What qualities should a

disease have to make it

worthwhile to investigate?

Disease investigations should have

some public health significance
The disease is important in terms of
the number of individuals it affects
The disease is important in terms of
the types of populations it affects
The disease is important in terms of its
causal pathway or risk characteristics

Research Questions/Hypotheses

Is there an association between Exposure (E)

& Disease (D)?
Hypothesis: Do persons with exposure have
higher levels of disease than persons without
exposure?
Is the association real, i.e. causal?
Sever

Big Picture
Look for links between exposure & disease
to intervene and prevent disease

Look to identify what may cause disease

Basic definition of cause
exposure that leads to new cases of disease
remove exposure and most cases do not occur

Big Picture
On a population basis
An increase in the level of a causal factor
will be accompanied by an increase in the
incidence of disease (all other things
being equal).
If the causal factor is eliminated or
reduced, the frequency of disease will
decline

Infectious Disease Epidemiology

Investigations/studies are undertaken to
demonstrate a link [relationship or association]
between an agent (or a vector or vehicle carrying
the agent) and disease

Exposure
[ Agent ]
[ Vector/Vehicle ]

Disease

Injury Epidemiology
Studies are undertaken to demonstrate
a link [association] between an agent /
condition and an injury outcome

Exposure

Disease

[ Agent Energy Transfer ]

[ Vehicle carrying the agent automobile ]
[ Condition Risk taking behaviour ]

Chronic Disease Epidemiology

Studies are undertaken to demonstrate
a link [relationship or association]
between a condition/agent and disease

Exposure

Disease

[ Condition e.g. gene, environment ]

Issues to consider
Etiology (cause) of chronic disease is often
difficult to determine
Many exposures cause more than one
outcome
Outcomes may be due to a multiple
exposures or continual exposure over time
Causes may differ by individual

Exposure
OR
Genetic Background
OR
Combination of Both
Association
? Causation ?

Disease or Other Outcome

Suppose we determine that an exposure is associated with
disease.
How do we know if the observed association reflects a causal
relationship?

First step in determining causation:

Understanding disease etiology

Experimental studies

in vitro systems
animal studies in controlled environments
Allows for
control of precise dose
control of environmental conditions
loss to follow up kept to a minimum

Problems with
extrapolating data to human populations
human diseases with no good animal models

Clinical pathologies

Second step in determining causation:

Conducting Studies in Human Populations
Heres where Epidemiology is important.
Epidemiology capitalizes on natural or
unplanned experiments. We take
advantage of groups who have been
exposed for non-study purposes.
All of the study designs are important here
and provide different evidence for or against
a causal hypothesis.

Figure 14-3 A frequent sequence of studies

in human populations.
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2005 Elsevier

Causation and Association

Epidemiology does not determine the cause of a disease in a given
individual
Instead, it determines the relationship or association between a given
exposure and frequency of disease in populations
We infer causation based upon the association and several other factors

Association vs. Causation

Association - an identifiable relationship
between an exposure and disease
implies that exposure might cause disease
exposures associated with a difference in disease
risk are often called risk factors

Most often, we design interventions based

upon associations

Association vs. Causation

Causation - implies that there is a
true mechanism that leads from
exposure to disease
Finding an association does not
make it causal

ASOSIASI VS KAUSASI
Untuk memutuskan apakah eksposur A
menyebabkabn penyakit B, kita pertama
kali harus menemukan apakah dua
variabel itu berasosiasi, misal apakah

satu ditemukan lebih umum pada

adanya yang lain.

CAUSAL

ASSOCIATION

ADALAH SUATU ASOSIASI ANTARA 2

KONDISI ATAU KARAKTERISTIK
DIMANA BILA TERJADI PERUBAHAN
(MIS: PERUBAHAN JUMLAH ATAU
PERUBAHAN KUALITAS) PADA 1
KONDISI, MAKA AKAN DIIKUTI OLEH
PERUBAHAN PADA KONDISI YANG
LAINNYA

CAUSALITY OR CAUSAL
ASSOCIATION
BERHUBUNGAN DENGAN CAUSE EFFECT
RELATIONSHIPS
UNTUK
MENENTUKAN SEBERAPA BERBEDA
SUATU KONDISI (MIS: FAKTOR
RISIKO) BERHUBUNGAN DENGAN
KONDISI LAINNYA (MIS: PENYAKIT)
MENENTUKAN PENYEBAB ATAU
ETIOLOGI

Two step process to carry out studies

and evaluate evidence
1.Determine if an association is present
-

Ecologic studies: studies of group characteristics

Cross-sectional studies: studies at one particular
time
Case-control or cohort studies: studies of
individual characteristics.

