epid 600 class 2 cause

8/14/2019 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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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



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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



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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



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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)



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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)



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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



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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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Smoking is a carcinogenTheory

Hypothesis


Interpretation of

results


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Smoking is a carcinogen

Smoking causes lung cancer

Theory

Hypothesis


Interpretation of

results


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Prospective cohort study

Theory

Hypothesis


Interpretation of

results


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Recruit 10,000 doctors,follow for 10 years

Theory

Hypothesis


Interpretation of

results


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High RR of lung cancerin smokers

Recruit 10,000 doctors,follow for 10 years

Theory

Hypothesis


Interpretation of

results


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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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OBSERVATION

Cheaper

Fewer ethical quandaries

Faster to organize and conduct

Can test multiple hypotheses and

associations

MAYBE

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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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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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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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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


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Risk of disease expected to decline when exposure to a

cause is reduced or eliminated

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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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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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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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T

BX

U

BA


Component causes




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T

BX

U

BA


Component causes

A component cause is any one of a set of conditions whichare necessary for the completion of a sufficient cause




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T

BX

U

BA


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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A

Y

W Obesity

Potato chips

No exercise

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A

Y

W Obesity

Potato chips

No exercise

NO EFFECT

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A

C

Y

W

Genes

Obesity

Potato chips

No exercise

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T

A

C

Y

W

Genes

Obesity

Potato chips

No exercise Highcholesterol

NO

EFFECT67


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T

BX

A

C

Y

W

Genes

Obesity

Potato chips


Smoking

Stress68


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T

BX

A

C

Y

W

Genes

Obesity

Potato chips


Smoking

Stress69


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T

BX

A

C

Y

W

Genes

Obesity

Potato chips


Smoking

Stress72


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T

BX

A

C

Y

W

Genes

Obesity

Potato chips


Smoking

Stress73


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T

BX

A

C

Y

W

Genes

Obesity

Potato chips


Smoking

Stress74


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T

BX

A

C

Y

W

Genes

Obesity

Potato chips


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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The underlying causal scenario of interest

Vitamin

D

Risk of

developingtuberculosis



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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?


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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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D No D

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D No D

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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

epid 600 class 2 cause

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