Epid 600 Class 2 Cause
Transcript of Epid 600 Class 2 Cause
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EPID 600; Class 2
What is a cause? Causal inference andinterpretation 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
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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 control of health problems
Therefore, epidemiology is fundamentally about the search
forcauses so that we may do something about them
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The wrath of God
for now, I will stretch out mine hand, that I may smite theeand thy people with pestilence
God, from Exodus (9:14)
Historical developments in the
understanding of disease etiology
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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
geographyFocused on illnesses and sick persons as unique
events
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1546: Fracastoro in On contagion, contagious diseases
and their treatment
Seminaria act on the humors of the body to create
diseaseThree modes of transmission: person to person,
fomites, airborne
Historical developments in the
understanding of disease etiology
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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 plantsViewed 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
Historical developments in the
understanding of disease etiology
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1700s
Giovanni Morgagni (clinicopathologic correlation)
Associated certain signs and symptoms with specific
pathologic changes in tissues and organsSpurred search for specific as opposed to general
causes of diseases
Historical developments in the
understanding of disease etiology
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1800s
1831
Civil registration of vital status established in England
1838
Englands 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)
Historical developments in the
understanding of disease etiology
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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)
Historical developments in the
understanding of disease etiology
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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
Kochs postulates
Proof that a particular microorganism is the
cause of a particular infectious disease
Historical developments in the
understanding of disease etiology
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Henle-Koch postulates
1. The agent must be present in every case of the disease2. The agent must be isolated from the host and grown in
vitro
3.The disease must be reproduced when a pure culture ofthe agent is inoculated into a healthy susceptible host
4. The same agent must be recovered once again from theexperimentally infected host
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Nelson, Williams, Graham. Infectious Disease Epidemiology Theory and Practice.Aspen Publishers, 2001 13
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Three questions in causal inference
1. Methodological question?How do we look for a cause?
3. Ontological questionWhat 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) havelower 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 thehypothesis
Interpretation of
results
Design, conduct, andanalysis of study
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When is an association causal?
Smoking is a carcinogenTheory
Hypothesis
Strategy to test thehypothesis
Interpretation of
results
Design, conduct, andanalysis of study
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When is an association causal?
Smoking is a carcinogen
Smoking causes lung cancer
Theory
Hypothesis
Strategy to test thehypothesis
Interpretation of
results
Design, conduct, andanalysis of study
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When is an association causal?
Smoking is a carcinogen
Smoking causes lung cancer
Prospective cohort study
Theory
Hypothesis
Strategy to test thehypothesis
Interpretation of
results
Design, conduct, andanalysis of study
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When is an association causal?
Smoking is a carcinogen
Smoking causes lung cancer
Prospective cohort study
Recruit 10,000 doctors,follow for 10 years
Theory
Hypothesis
Strategy to test thehypothesis
Interpretation of
results
Design, conduct, andanalysis of study
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When is an association causal?
Smoking is a carcinogen
Smoking causes lung cancer
Prospective cohort study
High RR of lung cancerin smokers
Recruit 10,000 doctors,follow for 10 years
Theory
Hypothesis
Strategy to test thehypothesis
Interpretation of
results
Design, conduct, andanalysis of study
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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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Advantages of observational vs.
experimental studies
OBSERVATION
Cheaper
Fewer ethical quandaries
Faster to organize and conduct
Can test multiple hypotheses and
associations
EXPERIMENT
Variables of interest more readily
controlled by investigator
Other extraneous variables more
readily controlled by investigator
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Advantages of observational vs.
experimental studies
OBSERVATION
Cheaper
Fewer ethical quandaries
Faster to organize and conduct
Can test multiple hypotheses and
associations
MAYBE
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Advantages of observational vs.
