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1 From Association to Causation

2 Outline Pathogen / Risk factors Etiology / Cause of disease Koch s postulates / Hills Criteria of Causation Identify Causation Necessary and Sufficient A complex Problem

3 John Snow SOHO

4 Dr. Snow ( 1813 ~ 1858 )

5 1849 Dr. Snow

6 1848 ~ < ~ ~ ~ ~ ~ ~ Data from Farr W: Vital Statistics,1885

7 19

8 Dr. Snow Soho Dr. Snow Soho

9 ??

10 Dr. Snow Dr. Snow

11 C.F. Cheffins Map modified by Dr. John Snow Soho Snow 1852 Dr. Snow

12 Dr. Snow

13 John Snow Dr. Snow Soho Robert Koch

14 Pathology The scientific study of the nature of disease and its causes, processes, development, and consequences. Also called pathobiology Pathogenesis Pathological changes Without the basis of pathology, the practice of medicine is only quackery.

15 Cause of AIDS HIV - Bench or laboratory work - Describes the underlying biology of disease - Identifies the infectious agent Risk Factors - Epidemiology ( unsafe sex, IDU etc.) - Tests the results of bench work on human population - Provides what still not know

16 Science Photo Library

17 ??

18 Biological Psychological Social Genetic Addiction Neurological Spiritual Family

19 Etiology ( Aetilogy ) 1. The study of causes or origins. 2. The cause of a disease 3., The word "etiology" is mainly used in medicine, where it is the science that deals with the causes or origin of disease, the factors which produce or predispose toward a certain disease or disorder. 4. The philosophical study of causation ( the relationship between causes and effects ) 5. / Assignment of a cause, an origin, or a reason for something. Philosophy is a study of the reality, causes, and principles underlying being and thinking.

20 Cause Of Disease Often in medicine we are called on to make judgments as to whether an exposure causes a disease. A factor (characteristic, behavior, event, etc.) that directly influences the occurrence of disease

21 Causation in Occupational Disease Establishing cause-effect relationships between agents (or exposures) and occupational diseases has become controversial in the courts and scientific research establishment. The outcome of litigated cases often hinges on whether expert opinion evidence is admissible i.e., whether it can be heard by a jury.

22 A Public Health History of Disease Causation

23 A Public Health History of Disease Causation 19 Louis Pasteur Robert Koch Koch

26 Causality at Different Levels Molecular cause Physiological cause Personal cause Social cause, etc

28 DNA Etiology of Human Disease at the DNA Level 1. mapping of human disease traits 2. molecular characterization of genetic defects 3. investigation of multigenic disorders 4. gene replacement in humans and animals models, and 5. diagnosis and therapy of genetic disease

29 DISEASE TRIANGLE Environment DISEASE Host Pathogen

31 70 ~ 90 %

37 / /

38 Henle-Koch The Henle-Koch postulates 19 Henle Koch

39 Henle-Koch The Henle-Koch postulates

40 Henle-Koch The Henle-Koch postulates Koch 1876

41 (1882) (1883) 1905 Robert Koch Germany

42 Hill Hills Criteria of Causation 1964 Surgeon General ~ Austin Bradford Hill

43 William Richard Doll Austin Bradford Hill English 3 20

44 Hill Hills Criteria of Causation Hill

45 Hill Hills Criteria of Causation Temporal Relationship Strength Dose-Response Relationship Consistency Plausibility Consideration of Alternate Explanations Experimental evidence Specificity Coherence

46 1. Temporal Relationship A A A cause must precede an effect in time. This one is true!

47 1. Temporal Relationship

48 1. Temporal Relationship

49 1. Temporal Relationship

50 2. Strength of Association RR

51 2. Strength of Association (RR) (OR) 1.8 ~22.6 OR 12.0,

52 2. Strength of Association OR 1. OR = % CI = ( 1.2 ~ 1.7 ) 2. OR = % CI = ( 1.8 ~ 12.3 ) 3. OR = % CI = ( 5.9 ~ 8.1 )

53 2. Strength of Association %,

54 3. Dose-Response Relationship

55 3. Dose-Response Relationship

56 3. Dose-Response Relationship

57 4. Consistency

58 4. Consistency

59 4. Consistency Meta

60 5. Plausibility, ;

61 5. Plausibility

62 6. Consideration of Alternate Explanations

63 6. Consideration of Alternate Explanations

64 7. Experimental evidence

65 8. Specificity ~

66 8. Specificity

67 9. Coherence

68 9. Coherence

69 N

70 ( ) ( ppm ) ( % ) ( ppm )