2. If an association is demonstrated,
determine whether the observed
association is likely to be a causal one
using pre-determined criteria.

General Models of Causation

Cause: event or condition that plays an
role in producing occurrence of a disease
How do we establish cause in situations
that involve multiple factors/conditions?
For example, there is the view that
most diseases are caused by the
interplay of genetic and
Environmental factors.

General Models of Causation

How do we establish cause?

Exposure

Disease

Additional Factors

Web of Causation
There is no single cause
Causes of disease are interacting
Illustrates the interconnectedness
of possible causes

RS Bhopal

Understanding Causality

Types of Association

Types of Causal relationships

causal
noncausal
direct
indirect

Types of causal factors

sufficient
necessary

Jenis-jenis hubungan sebab-akibat

A.Tidak berhubungan secara statistik
B.Berhubungan secara statistik
kausal langsung
kausal tidak langsung

TYPES OF ASSOCIATION
A. Not statistically
associated (independent)
B. Statistically associated
1. Noncasually (secondarily
associated)
2. Causially associated
a. Indirectly associated
b. Directly casual

 Hampir semua statistik berusaha menemukan

apakah dua variabel berhubungan, dan jika
demikian, seberapa kuat, dan apakah chance
(kebetulan) dapat menjelaskan asosiasi yang
diamati.
Statistik terutama dirancang untuk menilai
peranan chance dalam asosiasi itu.

Suatu nilai p hanya menceritakan kepada

kita seberapa mungkin asosiasi itu mempunyai
peningkatan secara kebetulan.

Oleh sebab itu, Analisis statistis sendiri tidak

dapat membangun bukti hubungan kausal.

Figure 14-5 Types of associations.

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2005 Elsevier

The relationship between coffee

consumption and pancreatic cancer

In 1981, MacMahon et al. reported results from

a case-control study of cancer of the pancreas.

There was an apparent dose response

relationship between coffee consumption and
cancer of the pancreas, particularly in women.

Was the disease caused by coffee

consumption or by some factor closely related
to coffee consumption?

MacMahon B, et al. N Engl J Med 1981 304:630 - 33

The relationship between coffee

consumption and pancreatic cancer

Smoking is closely associated with both

pancreatic cancer and coffee consumption.

There were many issues with control

selection and measurement of exposure
levels in cases and controls.

Subsequent studies were unable to

reproduce the result.

MacMahon B, et al. N Engl J Med 1981 304:630 - 33

Interpreting Associations - Causal and Non-Causa

Causal
Coffee Consumption

Non-Causal (due to
confounding)
Coffee Consumption

Real
Association

Spurious
Associatio
n

Smoking

Real
Association

Pancreatic Cancer

Pancreatic Cancer

Two Types of Association:

Real and Spurious

A real association is present if

the probability of occurrence of an event or

the quantity of a variable

depends upon the occurrence of one or

more other events, characteristics or
variables.

Spurious associations refer to noncausal associations due to chance, bias,

failure to control for extraneous variables
(confounding), etc.

Why is it important to distinguish

between causal and non-causal
associations?

Causal relationships are used to make

public health decisions and design
interventions.

In our example, if smoking was indeed

causal, it would be irresponsible to target
coffee drinking as an intervention.

Very important to consider all confounders.

Hubungan faktor dg penyakit

1. Hubungan statistik KAUSAL:
a. Langsung/DIRECT
* Dua arah
* Searah
b. Tak langsung/INDIRECT
2. Hubungan substantif

HUBUNGAN KAUSAL
DIRECT vs INDIRECT
DIRECT (LANGSUNG):
FAKTOR

OUTCOME

INDIRECT (TIDAK LANGSUNG):

FAKTOR OUTCOME
Step1
Step2

Figure 14-12 Direct versus indirect

causes of disease.
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2005 Elsevier

Types of Causal Relationships:

Direct vs Indirect
Direct
Factor

Indirect
Factor 1
Factor 2
Factor 3
Factor 4

Disease

Disease

Types of Causal Relationships:

Direct vs Indirect
Direct
F508 Polymorphism

Indirect
High cholesterol
Artery thickening
Hemostatic factors

Cystic Fibrosis

Myocardial infarction

Steps in causality
Need to answer 2 major questions
Is there actually an association?
If there is an association, is it
likely to be causal?

