From association to causation deriving inference from epidemiological studies

1. From association to causation
deriving inference from
epidemiological studies
Sima Naderi, 2th year of MPH−department of epidemiology &
biostatistics, Kabul university of medical science

2. Presentation outline
• Introduction
• Approaches for studying disease etiology
• Type of Association
• Causal relationship
• Type of causal relationship
• Guidelines to asses causality
• Causal inference and conclusion
• Reference
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3. Why to know cause of events/disease
• As human being, Enable each of us to navigate our complex world
• As a doctor, why to know cause of disease?
• As a researcher?
• As an academic org member?
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4. Introduction
• Ascertainment of cause and effect relationships is one of the central
and most difficult tasks of all scientific activities
• Epidemiological principles stand on 2 basic assumption:
• Human disease does not occur at random.
• The disease and its cause as well as preventive factors can be identified by a
thorough investigation of population.
• Identification of relation (association, causation) between disease and
suspected risk factors forms major part of epidemiological research.
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5. Historical theories of disease causation
• Supernatural cause of “ and Karma
• Theory of humors (humor means fluid)
• The miasmatic theory of disease
• Theory of contagion
• Germ theory
• Koch`s postulations
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6. Approaches for studying disease etiology
• Expose animals to risk factors such as carcinogens in control lab
• Control the exposure dose
• Control other environmental conditions and genetic factors
• Keep lost to follow up to minimum
• Can we extrapolate data across species and from animal to human
population?
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7. Approaches for studying disease etiology
• Epidemiology build on unplanned or natural
experiments
• People exposes to risk factor for non- study purposes
• E.g. exposure to atomic bomb radiation in Hiroshima and
Nagasaki 1945
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8. Approaches for studying disease etiology
• Sequence of study in human population
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Randomized trial
Cohort studies
Case control studies
Available data
Clinical observation

9. Approaches for studying disease etiology
1.Determining
association
b/n an
exposure and
disease
Studies of group
characteristics:
ecologies studies
Studies of
individual
characteristics:
case-control,
cohort
2.If
association
exist
Causal
Non causal
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10. Association
• Concurrence of two variable more often, than would be expected by
chance.
• Correlation indicates the degree of Association.
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11. Type of association
• Spurious or artificial
• Real
• Non causal
• causal
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12. Spurious association
• Spurious association arise because of bias, when 2 variables are
improperly compared.
• E.g.
• Conclusion: prenatal mortality in hospital delivery is higher compared
to home delivery
• This conclusion results due to bias in study
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Study in England 5174 home delivery 11156 hospital delivery
Prenatal MR= 5.4/1000 Prenatal MR= 27.8/1000

13. Real(causal/noncausal) association
.
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14. Non causal association
• McMahon`s study: observed an association of coffee consumption
with risk of pancreatic cancer.
Causal association
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Coffee Drinking
Pancreatic Cancer
Coffee Drinking
smoking
pancreatic cancer
Non Causal association (due to
confounding)

15. Type of causal association
Direct
Indirect
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factor disease
factor diseaseStep
2
Step
1

16. Evidence for causal relationship
• Infectious disease: Henle assumptions 1840 which was expanded by
Koch in 1880s:
• The organism is always found with the disease
• The organism is not found with any other disease
• The organism, isolated from one who has the disease, and cultured through
several generations, produces the disease( in experimental animals)
• NCDs, no organism to detect and culture causal relationship more
complex
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17. Type of causal association
• Necessary and sufficient, (one to one relation, based on Koch theory)
Without that factor the disease never develops, and in its presence the
disease always develops
This situation rarely occurred
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Factor A disease
HIV AIDS

18. Type of causal association
• Necessary, not sufficient
• Factor is necessary but not sufficient to produce the disease
• Multiple factors are required, often in a specific temporal sequence
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Factor A
+
Factor B
+
Factor C
Disease

19. Necessary, not sufficient
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initiator
+
promoter
+
trigger
cancer

20. Type of causal association
• Sufficient, but not necessary
• The factor alone can produce the disease, but so can other factor
• Radiation, benzene – either can produce leukemia
• Cancer does not develop in everyone who has experienced radiation or benzene
exposure
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Factor A
or
Factor B
or
Factor C
Disease

21. Sufficient, but not necessary
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radiation
or
Benzene
exp
or
smoking
leukemia

22. Type of causal association
• Neither necessary nor Sufficient
• More complex model (independent.v=risk factor)
• Probably most accurately represents the causal relationships that operate in
most chronic disease
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Factor A + factor B
or
Factor C + factor D
or
Factor E + factor F
Disease

23. .
• Diabetics are most likely at risk of myocardial infarction than non diabetics
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2 matched groups
Myocardial
infraction
Risk factor
Non diabeticsdiabetics
diabetes

24. Guidelines for judging whether an association
is causal
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25. .
Guidelines
for inference
causal
association
temporal
Biological
plausibility
Alternative
explanation
Consistency
and
replication
Cessation
effects
Specificity
of the
association
Strength of
association
Dose-
response
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Major criteria
Minor criteria
Austin Bradford hill
1965

