Life Course

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1 Life Course Approach to Disease Causation

2 :?? intervention?

3 Screening and Predictability

4 Review of RCT of Multiple Risk Factor Intervention Study No. of participation Duration of follow up All-cause mortality (OR, 95% CI) CHD mortality (OR, 95% CI) 1 WHO factory study / ( ) 0.95 ( ) 2 Gotheburg study / ( ) 1.00 ( ) 3 Oslo study 604/ ( ) 0.44 ( ) 4 Multiple risk factor intervention trial 6428/ ( ) 0.93 ( ) 5 Finnish businessmen study 612/ ( ) 4.01 ( ) 6 Hypertension detection and follow up programme 5485/ ( ) 0.88 ( ) 7 Johns Hopkins hypertension study 350/ ( ) 0.37 ( ) 8 Cost effectiveness of lipid lowering study 339/ ( ) 1.89 ( ) 9 Oxcheck study 8307/ ( ) 1.33 ( ) All study 0.97 ( ) 0.96 ( ) All study without 6, 7 study 0.99 ( ) 0.98 ( )

5 coronary heart disease.,,, lifestyle intervention ( : coronary heart disease).

6 (, ),. ( ).,,, web of causation.

7 Risk Factor Web of Causation Risk Factor Risk Factor Risk Factor Risk Factor Risk Factor Adult Disease Risk Factor Risk Factor Risk Factor Risk Factor Risk Factor Risk Factor McMahon (1960)

8 , web of causation., / (natural history), time lag. ( ).

9 ,??

10 ?? Davey Smith, Ben-Shlomo, Lynch (2002)

11 ? Barker s Hypothesis Fetal Origin Hypothesis Fetal Programming

14 Barker Hypothesis in BMJ Collections

15 ?

16 SMRs for CHD in England and Wales among Men aged years during Barker (1998)

17 Infant Mortality Rates per 1000 Births in England and Wales during Barker (1998)

18 SMRs for CHD in Women in at Ages and Infant Mortality per 1,000 Birth in in the 212 Areas of England and Wales r=0.73 Barker & Osmond, Lancet (1986)

SMRs for CHD in Men in 1968-78 at Ages 35-74 and Infant Mortality per 1,000 Birth

19 SMRs for CHD in Men in at Ages and Infant Mortality per 1,000 Birth in in the 212 Areas of England and Wales r=0.69 Barker & Osmond, Lancet (1986)

20 Programming,, critical point biologically plausible?

21 Animal Model Clue sweet gland sweet gland, 3.(Diamond, 1991) 5 testosterone propionate.(sonawane, 1988) (Deeming & Furguson, 1992) undernutrition (Widdowson & McCance, 1963)

22 Rat and Undernutrition Barker (1998) 3-6 undernourished 9-12 undernourished

23 Barker, BMJ (1995)

24 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

25 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

26 SMRs among Men Born in Sheffield according to Birthweight and Head Circumference Martyn et al, Lancet (1996)

27 Frankel et al, Lancet (1996) Birthweight, BMI in Middle Age, and CHD Incidence in Caerphilly, South Wales

28 Odds Ratio for Breast Cancer by Birthweight in the USA Nurses Study Ekbom, et al. Lancet (1992)

29 A Korean Study: Birthweight, Insulin Sensitivity, and Blood Pressure Choi et al, Diabetes Res Clin Pract (2000)

30 (birthweight, ponderal index, head circumference, etc) : CHD Stroke Diabetes - insulin action Blood Pressure Lung Function Obesity CHD risk factors - HDL, fibrinogen etc Schizophrenia

31 Fetal Origin Hypothesis in the Viewpoint of Life-course Approach

32 Lifecourse Approach vs. Fetal Origin Hypothesis Barker, ( ). fetal origin hypothesis., fetal origin hypothesis critical period., fetal origin hypothesis.

33 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

34 Childhood Adolescence Adulthood Old Age HI HI HI Risk Exposure Risk Exposure Risk Exposure Health Status LO LO LO

35 ,? 1. (independent effects)? 2. (cumulative effects)? 3., (interactive or synergistic effects)?

RH 2.3 2.1 Mortality of Men with Father s Manual Social Class Age + Adult SC, Car, Deprivation + Risk Factors 1.9 1.7 1.

