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EPID 600; Class 2

What is a cause? Causal inference and


interpretation of epidemiologic evidence
University of Michigan School of Public Health

Drug Abuse: A workshop on behavioral and economic research


October 18-20, 2004
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What is epidemiology?

The study of the distribution and determinants of health-


related states or events in specified populations, and the
application of this study to the control of health problems

2
What is epidemiology?

The study of the distribution and determinants of health-


related states or events in specified populations, and the
application of this study to control of health problems
Therefore, epidemiology is fundamentally about the search
for causes so that we may do something about them

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Historical developments in the
understanding of disease etiology

The wrath of God

“for now, I will stretch out mine hand, that I may smite thee
and thy people with pestilence”

God, from Exodus (9:14)

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Historical developments in the
understanding of disease etiology
Rational thinking about disease causation started in 400
BCE with Hippocrates in the Epidemics
Related symptoms of different illnesses to seasons and
geography
Focused on illnesses and sick persons as unique
events

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Historical developments in the
understanding of disease etiology
1546: Fracastoro in “On contagion, contagious diseases
and their treatment”
Seminaria act on the humors of the body to create
disease
Three modes of transmission: person to person,
fomites, airborne

6
Historical developments in the
understanding of disease etiology
1600s
Thomas Sydenham, “the English Hippocrates”
“All diseases then ought to be reduced to certain and determinate
kinds, with the same exactness as we see it done by botanic
writers in their treatises of plants”
Viewed diseases as distinct entities and began to hypothesize
about causes
William Petty and John Graunt
First to use numerical data to describe patterns of mortality
Proposed the establishment of a central government agency to
collect data on vital information (Petty)
Published Observations on the bills of mortality (Graunt)
Analyzed records on causes of death from each parish
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Historical developments in the
understanding of disease etiology
1700s
Giovanni Morgagni (“clinicopathologic correlation”)
Associated certain signs and symptoms with specific
pathologic changes in tissues and organs
Spurred search for specific as opposed to general
causes of diseases

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Historical developments in the
understanding of disease etiology
1800s
1831
Civil registration of vital status established in England
1838
England’s General Register Office established and headed by William
Farr recorded all births and deaths; Farr developed disease
classification system
Zymotic (epidemic, endemic, contagious)
Constitutional (gout, dropsy, cancer)
Local (diseases of 8 organ systems)
Developmental (diseases of childhood, old age, women, nutrition)
Violent (accidents, battle deaths, homicides, suicides, executions, etc)

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Historical developments in the
understanding of disease etiology
“Diseases which are communicated from person to person
are caused by some material which passes from the sick to
the healthy.”
John Snow (1813-1858)

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Historical developments in the
understanding of disease etiology
1876: Koch reproducibly transmits anthrax to mice using
the blood of infected cows
Same rod-like material recovered from cows and mice
Infection transmittable from mouse to mouse

Koch’s postulates
Proof that a particular microorganism is the
cause of a particular infectious disease

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Henle-Koch postulates

1.  The agent must be present in every case of the disease


2.  The agent must be isolated from the host and grown in
vitro
3.  The disease must be reproduced when a pure culture of
the agent is inoculated into a healthy susceptible host
4.  The same agent must be recovered once again from the
experimentally infected host

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Nelson, Williams, Graham. Infectious Disease Epidemiology Theory and Practice. Aspen Publishers, 2001 13
Three questions in causal inference

1.  Methodological question?


How do we look for a cause?
3.  Ontological question
What is a cause?
5.  Ethical question?
How do we decide if there is enough evidence to
act on a cause?

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1. The methodological question

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Association vs. Causation
Association is an identifiable relation between an exposure and a
disease

EXAMPLES

Incidence rate of lung cancer is higher among smokers than among


non-smokers

Postmenopausal women on hormone replacement therapy (HRT) have


lower rates of cardiovascular mortality than postmenopausal women
who are not on HRT

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Association vs causation
Therefore if association is present we have to determine if exposure is
truly a cause of disease

EXAMPLES

Does smoking cause lung cancer?

Does HRT cause a reduction in the risk of death from cardiovascular


diseases?

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So how do we determine if something
is causal?