Steps in causing causality

Is there actually an association?
Association actually exists and is
statistically meaningful
Association is not due to chance so is
statistically significant
The association occurs at individual level
and not on ecological level (aggregate or
geographical unit)
Based on appropriate population based rates
eg odds ratio or relative risks

Steps in causing causality

If there is an association,
is it likely to be causal
Association is not due to bias
Selection bias
Information or measurement bias
Confounding bias
Confirmatory criteria for causality is satisfied
Based on specific qualities of association between
risk factor and disease

Pembuatan kesimpulan kausal

Penggunaan kriteria kausal
dalam pembuatan kesimpulan
dari data.

Evaluasi Hubungan Kausal

Postulat Koch:
Hanya berlaku untuk penyakit infeksi, tidak
berlaku untuk penyakit non-infeksi

Kriteria Bradford Hill:

Berlaku pada seluruh kondisis

 Postulat Koch-Henle berlaku pada

penyakit-penyakit infeksi, tetapi tidak
berlaku pada penyakit non-infeksi
Pada penyakit non-infeksi: pada media
kultur tidak akan tumbuh kuman

Understanding Causality

Lets say you have determined:

there is a real association,

you believe it to be causal (ruled out
confounding),
figured out that it is a direct causal factor
sorted out the necessary vs. sufficient
factor issue

NOW have your proven CAUSALITY?

Nine guidelines for judging

whether an association is causal

Temporal relationship

Strength of association

Dose response
relationship
Replication of the
findings
Biologic plausibility

Consideration of
alternate explanations

Cessation of exposure

Specificity of the
association

Consistency with
other knowledge

Bila melihat data dari studi epidemiologis, kita

sering menggunakan kriteria kasual untuk
membantu dalam pembobotan bukti.
Hal yang paling umum digunakan adalah
sebagai berikut,
dinyatakan pertama kali dari kerja Ahli
statistik dari Inggris Austin Bradford Hill, dan
kemudian dikembangkan lebih lanjut oleh
Surgeon General's Office, Amerika Serikat,
dalam laporannya tahun 1964 tentang merokok
dan kanker.

16.3 Hills Framework

Hill, A. B. (1965). The environment and disease: association or causation?
Proceedings of the Royal Society of Medicine, 58, 295-300.

1.
2.
3.
4.
5.
6.
7.
8.
9.

Strength
Consistency
Specificity
Temporality
Biological gradient
Plausibility
Coherence
Experimentation
Analogy

Hills Postulates
1.

Strength of Association the stronger the association, the less

likely the relationship is due to chance or a confounding variable

2.

Consistency of the Observed Association has the association

been observed by different persons, in different places, circumstances,
and times? (similar to the replication of laboratory experiments)

3.

Specificity if an association is limited to specific persons, sites and

types of disease, and if there is no association between the exposure
and other modes of dying, then the relationship supports causation

4.

Temporality the exposure of interest must precede the outcome by

a period of time consistent with any proposed biologic mechanism

5.

Biologic Gradient there is a gradient of risk associated with the

degree of exposure (dose-response relationship)

Hills Postulates (cont)

6.

Biologic Plausibility there is a known or postulated mechanism by

which the exposure might reasonably alter the risk of developing the disease

7.

Coherence the observed data should not conflict with known facts about
the natural history and biology of the disease

8.

Experiment the strongest support for causation may be obtained through

controlled experiments (clinical trials, intervention studies, animal
experiments)

9.