71 ( ppm) H W H / W I II III ppm 0.12 ppm

74 Causation Identification?

75 Causation Identification????

76 Causation Identification

77 Causation Identification 1940s, Dr. Norman Gregg Gregg s

78 Causation Identification

79 Causal pathways

80 Causal pathways 1 2

81 Causation and the individual patient, /

82 Causation and the individual patient , 2, 4.

83 Causation and the individual patient???

84 Clinical judgment /?

85 Epidemiology judgment /?

86 Cancer Biology - -,

87 ?

88 The Etiology of Cancer

89 HLA EBV

90 Causation Identification?

91 ???

92 From Association to Causation 1. a. b. 2.

93 Causation Identification

94 Causation Identification

95 ( )

96 Ecologic studies

97 250 Switzerland USA Incidence Ratio per 100,000 Women Romania Japan Italy Israel Australia Yugoslavia Hong Kong Canada Sweden Spain Poland UK Finland Hungary France New Zealand Norway Fed. Repub. Of Germany Denmark Prentice RL, Kakar F, Hursting S, et al: Aspects of the rationale for the Women s Health Trial. J Natl Cancer Inst 80: , 1988.) Per Capita Supply of Fat Calories

98 Ecologic studies Prentice et al. J Natl Cancer Institute :

99 The ecologic fallacy

100 Ecologic studies?

101 Case-control and cohort studies

102 AIDS ( MACS ) The Multicenter AIDS Cohort Study (MACS) MACS HIV (NIAID), (,,, )

103 AIDS ( MACS ) The Multicenter AIDS Cohort Study (MACS) MACS HIV HIV HIV HIV HIV HIV CD4

104 Two step process to carry out studies and evaluate evidence 1. 2.

105 Alton Ochsner

106 Case-control and cohort studies

107 Two Types of association: Real and Spurious

108 From Association to Causation

109

110 1981 MacMahon MacMahon B, et al. N Engl J Med :630-33

111 - - -

112

113 A. B.

114

115 1 2

116

117 DeltaF508

118 2 Components of Causation Sufficient factor - - Necessary factor - -

119 Sufficient

120 Necessary ( )

121 Four types of causal relationships Necessary and sufficient Necessary but not sufficient Sufficient but not necessary Neither sufficient nor necessary

122 Necessary and sufficient HIV AIDS?

123 Necessary and sufficient A A

124 Necessary but not sufficient A + + B C

125 Necessary but not sufficient + +

126 Sufficient but not necessary A B C

127 Sufficient but not necessary?

128 Neither sufficient nor necessary A + B / C + D / E + F ~

129 Neither sufficient nor necessary + / + / / +

130 ~ Concept of Necessary vs. Sufficient Causes?

131 Mortality Rate per 100,000 Person- Years Adapted from Hammond EC, Horn D: JAMA 166: , 1958.) Never Smoked <1/2 Pack/Day 1/2-1 Pack/Day 1-2 Packs/Days 2+ Packs/Day

132 I II-1 II-2 II-3 III

133

134 / (Alzheimer s Disease )

135

136

137 ?

138 ? 5 OR

139 OR 3.2 ( 95 % CI : 1.1 ~ 8.2 )???

140 ( 95 % CI : P < 0.05 ) OR 2.3??

141 Probabilistic causality

142 Probabilistic causality

143 Probabilistic causality?

144 Probabilistic causality

145 Li Li ABS Li Li / Li Yan Yan Yan Yan Li Yan

146 2 18

147 Henle-Koch The Henle-Koch postulates

148 3 27

149 SCIENCE VOL JULY 2003

150 SARS 2003 ~ N 2003 SARS SARS ( )

151

152 SARS Co-v SARS Co-V??? /??????? ?! SARS

153 ? X X?? ZOONOSE???

154 Zoonosis Animal Human behavior Environment Intensive farming Virus Ecology

155 SARS SARS SARS Co-V? SARS Co-V? SARS Co-V??? SARS Co-V? SARS Co-V?????

156 Thanks Special thanks to my colleague Dr.

病因及其推断

病因及其推断 (Causes of Disease) ( ) ( ) ( ) 19 19 (Koch ) ) Koch Postulates Robert Koch established the relationship between the tubercule bacillus and tuberculosis. Developed the following three postulates The pathogen