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When is an association causal?

Theory

Hypothesis

Strategy to test the


hypothesis

Design, conduct, and


analysis of study

Interpretation of
results 19
When is an association causal?

Theory Smoking is a carcinogen

Hypothesis

Strategy to test the


hypothesis

Design, conduct, and


analysis of study

Interpretation of
results 20
When is an association causal?

Theory Smoking is a carcinogen

Hypothesis Smoking causes lung cancer

Strategy to test the


hypothesis

Design, conduct, and


analysis of study

Interpretation of
results 21
When is an association causal?

Theory Smoking is a carcinogen

Hypothesis Smoking causes lung cancer

Strategy to test the Prospective cohort study


hypothesis

Design, conduct, and


analysis of study

Interpretation of
results 22
When is an association causal?

Theory Smoking is a carcinogen

Hypothesis Smoking causes lung cancer

Strategy to test the Prospective cohort study


hypothesis

Design, conduct, and Recruit 10,000 doctors,


analysis of study follow for 10 years

Interpretation of
results 23
When is an association causal?

Theory Smoking is a carcinogen

Hypothesis Smoking causes lung cancer

Strategy to test the Prospective cohort study


hypothesis

Design, conduct, and Recruit 10,000 doctors,


analysis of study follow for 10 years

Interpretation of High RR of lung cancer


results in smokers 24
Induction vs. deduction

Induction

Specific observation General premise

Deduction

General premise Specific observation

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Confirmation vs. falsification

Confirmation
If A, then B, C, D
B, C, D, therefore A

Falsification
If A, then B, C, D
NOT B, C, D, therefore NOT A

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Observation

A physician at a local hospital notices that she has seen


two elderly patients presenting to the hospital in the span of
a week with encephalitis (brain inflammation). She selects
other patients to serve as “controls” and carries out a case-
control study

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Experiment

Convinced by laboratory data and by observational data in


humans, a group of scientists launch a trial of estrogen
replacement therapy among post-menopausal women to
explore if women taking hormone replacement therapy
have better control of menopausal symptoms and fewer
fractures

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Advantages of observational vs.
experimental studies
OBSERVATION EXPERIMENT

Cheaper Variables of interest more readily


controlled by investigator
Fewer ethical quandaries
Other extraneous variables more
readily controlled by investigator
Faster to organize and conduct

Can test multiple hypotheses and


associations

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Advantages of observational vs.
experimental studies
OBSERVATION

Cheaper

Fewer ethical quandaries

MAYBE
Faster to organize and conduct

Can test multiple hypotheses and


associations

30
Advantages of observational vs.
experimental studies
EXPERIMENT

Variables of interest more readily


controlled by investigator

MAYBE Other extraneous variables more


readily controlled by investigator

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A few well known causes of disease
Smoking
High cholesterol
M. tuberculosis
S. viridans
Head injury
Poverty [?]

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A few well known causes of disease
Smoking Lung Cancer
High cholesterol Cardiovascular Disease
M. tuberculosis Tuberculosis
S. viridans Endocarditis
Head injury Subarachnoid hemorrhage
? Poverty All-cause mortality

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2. The ontological question

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Criteria for Causal Inference
(Bradford Hill 1965)
Temporality
Strength of association
Biological plausibility
Dose-response
Replication of findings
Consideration of alternate explanations
Cessation of exposure
Coherence with established facts
Specificity of association

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Temporality

Exposure must precede disease


In diseases with long latency periods, exposures must
precede latency period
In chronic diseases, often need long-term exposure for
disease induction

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Strength of association

Strong associations are less likely to be caused by chance


or bias
A strong association means a very high or very low relative
risk

37
Strength of association

Strong associations are less likely to be caused by chance


or bias
A strong association means a very high or very low relative
risk

CAVEAT
Environmental associations with very low relative risks

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Biologic plausibility

The proposed mechanism should be biologically


(etiologically) plausible
Reference to a “coherent” body of knowledge

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Biologic plausibility

The proposed mechanism should be biologically


(etiologically) plausible
Reference to a “coherent” body of knowledge

CAVEAT
High oxygen concentration causing neonatal retrolental
fibroplasia

40
Dose-response relationship

Changes in exposure are related to trend in risk of disease


Strong evidence for causal relation suggesting biologic
relation

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Smith et al. 1994
(per 10,000
Age-adjusted
Mortality Rate

person-years)

