Causality

2021
Learning Objectives

• Describe the difference between association and causation

• Describe models of disease causation
• List the Bradford-Hill causal criteria.
What is causation

Dictionary: Producer of an effect, result, or outcomes.

Causation: Exposure that leads to new cases of disease

Cause (Rothman, lay terms) – an event, condition, or characteristic that preceded the disease event and without
which the disease event either would not have occurred at all or would not have occurred until some later time
What is causation

Three properties
• Association (cause and effect occur together)
• Time order (cause precedes effects)
• Connection or direction (predictable link between cause and
effect)
Association

Identifiable relationship (statistical connection) between an exposure

and a disease
Association
• Circumstances that a specific exposure is related to disease.
• Changes in the exposure in question cause changes in disease
risk.
• The exposure may cause disease, but whether or not the
exposure is a true cause of disease has yet to be proven.
(Association vs.) Causation
• Causation: True mechanism that leads from exposure to a disease
• e.g., long-term smoking causes lung cancer
 
• An association does not mean causation
• e.g., hospital stays are associated with an increased mortality rate, but this
does not mean they cause death
What Causes Diarrhea?
What Causes Cholera?
• Contaminated water
• Raw contaminated fruit/Vegetable
• Poor sanitation
Why we are concerned with cause?
• To prevent and control disease on time.
• We do not need to understand all casual factors to prevent disease
Models of Causal Relationships
Models of Causal Relationships
• Necessary & Sufficient

• Necessary but not Sufficient

• Sufficient but not Necessary

• Neither Sufficient nor Necessary

Necessary and Sufficient

Only Factor A Disease

Genetic Factors Sickle Cell

Necessary but not Sufficient

Factor A

Factor B Disease

+
Factor C
Necessary but not Sufficient
Exposure to M.
tuberculosis

+
Infection with
TB Disease
M. tuberculosis

+
Host Factors
Sufficient but not Necessary
Factor A
or

Factor B Disease
or

Factor C
Sufficient but not Necessary
Ionizing
Radiation
or

Benzene Leukemia
or

Electromagnetic
Fields
Bradford Hill: Considerations for Causal
Inference
• Strength of association
• Consistency of findings
• Specificity
• Temporality
• Biological gradient (dose-response)
• Biological plausibility
• Coherence with established facts
• Experiment
• Analogy
 Strength of Association

• Strong associations are less likely to be

caused by chance or by bias

• The stronger the relationship, the more

likely it is to be causal
• However, a weak association does not rule out a causal
relationship (ex: passive smoking and lung cancer).
Strength of Association
Relative risk Interpretation

1.1-1.3 Weak
1.4-1.7 Modest
1.8-3.0 Moderate
3-8 Strong
8-16 Very strong
16-40 Dramatic
40+ Overwhelming
 Specificity
• An exposure leads to a single or characteristic effect, or
affects people with a specific susceptibility (like the
concept of a “Necessary” cause)

• Easier to support causation when associations are specific

• But, obviously not always true
•  Many exposures cause multiple diseases
• e.g., smoking causes many diseases including heart disease, lung and
other cancers, emphysema
Specificity
Hepatitis A Botulism

Food OR Food OR
Sandwich 2.8 Bread 1.2
Fruit 3.2 Fruit 1.6
Salad 4.0 Tomatoes 4.0
Pastry 1.8 Tea 1.3
Milk 0.8 Cake 0.8
Temporality
• Exposure must precede disease

• In disease with latency periods, exposures must

precede the latent period

• In chronic disease, often long-term exposure for

disease induction
Temporality
• The exposure needs to precede the outcome
• This criteria is met in which type of studies?
Cohort studies
Case-control studies with appropriate referent exposure period
 Need onset date
 Need appropriate referent exposure period
 Not met in cross sectional studies
Temporality
Cutaneous Anthrax

Incubation Period
1 to 12 days

0 5 10 15 20
Days
Date of Exposure
 Biological Gradient

• “Dose- Response”
• Changes in exposure are related to a trend in risk
• Risk of outcome increases with increasing exposure to
the suspected risk factor
• Risk of outcome decreases with decreasing exposure to
the suspected risk factor
Biological Gradient
Age-standardized death rates, bronchogenic
carcinoma (by smoking history)
250