Analogy in some cases, it is fair to judge cause-effect relationships by

analogy With the effects of thalidomide and rubella before us, it is fair to
accept slighter but similar evidence with another drug or another viral disease
in pregnancy

Criteria 1: Strength
Relative risk as a measure of strength
Stronger RRs carry more weight
More difficult to explain away by confounders

But, do not dismiss small RRs

some causal relations will by nature have a
weak association
e.g., smoking and cardiovascular disease

KRITERIA KAUSAL
Postulat Hill (1)
1. Kekuatan asosiasi
asosiasi yang lebih kuat, kurang
mungkin berhubungan secara
kebetulan atau suatu variabel
perancu (confounding)

KEKUATAN
Apakah asosiasi itu kuat?
Perokok berat berasosiasi dengan
duapuluh kali lipat lebih tinggi tingkat
kanker paru-paru, dan dua kali lipat
tingkat penyakit jantung.
Asosiasi merokok dengan kanker paru
karena itu lebih kuat dari pada asosiasi
dengan penyakit jantung.
Asosiasi yang lebih kuat lebih
memungkin, itu adalah jadi sebab
sebenarnya.

Criterion 1: Strength
Stronger associations are less
easily explained by confounding
than weak associations
Ratio measures (like RR, SMR,
OR) are the best way to quantify
the strength of an association
Example: An RR of 10 is much
stronger evidence for causality
than an RR of 2

Strength of association
Which odds ratio would you be more likely to
infer causation from?
OR#1:

OR = 1.4

95% CI = (1.2 - 1.7)

OR#2:

OR = 9.8

95% CI = (1.8 - 12.3)

OR#3:

OR = 6.6

95% CI = (5.9 - 8.1)

Criteria 2: Consistency
Similar findings
using diverse methods
in different populations
under a variety of circumstances

Consistency alone does not prove causality

You can have consistently biased studies

KRITERIA KAUSAL
Postulat Hill
2. Konsistensi Asosiasi yang diamati
Mempunyai asosiasi yang diamati
oleh orang yang berbeda, tempat,
persoalan dan waktu yang berbeda?
(mirip dengan replikasi eksperimen
laboratorium)

KONSISTENSI
Konsistensi dapat juga berarti :
Replikasi pasti, sebagai ilmu
laboratorium, atau
Replikasi dalam banyak persoalan
yang berbeda.
Dalam epidemiologi, replikasi pasti
adalah tidak mungkin (impossible)

Criterion 2: Consistency
Consistency: studies using
diverse methods in different
populations under a variety of
circumstances lead to similar
conclusions
Example: Ecological, cohort,
and case-control done by
independent researchers
studying different populations
all showed a strong association
between smoking and lung
cancer.

KRITERIA KAUSAL
Postulat Hill (2)
3. Spesifisitas
Jika suatu asosiasi terbatas pada
orang, tempat dan tipe penyakit
tertentu (spesifik), dan jika tidak
ada asosiasi antara ekposur dan
model lain kematian, kemudian
hubungan itu mendukung kausasi

Criteria 3: Specificity
Factor leads to a specific disease
Requires knowledge at cellular level
Converse is NOT true
Some casual relations are non-specific
e.g., smoking causes multiple diseases

SPESIFISITAS
Kausalitas diperkuat jika eksposur
diasosiasikan dengan suatu penyakit
spesifik, dan bukan dengan
keseluruhan varitas penyakitpenyakit

Contoh 1.
Asbestos sebab penyakit paru-paru spesifik,
asbestosis, dapat dibedakan dari berbagai
penyakit paru-paru lainnya.
Tetapi eksposure timbal pada tingkat rendah
dihubungkan dengan IQ (Intelligent Quotient)
yang lebih rendah daripada suatu sindrom otak
yang dapat dibedakan.
Jadi timbal (Pb = Plumbum = timah hitam)
lebih tidak tentu sebagai sebab karena
kemungkinan rancu dengan sebab-sebab yang
lain, ini bukan efek yang spesifik, IQ rendah
(misal SES = Social Economic Status).

Criterion 3: Specificity
The factor is linked to a
specific causal mechanism
Example: Smoking is linked to
physical and chemical
carcinogenesis of epithelial
cells
Comment: Mechanisms are
difficult to establish when there
is a vacuum of knowledge

Aristotle
(384 322 BCE)

KRITERIA KAUSAL
Postulat Hill
4.

Temporalitas/Urutan waktu
Eksposur yang menjadi
perhatian harus mendahului
outcome (penyakit) menurut
periode waktu yang konsisten
dengan berbagai usulan
mekanisme biologik

URUTAN WAKTU
Ini kriteria yang sangat penting secara
sederhana menyatakan bahwa orang
harus mengetahui pasti bahwa sebab
mendahului akibat dalam waktu.
Kadang-kadang ini sulit mengetahui ,
terutama dalam studi kroseksional
(penelitian survei).