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10
20
30
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50
60
70
80
90
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9
Relation between income and mortality

42
Dose-response relationship

Changes in exposure are related to trend in risk of disease


Strong evidence for causal relation suggesting biologic
relation

CAVEAT
Thresholds, i.e., no disease past a certain level of
exposure

43
Replication of findings

Relations that are demonstrated in multiple studies are


more likely to be causal
Consistent results found in different populations, in different
times, with different study designs

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Replication of findings

Relations that are demonstrated in multiple studies are


more likely to be causal
Consistent results found in different populations, in different
times, with different study designs

CAVEAT
Heterogeneity of effect in different countries

45
Consideration of alternate explanations

Extent to which investigator has ruled out other possible


explanations
Methodologically sound studies with no potential residual
confounding

46
Consideration of alternate explanations

Extent to which investigator has ruled out other possible


explanations
Methodologically sound studies with no potential residual
confounding

CAVEAT
Alternate explanations limited by understanding of biology
and sophistication of analysis

47
Cessation of exposure

Risk of disease expected to decline when exposure to a


cause is reduced or eliminated

48
Cessation of exposure

Risk of disease expected to decline when exposure to a


cause is reduced or eliminated

CAVEAT
Pathogenic process already started; removal of cause
does not reduce disease risk

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Coherence with established “facts”

If a relation is causal, would expect observed findings to be


consistent with other data
Hypothesized causal relations need to be consistent with
epidemiologic and biologic knowledge

50
Coherence with established “facts”

If a relation is causal, would expect observed findings to be


consistent with other data
Hypothesized causal relations need to be consistent with
epidemiologic and biologic knowledge

CAVEAT
Data may not be available yet to directly support proposed mechanism
Science must be prepared to reinterpret existing understanding of
disease process in the face of new evidence

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Specificity of the association

Specific exposure associated with only one disease


Arises from old Henle-Koch postulates for causation

52
Specificity of the association

Specific exposure associated with only one disease


Arises from old Henle-Koch postulates for causation

CAVEAT
Many exposures are linked to multiple diseases

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Overall caveats to “criteria”

“None of my ... [criteria] can bring undisputable evidence


for or against the cause-and-effect hypothesis and none
can be required as a sine qua non.”

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Therefore, causal inference…

  Causal inference is not a simple (or quick) process


  No single study is sufficient in establishing causal
inference
  Requires critical judgment and interpretation
  Can one “prove” causality?

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What is a cause? (Rothman)

A cause of a disease is an event, condition, or


characteristic that preceded the disease event and without
which the disease event would not have occurred at all or
would not have occurred until some later time.

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Sufficient and component causes

U T

A B X B

Sufficient Cause 1 Sufficient Cause 2


A sufficient cause is a set of minimal conditions
or events that inevitably produce disease 57
Sufficient and component causes

Component causes

U T

A B X B

Sufficient Cause 1 Sufficient Cause 2


A sufficient cause is a set of minimal conditions
or events that inevitably produce disease 58
Sufficient and component causes

A component cause is any one of a set of conditions which


are necessary for the completion of a sufficient cause

Component causes

U T

A B X B

Sufficient Cause 1 Sufficient Cause 2


A sufficient cause is a set of minimal conditions
or events that inevitably produce disease 59
Sufficient and component causes

A necessary cause is a component cause that is a member


of every sufficient cause

U T

A B X B

Sufficient Cause 1 Sufficient Cause 2

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For example: Tuberculosis

Necessary but not sufficient

M. tuberculosis
Poor Immuno- M. tuberculosis
nutrition suppression

Sufficient Cause 1 Sufficient Cause 2

Neither necessary nor sufficient 61


“Causing” a myocardial infarction

Potato chips
Y
W
No exercise

62
“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise
A

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“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise
A
NO EFFECT

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“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise
A
C

Genes

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“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise High
A
cholesterol
C
T
Genes