217.3

200

150 143.9
Mortality Rate per
100,000 Person-
Years
100

59.3
51.4
50
Adapted from
3.4
Hammond EC,
0 Horn D: JAMA
Never <1/2 1/2-1 1-2 2+ 166:1294-1308,
Smoked Pack/Day Pack/Day Packs/Days Packs/Day 1958.)
 Biological Plausibility

• The proposed causal mechanism should be biologically

(etiologically) plausible

• The findings make biologic sense

• Results agree with current biological

knowledge of the disease
Biological Plausibility
Plausible
• A disease shows a higher incidence in
individuals who are more sexually active
• The disease could be a sexually transmitted
disease

Not Plausible
• HIV is caused by smoking
• This would go against the current knowledge on
the biological mechanism for HIV
 Coherence and Consistency of Findings
• Relationships that are demonstrated in multiple studies
are more likely to be causal, i.e., consistent results are
found:

• In different populations,

• In different circumstances, and

• With different study designs.

 Coherence and Consistency of Findings
• Lung Cancer
Consistent results are found
• Numerous studies: case-control,
retrospective cohort, prospective cohort
• Show an association between cigarette
smoking and lung cancer
Coherence and Consistency of Findings
• Doll R, Hill AB. Smoking and carcinoma of the lung. Brit Med
J. 1950 (Case-Control Study)

• Yaun J et al. Morbidity and mortality in relation to cigarette

smoking in Shanghai, China. A prospective male cohort study
(Prospective Cohort Study)

• Fritschi et al. Mortality and cancer incidence in a cohort of

meatworkers (Retrospective Cohort Study)

***All of these (as well as many other studies) show a causal

link between smoking and lung cancer
Experiment
• Experimental evidence shows an exposure-disease
relationship

• The researcher is able to modify factors under

controlled conditions in order to study how the
modifications effect the outcome.

• Human experiments

• Animal experiments
Experiment

• In the 18th century, a famous English physician named

Edward Jenner made the observation that milkmaids who
became infected with cowpox did not become infected with
smallpox.

• In 1796 Jenner inoculated a young boy with cowpox, then

six weeks later exposed the boy to smallpox. The boy did not
become infected with smallpox.

• The experiment showed that those who had previously

developed cowpox were immune to smallpox. This work
paved the way for the modern vaccination.
 Analogy
• Existence of other cause-effect relationship analogous
to the one studied supports causal relationship

• Other similar associations exist

• If a particular drug is a carcinogen, then other drugs within

the same class of drugs may be carcinogens

• Weak criterion for causality. Useful for speculating how risk

factor may operate in different context
Modern Models of Disease Causation

All models are oversimplifications, but are they

useful?
• Epidemiologic triad (epidemiologic triangle)
• Web of causation
• Rothman’s pies
• Others
Epidemiologic Triad

Agent

Host Environment
Epidemiologic Triad

Agent

Disease

Host Environment
Agent

Agent

 External factor whose presence, excessive

presence, or, (in deficiency diseases) relative
absence is essential for the disease to occur
– Infectious agents
– Chemical agents
– Physical agents
– Nutritional agents
– Other
Host Factors Host

• Intrinsic factors that influence an individual’s exposure,

susceptibility, or response to an agent
• Age
• Sex
• Behaviors
• Genetics
• Immunologic status
• Nutritional status
• Anatomic structure
• Presence of disease or medications
Environmental Factors Environment

• Extrinsic factors that affect the agent and

opportunity for exposure
• Physical factors
• Geology
• Climate
• Tight buildings
• Ecologic factors
• Vector presence, density
• Social, Political, Economic factors
• Crowding
• Sanitation
• Availability of health services
Epidemiologic Triad

Agent

Malaria

Host Environment
Web of Causation
Web of Causation for Myocardial Infarction
 Rothman’s Causal Pies

Single component cause

Single causal pathway

Rothman KJ, Modern Epidemiology 2nd ed.

Rothman’s Causal Pies Deconstructed
• Sufficient cause = set of conditions without any one
of which the disease would not have occurred (One
whole pie, single causal pathway)
• Component cause = any condition necessary for the
completion of a sufficient cause (Piece of pie)
• Necessary cause = component cause that is member
of every sufficient cause (Same piece of pie appears in
every whole pie)

Rothman KJ, Modern Epidemiology 2nd ed.

 Rothman’s Causal Pies
 Completion of sufficient cause = disease occurs
 Component causes can act far apart in time

Q. Name a necessary cause.

A. Component cause A (appears in every pie)
Rothman KJ, Modern Epidemiology 2nd ed.