1.229 (1.161-1.301)3,285 117,203 -164
1.080 (1.018-1.146)1.039 (0.979-1.102)1.119 (1.055-1.186)2,762 120,022 165-167
1.008 (0.952-1.068)0.979 (0.925-1.036)1.017 (0.961-1.077)3,095 165,735 168-170
1.011 (0.949-1.077)0.989 (0.929-1.053)1.009 (0.947-1.074)1,959 114,671 171-173
1111,923 125,389 174-
Age, income, risk factors* adjusted
Age, income adjustedAge adjusted
Hazard ratio (95% CI)No. of deathFrom 1995-2000
No. of subjects
Quintile of height (cm)
* Risk Factor: BMI, cholesterol, blood glucose, systolic blood pressure, smoking history, alcohol intake, HBsAg
Age-adjusted rates of cause-specific mortality among 386,627 Korean men aged 40-64, 1992-1998
Song et al, Am J Epidemiol(2003)
Korean Examples: Height and Dementia
Kim et al, J Neurol Neurosurg Psychiatry (2003)
0.0
0.5
1.0
1.5
2.0
2.52
favo
rabl
e
1 fa
vora
ble
0 fa
vora
ble
2 fa
vora
ble
1 fa
vora
ble
0 fa
vora
ble
2 fa
vora
ble
1 fa
vora
ble
0 fa
vora
ble
Cumulative Socioeconomic Position and Relative Risk of Dying: Korea Labor and Income Panel Study
Rel
ativ
e ri
sks
Education Occupational status:Approach 1
**
Occupational status:Approach 2
Khang, 2004
Childhood and Adult Socioeconomic Positions and Their Effect on
Current Smoking Habits in Korea Labor and Income Panel Study (Odds ratios and their 95%CI)
1.93(0.96-3.88)
1.90(0.95-3.80)
1.18(1.01-1.39)
1.20(1.03-1.41)
Equivalizedhoushold income
0.86(0.42-1.79)
0.94(0.45-1.94)
1.24(1.05-1.47)
1.26(1.06-1.50)
Father's socioeconomic status
2914 females 25-642922 Males aged 25-64
Khang, 2004