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“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise High
A
cholesterol
C
T
Genes
NO
EFFECT
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“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise High
A
cholesterol
C
T
Genes
X B
Smoking
Stress 68
“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise High
A
cholesterol
C
T
Genes
X B
Smoking
Stress
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Limitations of sufficient cause model

  Omits discussion of origins of causes, focuses on


proximal causes
  Specific components but not linkages among them
  Does not consider factors that control distribution
of risk factors
  Ignores dynamic non-linear relations

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“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise High
A
cholesterol
C
T
Genes
X B
Smoking
Stress71
“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise High
A
cholesterol
C
T
Genes
X B
Smoking
Stress 72
“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise High
A
cholesterol
C
T
Genes
X B
Smoking
Stress 73
“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise High
A
cholesterol
C
T
Genes
X B
Smoking
Stress 74
“Causing” a myocardial infarction

Potato chips
Y
W Obesity
No exercise High
A
cholesterol
C
T
Genes
X B
Smoking
Stress 75
Tuberculosis infection

Tuberculosis is among the top ten causes of death


in the world
Tuberculosis is caused by infection with M.
tuberculosis
But knowing who is infected with M. tuberculosis
does not necessarily inform us about the
distribution of those with TB disease in
populations…

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http://www.who.int/mediacentre/factsheets/fs104/en/index.html
Tuberculosis infection

About 2 billion people


are infected with M.
tuberculosis worldwide
However, only 5-10% of
those infected actually
develop the disease
So can we say that M.
tuberculosis is the cause
of TB?

http://www.who.int/mediacentre/factsheets/fs104/en/index.html
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Vitamin D deficiency and TB

Attack of macrophages is a critical step in the


development of TB
Vitamin D modulates monocyte-macrophage activity in
the body
Perhaps deficiencies in serum vitamin D levels cause
TB?
A meta-analysis conducted to evaluate the evidence

Nnoaham and Clarke. Int J Epidemiol. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. 2008; 37: 113-119
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Vitamin D deficiency and TB

The underlying causal scenario of interest

Vitamin Risk of
D developing
tuberculosis

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Nnoaham and Clarke. Int J Epidemiol. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. 2008; 37: 113-119
Vitamin D deficiency and TB

TB case mean Healthy control


vitamin D level mean vitamin D
(nmol/L) level (nmol/L)

Study 1 16.0 27.25


Study 2 65.75 69.5
Study 3 39.75 65.5
Study 4 69.5 95.5
Study 5 46.5 52.25
Study 6 26.75 48.5

Is this enough evidence to call Vitamin D


a cause of active TB?

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Nnoaham and Clarke. Int J Epidemiol. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. 2008; 37: 113-119
Vitamin D deficiency and TB

Do we have evidence to believe that the association


is not in the reverse direction? (Temporal order)

Vitamin D Risk of developing


tuberculosis

Do we have evidence to conclude that these cases


would not have occurred but for vitamin D
deficiency?

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Counterfactual thinking
Observed

Sick

Counterfactual (parallel universe)

Healthy

82
Counterfactual thinking
Observed

Sick

Counterfactual (parallel universe)

Sick

83
The counterfactual universe

84
The counterfactual universe

D No D

85
The counterfactual universe

D No D

86
The counterfactual universe

D No D D No D

87
The real universe

88
The real universe

D No D

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The real universe

E No E

D No D

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The real universe

So the question, how are these


two parts different? Are they
E No E “exchangeable”? Epidemiology
is centrally concerned with
ensuring exchangeability or
comparability of these two parts
of the population

D No D

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3. Ethics and the public health balance

  When is there enough evidence to say something is a


“cause”?
  When should we decide that something is a cause and
act on it?
  Does “first do no harm” always apply at the population
level?
  Are there different guidelines for solutions where we have
to DO something vs. solutions where we try to remove
something?

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Coda

"All scientific work is incomplete - whether it be


observational or experimental. All scientific work is liable
to be upset or modified by advancing knowledge. That
does not confer upon us a freedom to ignore the
knowledge we already have, or to postpone the action it
appears to demand at a given time.“
Sir Austin Bradford Hill

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