Contoh 1.
Studi telah menemukan hubungan
terbalik antara tekanan darah seseorang
dengan kadar kalsium serum. Tetapi
yang mana sebab dan yang mana akibat?
Urutan waktu dapat juga menjadi tidak
tentu bila penyakit mempunyai periode
laten yang panjang, dan bila eksposur
mungkin juga mewakili efek durasi yang
panjang.

Criterion 4: Temporality
Exposure precedes disease by a reasonable
amount of time
Lead encephalopathy scenario 1:

Lead encephalopathy scenario 2:

Gerstman

Chapter 16

68

KRITERIA KAUSAL
Postulat Hill (3)
5. Gradien biologik
Ada suatu gradien risiko
berhubungan dengan derajat
eksposur (hubungan dosisrespons)

Hubungan Dosis-respons
Jika suatu gradien teratur risiko
penyakit ditemukan paralel terhadap
gradien eksposur (misal: perokok ringan
mendapat kanker paru pada tingkat
menengah antara bukan perokok dengan
perokok berat) kemungkinan hubungan
kausal diperjelas.
Dosis-respons umumnya dipikirkan
sebagai suatu sub-kategori kekuatan.

Contoh:
Untuk setiap peningkatan
jumlah rokok yang dihisap,
risiko kanker paru meningkat.

Cohort study: Tobacco smoking and lung

cancer, England & Wales, 1951

Source: Doll & Hill

Biological Gradient
There is evidence of a dose-response relationship
Changes in exposure are related to a trend in
relative risk

CRITERION 5: Biological Gradient

Increases in exposure dose dose-response in risk

Gerstman

Chapter 16

74

KRITERIA KAUSAL
Postulat Hill (3)
6. Plausibilitas biologik
Diketahui atau ada mekanisme
yang dipostulasikan menurut
ekposur yang mungkin
beralasan setelah risiko
perkembangan penyakit

Criteria 6: Plausibility
Plausible = makes sense in face of
known biological and and other
facts
But what of new previously
unexplained associations?
Where does new knowledge
come from?

Criterion 6: Plausibility
Plausible mechanism
in face of known
biological facts
Plausibility (defined):
appearing worthy of
belief

Gerstman

Comment: All that is

plausible is not always true

Chapter 16

77

KRITERIA KAUSAL
Postulat Hill (4)
7. Koherens
Data yang diamati tidak harus
konflik dengan fakta yang
diketahui tentang riwayat
alamiah dan biologi penyakit

KOHERENS
Apakah asosiasi sesuai (cocok) dengan

pengetahuan biologis?
Seseorang harus mencari dukungan
pemeriksaan laboratorium, atau
dari aspek kondisi biologi yang lain.

Criteria 7: Coherence
Do the facts cohere
(i.e., to stick
together)?

Criterion 7: Coherence
All facts stick together to
form a coherent whole.
Example: Epidemiologic,
pharmacokinetic,
laboratory, clinical, and
biological data create a
cohesive picture about the
smoking and lung cancer.
Gerstman

Chapter 16

81

KRITERIA KAUSAL
Postulat Hill (4)
8. Eksperimen
Dukungan yang paling kuat untuk
mendukung penyebab mungkin
dapat diperoleh melalui
ekperimen yang dikontrol
(percobaan klinis, studi
intervensi, percobaan hewan)

Criteria 8: Experimentation
Experimental evidence should support
observational studies
Types of experiments
Epidemiologic (trials)
In vitro
Animal models
Natural experiments

Criterion 8:

Experimentation

Experimental evidence
supports the
epidemiologic evidence
In vitro and in vivo
experiments
Experimentation is
often not possible in
humans
Animal models of
human disease
Gerstman

Chapter 16

84

KRITERIA KAUSAL
Postulat Hill (5)
9. Analogi
Pada beberapa kasus, adalah wajar
menilai hubungan sebab akibat
menurut analogi.
Dengan efek talidomid dan rubella
sebelum kita, adalah wajar bersikap
menerima tetapi pembuktian yang mirip
dengan obat atau virus yang
menyebabkan penyakit pada kehamilan

CONTOH:
Adanya penanda (marker) serologis
infeksi Hepatitis B dihubungkan dengan
laju peningkatan yang besar kanker hati.
Bahwa infeksi Hepatitis B adalah sebab
yang benar dari kanker hati, juga
ditunjang oleh penemuan genom viral
dalam berbagai kanker hati.

