CONCEPT OF CAUSATION
(DISEASE)
ROLL NO. 81-87
Objectives:
● Pre- scientific concept of diseases
● Germ Theory and Koch’s postulates
● Web of Causation and multifactorial
causation of disease
● Bradford Hill’s Criteria
● Randomised Controlled Trials
Pre-Scientific Concepts of Disease
Introduction
• Understanding disease concepts is vital for
public health development.
• Pre-scientific concepts laid the foundation for
later medical theories.
• Influenced early public health practices,
rituals, and health systems.
Broad Classification
Pre-scientific concepts of disease:
• Supernatural theory
• Humoral theory
• Miasmatic theory
• Contagion theory (early stage)
Supernatural Theory
• Diseases caused by:
- Wrath of gods
- Evil spirits or demons
- Sin or immoral behavior
• Treatment:
Prayers, rituals, sacrifices, exorcisms
• Still found in some cultures today.
Humoral Theory
• Origin: Ancient Greece – Hippocrates
and Galen
• The concept of humors have arose in early
egyptian medicine
• But Systematized during greek era
• Hippocrates suggested that humors - Blood,
Phlegm, Yellow Bile and Black Bile are Vital body
fluids
• A person’s physical well-being and mental health
depend on a dynamic balance between the four
major humours
• When the quality and quantity of the humours is in
balance, health prevails.
• When out of balance, disease will appear’
FIG: Example of common ailments and their corresponding humoral status are
shown
TREATMENT:
• Balance the humoral imbalance in body
• Herbal Medicines
• Dietary and lifestyle modifications
Miasmatic Theory
Fig 1
An 1831 color
lithograph by
Robert Seymour
depicts cholera as a
robed, skeletal creatu
re
emanating a deadly
black cloud
• Disease caused by “bad air” or “miasma” from
decaying matter
•The theory held that epidemics were caused by
miasma, emanating from rotting organic matter
• Prominent in the 18th and early 19th centuries
• Encouraged: - Sanitation reforms
- Urban drainage
• Example: Belief during cholera epidemics,
plague and chlamydia
Early Contagion Theory
• Proposed by Girolamo Fracastoro (1546)
• Infections are caused by transferable seed like
beings,seminaria or germs ,which could cause
infections
• According to Fracastoro ,
• Some diseases, such as syphilis and
gonorrhea were only transmitted by direct
contact
• Other diseases were transmitted by fomites as
clothing, that had been in contact with the
sick.
• The third category he placed diseases such as
tuberculosis and smallpox capable of infecting
persons at a distance from the sick and
transmitted by air.
• Fracastoro’s theory is considered to be the
first theoretical statement of the contagious
theory of the disease
• This theory paved way for development of
Germ Theory of Disease
Conclusion
• Pre-scientific concepts were stepping stones
in disease understanding
• Though obsolete scientifically, they impacted
social and health practices
• Understanding history helps contextualize
modern public health
Germ Theory Of Disease
Definition:
• Germ theory of disease states that certain
diseases are caused by the invasion of the
body by microorganisms, Organisms too
small to be seen through a microscope .
Germ Theory of disease is given by
Robert Koch Louis Pasteur Joseph Lister
▪ This theory gained momentum during 19th
and early part of 20th century.
▪ The emphasis had shifted from empirical
causes(Ex bad air) to microbes as the sole
cause of disease.
▪ The concept of cause embodied in the germ
theory of disease is generally referred to
as a one to one relationship between
causal agent and disease .
▪ The disease model accordingly is
Disease agent Man Disease
• Swan neck Flask experiment :
1) This was performed Louis Pasteur.
2) It disapprove the spontaneous generation theory
and support the germ theory.
Implication of Germ Theory
1. It led to better disease prevention ,diagnosis
and treatment .
2. It leads to improved hygiene and sanitation.
3. Public health policies to control infections .
4. It leads to safe surgeries and medical
procedure.
5. It laid to foundation for sterilisation and
aseptic techniques in medicine.
Drawbacks of Germ Theory
1) It led many epidemiologist to take one sided
view of disease causation.
2) It is now recognised that a disease is rarely
caused by a single agent alone ,but rather
depends upon a number of factors, which
contribute to its occurrence.
3) Also, many metabolic disease are also there in
which there is no any involvement of any
pathogen.