26. Temporal relationship
• Exposure to the factor must occurred before the disease developed
• Length of the interval between the exposure and outcome (asbestos
in lung cancer__15-20 year)
• Temporal relationship easily established in prospective cohort than in
case-control and retrospective cohort as
The only criteria that is inarguable
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27. Temporal relationship
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28. Dose-response relationship
• As dose of exposure increases, the risk of disease also increases
• If a dose-response relationship is present, it is strong evidence for a
causal relationship
• Absence of dose-response relationship dose not necessarily rule out a
causal relationship
• In some cases threshold may exist
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30. Strength of association
• Measured by
• OR
• RR
• The stronger association the more likely it is that the relation is causal
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31. Biological plausibility
• Coherence with the current body of biologic knowledge
• Sometimes, epidemiological observation preceded biologic
knowledge (mechanism of action, evidence from animal experiment)
• E.g. Gregg`s observation on rubella and congenital cataracts preceded any
knowledge of teratogenic viruses
• If epidemiological findings are not consistent with the existing
knowledge-interpreting the meaning of observed association might
be difficult
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32. Consideration of alternate explanation
• Explanations of relationship as a causal or due to confounding
• The extent to which the investigators have taken other possible
explanation into account and the extent to which they ruled out such
explanation are important considerations
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33. Cessation of exposure
• If a factor is a cause of a disease, the risk of disease is decline when
exposure to the factor is reduced or eliminated
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34. Consistency & Replication of findings
• If the relationship is causal, we would expect to find it consistency in
different studies (cohort, case-control) and in different populations.
• Causal association b/n smoking and lung cancer is found consistently
in:
• 50 retrospective studies
• 9 prospective studies
• Some times there are good reasons why study results differ. For
example, one study may have looked at low level exposure while
another looked at high level exposure.
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35. Specificity of the association
• Specificity implies a one to one relationship between the exposure
and outcome (weakest criteria).
• Not everyone who smokes develop lung cancer
• Not everyone who develops cancer has smoked
• Lack of specificity does not negate causation
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36. Additional model for causality
• Kennet rothman`s component cause theory: describe the
circumstances leading to a health outcome as being parts of one pie
chart, or a “causal pie”. without each component in place, the disease
or health outcome would not have occurred at that specific point in
time
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37. Slip on an icy sidewalk and break the wrist
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Causal pie
calcium intake impaired balance type of shoe Icy path fall

38. Directed acyclic graph
• One method used to create a conceptual diagram that maps the
relationship between the main exposure, outcome of intrest, and all
potential confounders for a given study.
• Confounders should identified for:
• Adjusting, less biased association
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Covariates
exposure outcome

39. Observed association & causal inference
• Could it be due
to bias
No
• Could it be
confounding
no • Could it be
result of chance
No
• Could it be
causal relation
yes • Apply
guidelines and
make judgment
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40. conclusion
• The causal inference resulted from the epidemiological studies are
very important to public health and provide inputs for political and
judicial decisions.
• E.g. the causal association b/n smoking and lung cancer has resulted
in labeling of cigarette packets and increased campaign ads.
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41. Wrong Causal inference
• Suppose a study find an association b/n paternal silk tie ownership
and infant mortality
• On the back of this, the government implements a program in which
5 silk ties are given to all men aged 18-45 with a view to reducing
infant mortality.
• We would all agree that this is madness
• This is because we understand the difference b/n association and
causation
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42. Assessment of the evidence suggesting helicobacter
pylori as a causative Agent of Duodenal ulcer
1. Temporal relationship About 11% of chronic gastritis patients duodenal occurs over a 10 year
period
2. Strength of association H.Pylori found - 90% of patients with duodenal ulcer
3. Dose-response R Density of H.Pylori per mm2 of gastric mucosa – higher in duodenal ulcer
patients
4. Replication of the findings Many of the observation – H.pylori – replicated repeatedly
5. Biological possibility • Earlier- difficult to invasion bacterium infecting the stomach antrum
causing ulcers in the duodenum, now recognized – H.pylori- binding
sites on antral cell.
• Induces mediators of inflammation
• Infected mucosa – weakened, susceptible to damaging effects of acid
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43. Assessment of the evidence suggesting helicobacter
pylori as a causative Agent of Duodenal ulcer
6. Cessation of
exposure
• Eradication – heals duodenal ulcers at the same rate as histamine
receptor antagonists
• Long-term ulcers recurrence rate – zero after H.pylori was eradicated
using triple – anti microbial therapy
7. Specific of
association
Prevalence of H.pylori in duodenal ulcers patients – 90% to 100%
8. Consistency
with other
knowledge
High prevalence of ulcer disease in later part of 19th century – consistent with
high prevalence of H.pylori due to poor living condition at the same period
9. Consideration
of alternative
explanation
Smoking risk of duodenal ulcer – H.pylori infected patients but not a risk
factor – H.pylori eradicated patients
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44. Reference
• Gordis leon. Textbook of epidemiology, 5th edition, chp 14, P243-260
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45. Thanks for attention
?
!
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