Synthesis: Causal Inference
Kassiani Mellou, based on EPIET material
EPIET Introductory Course,
Lazareto, Menorca 2011
How do we understand causality?
Intuitively?
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3
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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)
5
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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RR = 89.7
95%CI = 82.5 – 91.4
p<0.001
Does a statistical association
automatically mean that there
is a causal relationship?
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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 Relationship
1.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations have
been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunders publishers July 2008
11
Criteria for a Causal Relationship
1.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations have
been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
12
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.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations have
been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
14
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
ofDown
DownSyndrome
syndromeby
byBirth
birthOrder
order
Cases of
180
160
140
Cases per 120
100 000
live births 100
80
60
40
20
0
1
2
3
Birth order
4
5
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Cases of Down Syndrome by Maternal Age
Cases of Down Syndrome
Groups by age groups
Cases per
100000 live
births
1000
900
800
700
600
500
400
300
200
100
0
< 20
20-24
25-29
30-34
35-39
40+
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 smoking
Cigarette 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.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations have
been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
20
Biologic Plausibility
Is consistent with current biological and
medical common knowledge.
Smoking
Ingesting of chemicals and known
carcinogens
DNA mutations
lung 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.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations have
been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
23
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.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations have
been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
25
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.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations have
been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
27
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.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations
have been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
30
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.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations have
been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
33
Specificity of the association
One cause has one effect.
abestosis
Asbestos exposure
mesothelioma
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lung cancer
Rothman and Greenland
One 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
Use of cane
to support
walking
Type of
footwear
Weather
conditions
brittle bones
Source: Rothman KJ, Greenland: Causation and Causal Inference in Epidemiology,36
(Am J PH, 2005)
Criteria for a Causal Relationship
1.
2.
3.
4.
5.
6.
7.
Temporal relationship
Strength of the association
Biologic plausibility
Dose–response relationship
Replication of the findings
Effect of removing the exposure
Extent to which alternate explanations have
been considered
8. Specificity of the association
9. Consistency with other knowledge
L Gordis: Epidemiology 4th revised edition, W. Saunder publishers July 2008
37
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)
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Thank you for your attention!