4) Therefore, modern medicine has moved away
from strict adherence to the germ theory of
disease.
Koch’s Postulates
Robert Koch
● Robert Koch provided remarkable
contribution to the field of
microbiology.
● He was a German general
practitioner (1843-1910).
● Discovered the mycobacterium
and vibrio cholera.
● His contribution are as follows:
1. He introduced solid media for the culture of bacteria.
2. He also introduced methods for isolation of bacteria in
pure culture.
3. He described hanging drop methods for testing motility.
4. He discovered bacteria such as the anthrax bacilli, tubercle
bacilli and cholera bacilli.
Anthrax bacilli Tubercle bacilli Cholera bacilli
Koch's Postulates
Robert Koch had postulated that a microorganism can be accepted as the
causative agent of an infectious disease onlyif four criteria are fulfilled. These
criteria are as follows:
1. The microorganism should be constantly associated with the lesions of
the disease.
2. It should be possible to isolate the organism in pure culture from the
lesion of the disease.
3. The same disease must result when the isolated microorganism is
inoculated into a suitable laboratory animal.
4. It should be possible to re-isolate the organism in pure culture from the
lesions produced in the experimental animals.
● An additional fifth criterion was introduced subsequently which
states that antibody to the causative organism should be
demonstrable in the patient's serum.
Exceptions to Koch’s Postulates:
● Mycobacterium leprae and Treponema pallidum
● Neisseria gonorrhoeae
Web of Causation
&
Multifactorial causation of disease
General Models of Causation
The epidemiological triad (triangle)
The wheel
The Web
The Triangle of epidemiology
It shows interaction and interdependence of :
1.agent(the cause of disease),
Can be bacteria, viruses, parasites, fungi, molds.
2. host (organism that harbours the disease),
The level of immunity, genetic makeup, level of exposure, state of health and
overall fitness of the host can determine the effect an agent can have on it.
The ability of pathogen to accept the new environment can also be a
determining factor because some pathogens thrive only under limited ideal
conditions.
3. Environment (surroundings & conditions external to human)
Includes biological, social, cultural, physical aspects (environment can be
within a host or external to it)
4.time (incubation period/life expectancy/duration of the course of illness)
Severity of illness in relation to how long a person is affected or until the
condition causes death or passes the threshold of danger towards
recovery.
5. Vector : involved in transmission
and propagation of parasites
(mechanical, biological)
Multifactorial Causation of disease
“Disease is caused due to multiple factors.”Pettenkofer of Munich.
The purpose of knowing the multiple factors of disease is to
quantify and arrange them in priority sequence for modification
to prevent or control disease.
Drawback of Germ Theory: The so-called modern diseases
of civilization, e.g. Lung Cancer, CAD, bronchitis, psychiatric
disorders cannot be explained on the basis of germ theory of
disease .
Unlike infectious diseases, they can’t be prevented by isolation,
immunization or improvement in sanitation.
Advanced model of the triangle of epidemiology
It includes all facets of the communicable disease model
and also the modern diseases.
In this new model the term agent is replaced by causative
factors.
Web Of Causation
Suggested by MacMahon & Pugh in their book:
Epidemiologic Principles and Methods
Considers all the predisposing factors of any type and their complex
interrelationship with each other.
The web of causation doesn’t implies that the disease cannot be
controlled unless all the causes are removed.
It depends on the relative importance / relative risk of these factors.
Suitable for the study of chronic disease, where disease agent is often not
known & it is the outcome of interaction between multiple factors
(biological, environmental, immunological, nutritional, genetic,
social/spiritual)
Individual interventions can be employed at individual
technical levels , whereas supraindividual factors can
be at higher or second level intervening at population
level health.
Social inequalities influences the genesis and
perpetuation of certain disorders, and social
determinants do affect genetic endowments, which in
turn will influence other determinants, thus setting up
a vicious or virtuous cycle, depending upon the
outcome.
Natural history of disease refers to the progress of a
disease process in an individual over time, in the
absence of intervention.
The process begins with exposure to or accumulation of
factors capable of causing disease.
Without Medical intervention, the process end with :
--Recovery
--Disability
--or Death
Helps to suggest ways to interrupt the risk of transmission.
Sometimes removal of just one link may be sufficient to control disease.
When the disease is multifactorial numerous factors or variables become
implicated in the web.