experimental studies
EXPERIMENT
Variables of interest more readily
controlled by investigator
Other extraneous variables more
readily controlled by investigator
MAYBE
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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-responseReplication 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
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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
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 retrolentalfibroplasia
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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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Relation between income and mortality
0
10
20
30
4050
60
70
80
90
32,
499
$US 1980
Age-adjusted
Mortality Rate(per 10,000
person-years)
Smith et al. 1994 42
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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
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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
CAVEATHeterogeneity of effect in different countries
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Consideration of alternate explanations
Extent to which investigator has ruled out other possible
explanations
Methodologically sound studies with no potential residual
confounding
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Extent to which investigator has ruled out other possible
explanations
Methodologically sound studies with no potential residual
confounding
CAVEATAlternate explanations limited by understanding of biology
and sophistication of analysis
Consideration of alternate explanations
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Cessation of exposure
Risk of disease expected to decline when exposure to a
cause is reduced or eliminated
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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
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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
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
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Specificity of the association
Specific exposure associated with only one disease
Arises from old Henle-Koch postulates for causation
CAVEATMany 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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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
T
BX
U
BA
Sufficient Cause 1 Sufficient Cause 2
A sufficient cause is a set of minimal conditions
or events that inevitably produce disease 57
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Sufficient and component causes
T
BX
U
BA
Sufficient Cause 1 Sufficient Cause 2
Component causes
A sufficient cause is a set of minimal conditions
or events that inevitably produce disease 58
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Sufficient and component causes
T
BX
U
BA
Sufficient Cause 1 Sufficient Cause 2
Component causes
A component cause is any one of a set of conditions whichare necessary for the completion of a sufficient cause
A sufficient cause is a set of minimal conditions
or events that inevitably produce disease 59
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Sufficient and component causes
T
BX
U
BA
Sufficient Cause 1 Sufficient Cause 2
A necessary cause is a component cause that is a memberof every sufficient cause
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Causing a myocardial infarction
Y
W
Potato chips
No exercise
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Causing a myocardial infarction
A
Y
W Obesity
Potato chips
No exercise
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Causing a myocardial infarction
A
Y
W Obesity
Potato chips
No exercise
NO EFFECT
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Causing a myocardial infarction
A
C
Y
W
Genes
Obesity
Potato chips
No exercise
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Causing a myocardial infarction
T
A
C
Y
W
Genes
Obesity
Potato chips
No exercise Highcholesterol
NO
EFFECT67
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Causing a myocardial infarction
T
BX
A
C
Y
W
Genes
Obesity
Potato chips
No exercise Highcholesterol
Smoking
Stress68
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Causing a myocardial infarction
T
BX
A
C
Y
W
Genes
Obesity
Potato chips
No exercise Highcholesterol
Smoking
Stress69
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Causing a myocardial infarction
T
BX
A
C
Y
W
Genes
Obesity
Potato chips
No exercise Highcholesterol
Smoking
Stress72
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Causing a myocardial infarction
T
BX
A
C
Y
W
Genes
Obesity
Potato chips
No exercise Highcholesterol
Smoking
Stress73
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Causing a myocardial infarction
T
BX
A
C
Y
W
Genes
Obesity
Potato chips
No exercise Highcholesterol
Smoking
Stress74
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Causing a myocardial infarction
T
BX
A
C
Y
W
Genes
Obesity
Potato chips
No exercise Highcholesterol
Smoking
Stress75
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Tuberculosis infection
Tuberculosis is among the top ten causes of death
in the world
Tuberculosis is caused by infection with M.
tuberculosisBut knowing who is infected with M. tuberculosis
does not necessarily inform us about the
distribution of those with TB disease in
populations
http://www.who.int/mediacentre/factsheets/fs104/en/index.html
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Tuberculosis infection
About 2 billion people
are infected with M.
tuberculosis worldwide
However, only 5-10% of
those infected actuallydevelop the disease
So can we say that M.
tuberculosis is the cause
of TB?
http://www.who.int/mediacentre/factsheets/fs104/en/index.html77
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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: 113-11978
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Vitamin D deficiency and TB
The underlying causal scenario of interest
Vitamin
D
Risk of
developingtuberculosis
Nnoaham and Clarke. Int J Epidemiol. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. 2008; 37: 113-11979
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Vitamin D deficiency and TB
TB case mean
vitamin D level(nmol/L)
Healthy control
mean vitamin Dlevel (nmol/L)
Study 1 16.0 27.25
Study 2 65.75 69.5Study 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?
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
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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Sick
Healthy
Observed
Counterfactual (parallel universe)
Counterfactual thinking
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Sick
Sick
Observed
Counterfactual (parallel universe)
Counterfactual thinking
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The counterfactual universe
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The counterfactual universe
D No D
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The counterfactual universe
D No D
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The counterfactual universe
D No D D No D
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The real universe
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The real universe
D No D
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The real universe
D No D
E No E
So the question, how are these
two parts different? Are they
exchangeable? Epidemiology
is centrally concerned with
ensuring exchangeability or
comparability of these two parts
of the population
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3. Ethics and the public health balance
When is there enough evidence to say something is acause?
When should we decide that something is a cause andact on it?
Does first do no harm always apply at the populationlevel?
Are there different guidelines for solutions where we haveto DO something vs. solutions where we try to remove
something?
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"All scientific work is incomplete - whether it beobservational 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 itappears to demand at a given time.
Sir Austin Bradford Hill
Coda