36 RH Mortality of Men with Father s Manual Social Class Age + Adult SC, Car, Deprivation + Risk Factors CHD Stroke Lung Cancer Stomach Cancer Other Cancer Respiratory External Davey Smith et al. BMJ (1998)

37 Infant mortality against stomach cancer mortality for men aged in 27 countries Stomach cancer mortality rate per 100K, PORTUGAL JAPAN POLAND BULGARIA CZECHOSL ITALY AUSTRIA IRELAND NETHLANDS UK SPAIN NORWAY FINLAND NZ GREECE SWE SWITZ BELGIUM FRA DEN AUSTRALIA CANADA USA RUSSIA HUNGARY ROMANIA CHILE Infant mortality rate per 1000, Leon & Davey Smith, BMJ (2000)

38 Stomach cancer Hemorrhagic stroke Helicobacter Pylori Salt

39 OR Physical Functioning in 1994 IADL ADL Nagi scale Number of Times Income less than 200% Poverty Lynch, et al. NEJM (1997)

40 OR 6 5 DSM-III Psychological Functioning in 1994 Depressive Symptoms Cynicism Lack of Optimism Number of Times Income less than 200% Poverty Lynch, et al. NEJM (1997)

41 OR 5 4 Cognitive and Social Functioning in 1994 Cognitive Function Social Isolation Number of Times Income less than 200% Poverty Lynch, et al. NEJM (1997)

42 Serial Changes in Childhood BMI to Impaired Glucose Tolerance in Young Adulthood Bhargava et al, NEJM (2004)

43 Life Course Effect? Life Course Approach,

44 Latent Approaches 1. Sensitive Period T S T S+1 E D 2. Critical Period T C e.g., fetal origins T C+1 E D

45 Latent Approaches e.g., unprotected sex 3. Unspecified Effect T E 0 T E 1 T E2 T E+1 E E E D

46 Accumulation Approaches 1. Pathways Chains of risk e.g., social pathways + respiratory infection T 1 T 2 T 3 T 4 T D E1 E2 E3 E4 D

47 Accumulation Approaches e.g., smoking duration 2. Dose-Response T 1 T 2 T 3 T 4 T D E1 E1 E1 E1 D

48 Accumulation Approaches 3. Clustering e.g., child poverty + parental divorce + child abuse = ecological niche T 1 T 2 T 3 T D E 1 E 1 E 6 E 2 E 4 E 2 D E 3 E 5 E 7

49 Accumulation Approaches 4. Uncorrelated T 1 T 2 T 3 T D E 1 E 1 E 6 E 2 E 4 E 2 D E 3 E 5 E 7 E1 + E4 + E7 = D

50 Interaction Approaches e.g., LBW + BMI Poor childhood + education Interaction T 1 T 2 T D E 1 E 2 E 1 Lo E 2 D Hi E 2

51 Poor childhood Poor education Poor adult socioeconomic position Air pollution Passive smoking Poor diet Air pollution smoking Poor adult diet Occupational hazards Infant respiratory infections Poor growth Poor lung in- utero development Childhood respiratory illness Genetic predisposition Kuh and Ben-Shlomo (1997) Rapid decline in lung function and onset of adult respiratory disease

52 Lifecourse Effect?

53 The Logic for a Conception-to-Death Cohort Study When 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)

54 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 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, computerassisted 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)

55 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 Hofman et al, Paediat Perinat Epidemiol (2004)

56 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)

57 Lifecourse Approach

58 Relation btw Height and All-cause Mortality, Civil Servants Data of Korea Quintile of height (cm) No. of subjects No. of death From Age adjusted Hazard ratio (95% CI) Age, income adjusted Age, income, risk factors* adjusted ,389 1, ,671 1, ( ) ( ) ( ) ,735 3, ( ) ( ) ( ) ,022 2, ( ) ( ) ( ) ,203 3, ( ) ( ) ( ) * Risk Factor: BMI, cholesterol, blood glucose, systolic blood pressure, smoking history, alcohol intake, HBsAg

59 Age-adjusted rates of cause-specific mortality among 386,627 Korean men aged 40-64, Song et al, Am J Epidemiol (2003)

60 Korean Examples: Height and Dementia Kim et al, J Neurol Neurosurg Psychiatry (2003)

61 2.5 Cumulative Socioeconomic Position and Relative Risk of Dying: Korea Labor and Income Panel Study Khang, Education * Occupational status: Approach 1 Occupational status: Approach Relative risks 2 favorable 1 favorable 0 favorable 2 favorable 1 favorable 0 favorable 2 favorable 1 favorable 0 favorable

62 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) 2922 Males aged females Father's socioeconomic status 1.26 ( ) 1.24 ( ) 0.94 ( ) 0.86 ( ) Equivalized houshold income ( ) ( ) ( ) ( ) Khang, 2004

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