ASSOCIATION: concurrence of 2 variables more often than would be expected
by chance
OR
Events are Associated when they occur more frequently together than one
would expect by chance.
CORRELATION: indicates the degree of association between 2 characteristics.
The correlation coefficients range from -1.0 to +1.0 .
A correlation coefficient of 1.0 means that 2 variables exhibit perfect linear
relationship.
Association can be broadly grouped under 3 headings:
1. Spurious association
2. Indirect association
3. Direct(causal) association
(i) one to one casual association
(ii) Multifactorial causation
Factor 1
Reaction at
Disease
Factor 2 cellular level
Factor 3
Alternative casual factors each acting independently
e.g. Lung cancer
Factor 1
+ Reaction at
Factor 2 Disease
cellular level
+
Factor 3
Multifactorial causation showing synergism
Here each of the several factors act independently , but
when an individual is exposed to 2 or more factors, there
may be a synergistic effect.
BRADFORD HILL’S CRITERIA
• BRADFORD HILL’S
CRITERIA
▪ Bradford Hill’s criteria also known as Hill’s criteria for
causation, are a group of Nine principles, established
in 1965 by the English epidemiologist Sir Austin Bradford Hill.
▪ They can be useful in establishing epidemiologic evidence of a
causal relationship between a presumed cause and observed
effect and have been widely used in public health research.
▪ They are most commonly applied to non-communicable
(chronic)
disease like cancer, Heart disease, lung disease etc.
• BRADFORD HILL’S
CRITERIA
1. Temporal association
2. Strength of association
3. Specificity of the association
4. Consistency of the association
5. Biological plausibility
6. Coherence of the association
7. Biological Gradient
8. Experiment
9. Analogy
1. TEMPORAL
ASSOCIATION
▪“Temporality is the sine qua non , means if a
factor is believed to be the cause of a
disease, then it must precede the occurance
of the disease.”
▪ Temporality is the most crucial Hill criterion
because it is the only absolute essential
criterion for establishing a causal
relationship.
▪ Example- If smoking is a cause of lung
cancer, then smoking must occur before the
development of lung cancer.
2. STRENGTH OF
ASSOCIATION
▪The stronger an association, the more
likely it is causal. This does not means
that weak association are not causal,
but strong association are less likely to
be explained by confounding or bias.
▪Example – Heavy cigarette smokers
have 20-30 times more risk to develop
lung cancer as compared to non
smoker.
3. SPECIFICITY OF THE
ASSOCIATION
▪ Specificity means that a cause leads to a
single effect, not multiple effects . While
helpful, this criterion is not essential as
many diseases are multifactorial.
▪Example – Asbestos causes Mesothelioma
Treponema pallidium causes
Syphilis.
4. CONSISTENCY OF THE
ASSOCIATION
▪ Consistency means that an association is
observed repeatedly by different researchers ,
in different populations , and under different
circumstances.
▪Example – Cigarette smoking is associated with
lung cancer . It shows consistency because
observed in multiple studies , different
populations and by different researchers.
Doll and Hill ( 1950s, Uk ) , Hammond and
Horn (1958,USA)
5. BIOLOGICAL
PLAUSIBILITY
▪ It will be helpful if the causation we
suspect is biologically plausible. But this is
feature we cannot demand. What is
biologically plausible depends upon the
biological knowledge of the day .
▪ Example– Smoking → Lung Cancer
▪Tobacco smoke contains carcinogens (e.g.,
benzopyrene, nitrosamines).
▪These chemicals are known to cause
genetic mutations in lung tissue.
6. COHERENCE OF THE
ASSOCIATION
▪The cause-and-effect interpretation of our
data should not seriously conflict with the
generally known facts of the natural
history and biology of the disease.
▪Example - If smoking is linked to lung
Cancer in population studies, and also
causes cancer in lab animals and
damages lung tissue – all the evidence fits
together. That makes the association
coherent.
7. BIOLOGICAL
GRADIENT
▪If a dose – response curve is seen , this is an
additional argument in favour of causation.
▪ More exposure- More risk
Less exposure –Less risk
▪ Example – Smoking and lung cancer .
People who smoke 1cigarette/day have
low risk than who smoke 10cigarett
/day.
8. EXPERIMENT
▪ Experiment means that if
changing the exposure, changes
the outcome, it supports cause –
and – effect relationship
▪ Example – when smokers quit
smoking, their lung function
improves , and their risk of lung
cancer and heart disease
decrease.
