Synthesis: Causal Inference EPIET Introductory Course, Lazareto, Menorca 2011 Kassiani Mellou, based on EPIET material.
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Synthesis: Causal Inference
EPIET Introductory Course, Lazareto, Menorca 2011
Kassiani Mellou, based on EPIET material
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How do we understand causality?
Intuitively?
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How is cause defined?
“Antecedent event, condition, or characteristic that was necessary for the
occurrence of the disease event and without, the disease event either would not
have occurred at all or until some time later.”
Rothman KJ, Greenland: Causation and Causal Inference in Epidemiology, (Am J PH, 2005)
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Cause in the context of epidemiology
Count and compare AND
Search for cause and effect
• Source of the outbreak?
• Risk factor for disease?
Why?
• Implement control measures
• Give recommendations
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p<0.001Does a statistical association automatically mean that there
is a causal relationship?
RR = 89.795%CI = 82.5 – 91.4
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Statistical association
• Causal ?
• Result of
• chance
• selection bias
• information bias
• confounding
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Henle-Koch-Postulates (1890)
1. Pathogen must identified in ill person/animal
2. Pathogen must be culturable
3. Cultured pathogen should cause illness in test animal
4. Pathogen must be reisolated and found identical to original
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Bradford Hill’s criteria (1965)1. Strength of Association
2. Consistency
3. Specificity
4. Temporality
5. Biological gradient (dose response)
6. Plausibility
7. Coherence
8. Experimental Evidence
9. Analogy
AB Hill: The Environment and Disease: Association or Causation?Proc Royal Soc Med 1965;58:295-300
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Criteria for a Causal Relationship1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations have
been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunders publishers July 2008
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Criteria for a Causal Relationship
1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations have
been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
13
Temporal Relationship
Exposure must precede disease
Essential criterion for causality
Knowledge of:
• Latency period
• Incubation period
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Criteria for a Causal Relationship
1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations have
been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
15
Strength of Association
Strong associations are more likely being causal than weak ones.
Smoking > 20 cigarettes/day laryngeal carcinoma (RR 20)
BUT not all strong associations are causal…
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Cases of Down Syndrome by Birth Order
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Cases of Down Syndrome by Maternal Age Groups
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Strength of Association
Strong associations are more likely being causal than weak ones.
Smoking > 20 cigarettes/day laryngeal carcinoma (RR 20)
BUT:Not all strong associations are causal…And weak associations do not rule out
causality…
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Smoking and Lung cancer? Breast cancer? Passive smokingCigarette smoking and lung cancer
RR= ~ 10
Cigarette smoking and breast cancer
RR = ~ 1 -1.5
Passive smoking and lung cancer
RR = ~ 1.4
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Criteria for a Causal Relationship
1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations have
been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
21
Biologic Plausibility
Is consistent with current biological and medical common knowledge.
SmokingIngesting of chemicals and known
carcinogens DNA mutationslung cancer
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Biologic Plausibility
Is consistent with current biological and medical common knowledge.
• Percivall Pott - scrotum cancer observed in chimney sweeps (1775)
• Peptic ulcers and Helicobacter pylori (1980s)
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Criteria for a Causal Relationship
1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations have
been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
24
Dose-response Relationship
Risk increases with more intense/more frequent exposure
But:• High dose at which any further increase has
no effect• Low dose may be that no response occurs or
can be measured
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Criteria for a Causal Relationship
1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations have
been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
26
Replication of findings
Findings found in:
• different populations
• by using different study designs
Jan Hendrik Schön – organic electronics
Hwang Woo-suk – stem cell research
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Criteria for a Causal Relationship
1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations have
been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
28
Effect of removing the exposure
A decrease in the outcome of interest is seen when the exposure is removed.
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Criteria for a Causal Relationship
1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations
have been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
31
Extent to which alternate explanations have been considered
Has adjustment been made for possible confounding?
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”The Norwegian comedian Marve Fleksnes once stated: I am probably allergic to leather because
every time I go to bed with my shoes on, I wake up with a headache the next morning.”
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Criteria for a Causal Relationship
1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations have
been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
34
Specificity of the associationOne cause has one effect.
Asbestos exposure mesothelioma
abestosis
lung cancer
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Rothman and GreenlandOne cause – one effect – simplistic and
not true
Most outcomes are as the result of many contributing causes
• Necessary
• Sufficient
• Probabilistic
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Earlier head trauma
leading to equilibrium problems
Condition of the sidewalk
Weather conditions
Type of footwear
brittle bones
Source: Rothman KJ, Greenland: Causation and Causal Inference in Epidemiology, (Am J PH, 2005)
Use of cane to support
walking
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Criteria for a Causal Relationship
1. Temporal relationship2. Strength of the association3. Biologic plausibility4. Dose–response relationship5. Replication of the findings6. Effect of removing the exposure7. Extent to which alternate explanations have
been considered8. Specificity of the association9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
38
Consistency with other knowledge
If an association is supported by the results of different disciplines
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Summary
• Not a checklist! (don’t stop thinking)
• Beware of biologic plausibility
• Always aim for better evidence
• Association is not causality!!!
• Keep an open mind
• Remain critical
(… especially of your own studies)
Thank you for your attention!
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