Sebaliknya, Reserpine (suatu obat antihipertensif) dipikirkan menjadi suatu

sebab kanker payudara berdasarkan atas
studi yang dilakukan awal tahun 1970an.
Tetapi tidak ada informasi biologis yang
menunjang, atau berbagai mekanisme
biologis yang dapat dijelaskan secara
benar. Rangkaian studi yang lebih besar
gagal mendukung hubungan ini..

Criteria 9: Analogy
Similarities among things that are
otherwise different
e.g., before HIV was discovered,
epidemiologists noticed that AIDS and
Hepatitis B had analogous risk groups
Evidence of similar transmission
Note: analogy is a weak form of
evidence

Criterion 9: Analogy
Similarities among things
that are otherwise different
Weak form of evidence
Example: Before the HIV
was discovered,
epidemiologists noticed that
AIDS and Hepatitis B had
analogous risk groups,
suggesting similar types of
agents and transmission
Gerstman

Chapter 16

89

Criteria for Causation:

Smoking and Lung Cancer

Temporal relationship
Biologic plausibility
Consistency
Alternatives
Cessation effects
Specificity of
association
Strength of
Association

Dose-response

Smoking before Ca
Yes
> 36 studies
?
Yes
Point of attack
25 x > 25+
cigarettes /day*
Yes

*.Estimated that 80% of all Lung cancer due to Cigarette smoking

Why was it relatively easy to determine

that smoking was a cause of lung cancer?

History of exposure to cigarettes can be

assessed with reasonable accuracy.
Cigarette smoking is common and present
in persons whose environment is
otherwise similar to that of nonsmokers.
Lung cancer incidence in smokers is much
greater than in nonsmokers.
Lung cancer is uncommon in nonsmokers.

Why will it be relatively hard to determine

if community air pollution is a cause of
lung cancer?

Difficult to measure pertinent exposure

Long latent period of disease
Migration
Little variation in exposure among
individuals within a community
Lung cancer is common, even among
persons not exposed to pollution.

DIRECT
ASSOCIATION

NO
ASSOCIATION
NO POSSIBILITY FOR POSSIBILITY
ASSOCIATION
ASSOCIATED

-Physically not
possible
-Scientifically/
medically not
probable
-Statistically
not associated

-Remote
cause-effect a
possibility
-Not
statistically
associated at
an acceptable
level (50%60%)
-Secondarily
association

ASSOCIATED

-Cause-effect
associated
exists
-Causally
associated
but an indirect
association
-Scientifically
connected
Statistically
associated
but not
causative
association

Figure 10.4 Continuum of association

DIRECT CAUSEEFFECT

-Causality
assurance
-Association
affirmed
-Scientifically
and
biomedically
proven
-Physically
possible
-Statistically
proven

Associations are observed

Causation is inferred
It is important to remember that these
criteria provide evidence for causal
relationships.
All of the evidence must be considered
and the criteria weighed against each
other to infer the causal relationship.

Causal Inference: Realities

No single study is sufficient for causal
inference
Causal inference is not a simple process
consider weight of evidence
requires judgment and interpretation

No way to prove causal associations for

most chronic diseases and conditions

Judging Causality

Weigh weaknesses
in data and other
explanations
RS Bhopal

Weigh quality
of science and
results of causal
models

Epidemiology Kept Simple

Chapter 16
From Association to Causation
(Causal Inference)
Gerstman

Chapter 16

99

References
1.

2.

3.

4.
5.

Porta M. A dictionary of epidemiology. New York,

Oxford: Oxford University Press, 2008.
Susser MW. What is a cause and how do we know
one ? A grammar for pragmatic epidemiology.
American Journal of Epidemiology 1991; 133: 635648.
Rothman J, Greenland S. Modern epidemiology.
third edition. Lippincott - Raven Publishers, 2008.
Gordis L, Epidemiology .fourth edition .Saunders
Elsevier,2009