9. ANALOGY
▪Analogy means similar exposure cause
similar effects.
▪ Analogy is the weakest of all the criteria.
▪It is supportive but not conclusive.
▪ Example – Thalidomide → Congenital
Malformations
▪Based on this known association, other
structurally similar drugs were also
evaluated for teratogenic effects.
SUMMARY
No. Criterion Explanation
1️⃣Temporality Cause must come before the effect (most essential)
2️⃣Strength Strong associations are more likely to be causal
3️⃣Consistency Repeated findings in different settings
4️⃣Specificity One cause leads to one effect (not always applicable)
5️⃣Biological Gradient More exposure → more risk (dose-response)
6️⃣Plausibility Association fits with current biological/scientific knowledge
7️⃣Coherence Fits with natural history and biology of the disease
8️⃣Experiment Intervention removes or reduces disease → supports
Causation
9️⃣Analogy Similar exposures cause similar effects
Randomized Controlled Trials
(RCTs)
Introduction to RCTs
• An RCT is a type of experimental study
designed to evaluate the effectiveness of an
intervention by randomly allocating
participants into experimental and control
groups.
• Purpose: To eliminate bias and establish
causality.
Historical Perspective
• First RCT: James Lind's scurvy trial in 1747.
• Evolution: From simple trials to complex,
multicenter studies.
Key Features of RCTs
• - Randomization: Ensures equal distribution of
confounding factors.
• - Control Group: Provides a baseline to
compare the intervention effect.
• - Blinding: Minimizes bias.
• - Prospective Design: Follow participants over
time.
Steps in Conducting an RCT
• 1. Formulate a Hypothesis
• 2. Select Participants
• 3. Random Allocation
• 4. Implement Intervention
• 5. Follow-Up
• 6. Outcome Assessment
• 7. Data Analysis
Randomization Techniques
• - Simple Randomization: Using random
numbers
• - Block Randomization: Ensures equal group
sizes
• - Stratified Randomization: Controls for
specific variables
Blinding in RCTs
• - Single-Blind: Participants unaware
• - Double-Blind: Participants and researchers
unaware
• - Triple-Blind: Participants, researchers, and
analysts unaware
Types of RCTs
• - Parallel Group Design: One intervention per
participant
• - Crossover Design: Multiple interventions
sequentially
• - Factorial Design: Evaluates multiple
interventions
• - Cluster Randomized Trials: Randomize groups
Advantages of RCTs
Disadvantages of RCTs
Applications of RCTs
Why RCTs are still considered the gold
standard?
1. No Better Alternative
- No other design matches RCTs’
randomization + control
2. Mitigable Limitations
- Pragmatic RCTs, Intention To Treat
Analysis(ITT) address flaws
3. Foundation of Evidence
- Clinical guidelines rely on RCT data
"RCTs are the least flawed method to prove
causality, despite limitations."
RCT in patients with COVID-19
Aim :To systematically review RCTs involving
moderate to severe COVID -19 patients.
• To assess the risk of bias in these trials using a
standard tool(RoB 2.0)
• To identify areas where methodological
improvements are needed .
Methodology
40 randomized trials were selected .
1.Five domains were assessed
– Randomisation process
– Deviations from intended interventions
– Missing outcome data
– Measurement of the outcome
– Selection of the reported result
Key findings
1.47% of the RCTs were rated as having high
risk bias .
2.Common issues included
– Lack of blinding
– Selective reporting of outcomes
– Protocol deviations
– Trial conducted in low and middle income
countries were more likely to show higher bias .
Limitation : only moderate to severe COVID -19
cases were included .
Rapidly evolving research environment during the
pandemic may have affected study quality.
Implications for future research
• Improve trail design with proper randomisation
and blinding
• Publish trial protocols before starting the study .
• Ensure transparent and complete reporting of
results.
Conclusion
• RCTs remain the gold standard for evaluating
interventions.
• They require meticulous planning and ethical
oversight.
• Results must be interpreted considering study
limitations.
References
• Park K. Preventive and Social Medicine, 27th
Edition
• Gordis Epidemiology
• Randomized controlled trials in patients with
COVID-19: a systematic review and critical
appraisal-PubMed Central
• Austin Bradford Hill:The Environment and
Disease:Association or Causation?
