L59 - Introduction to Disease Causation

What is Disease Causation?

Understanding the factors and mechanisms that contribute to disease development

How do we Progress from Patient Observations to Causal Inference?

• Identify patterns

• Investigate exposures

• Assess determinants

• Evaluate causal evidence

What are the Three Phases of the Causal Pathway?

1. Etiological phase

2. Preclinical phase

3. Clinical phase

What is the Etiological Phase?

The period before biological disease onset when agent, host, environmental, risk, and protective factors operate

• EX: SARS-CoV-2 Exposure

What is the Difference between Preclinical and Clinical Phases?

• Preclinical disease develops before recognizable signs

  • EX: SARS-CoV-2 Test Postitve

• Clinical disease involves symptoms, diagnosis, and treatment

What is a Direct Causal Pathway?

A pathogen directly produces disease without intermediate factors and is both necessary and sufficient for disease

Why are Direct Causal Pathways Rare in Real Life?

Individuals differ in susceptibility, immunity, exposure, and disease outcomes

What is an Indirect Causal Pathway?

A pathway in which additional factors modify the relationship between exposure and disease development

What is the Difference between Direct and Indirect Causation?

• Direct: No modifying factors

• Indirect: Additional factors influence disease outcomes.

What is the Epidemiologic Triad?

A framework describing how agent, host, and environmental factors interact to influence disease occurrence

What are the Three Components of the Epidemiologic Triad?

1. Agent

2. Host

3. Environment

What is a Complex Web of Causation?

A network of interacting biological, environmental, and social factors that contribute to disease

What are Examples of Agent Determinants for Infectious Diseases?

• Survival outside the host

• Virulence

• Infectiousness

• Exposure dose

• Duration of contact

What are Examples of Host Determinants for Infectious Diseases?

• Reproductive status

• Susceptibility

• Behavior

• Movement

What are Examples of Environmental Determinants for Infectious Diseases?

• Housing

• Vectors and proximity to other species

• Climate

• Water availability

What are Examples of Determinants for Noninfectious Diseases?

AGENT

• Exposure dose

• Duration of exposure

• Agent potency

• Degradation

• Biomagnification

HOST

• Genetics

• Stress

• Immune response

ENVIRONMENT

• Weather

• Wind

What is a Cause in Epidemiology?

A factor, event, condition, or exposure that plays an essential role in producing disease or influencing when it occurs

Why does Correlation Not Prove Causation?

Two factors may be associated because of a shared factor, without causing each other

What is the Difference between Association and Causation?

• Association → Means two factors occur together

• Causation → Means one factor contributes to producing the outcome

What is a Risk Factor?

A characteristic or exposure associated with an increased likelihood of disease

What is a Protective Factor?

A factor that reduces the likelihood of disease

• EX: Vaccination

Why is Establishing Disease Causation Difficult?

Disease often involves multiple interacting factors, and observed associations do not necessarily indicate causation

What is the Main Purpose of Causal Frameworks?

To systematically evaluate evidence and determine whether an observed association is likely causal

Why are Causal Frameworks Not Considered Rigid Checklists?

No

• Framework provides absolute proof, and some criteria may not apply to every causal relationship

What are the Four Steps of Koch's Postulates?

1. Presence in disease

2. Isolation

3. Reproduction of disease

4. Re-isolation

What are Koch's Four Postulates?

The organism is present in diseased hosts, isolated and cultured, causes disease in a susceptible host, and is re-isolated

What are the Major Limitations of Koch's Postulates?

• Difficulty culturing some agents

• Asymptomatic carriers

• Variable outcomes

• Limitations of animal models

• Noninfectious diseases

What was the Importance of the Framingham Heart Study?

It used a cohort study to investigate how factors such as smoking, cholesterol, and blood pressure relate to cardiovascular disease

What was the Importance of the Doll and Hill Study?

It used a case-control approach to demonstrate a strong association between cigarette smoking and lung cancer

What are the Nine Criteria in the 1964 Guidelines?

1. Temporality

2. Strength

3. Dose-response

4. Experiment

5. Consistency

6. Biological plausibility

7. Alternate explanations

8. Specificity

9. Coherence

What is the Most Essential Criterion for Causation?

Temporality: exposure must occur before disease develops

What is Temporality, and Why Is It Essential?

Exposure must occur before the biological onset of disease → A cause cannot follow its effect

Nine Criteria in the 1964 Guidelines (1/9)

What is Strength of Association?

The magnitude of the observed relationship between an exposure and disease

• Stronger associations may support causality

Nine Criteria in the 1964 Guidelines (2/9)

What is a Dose-Response Relationship?

A pattern in which disease risk changes with the amount of exposure, often increasing as exposure increases

Nine Criteria in the 1964 Guidelines (3/9)

What is the Experiment Criterion for Causation?

Disease risk may decrease when exposure to the suspected causal factor is removed

Nine Criteria in the 1964 Guidelines (4/9)

What is Consistency or Replication?

Similar findings are observed across independent studies, populations, times, or circumstances

Nine Criteria in the 1964 Guidelines (5/9)

What is Biological Plausibility?

The proposed causal relationship is consistent with a reasonable biological mechanism

Nine Criteria in the 1964 Guidelines (6/9)

What are Alternate Explanations in Causal Inference?

Other possible reasons for an observed association

• Including confounding factors

Nine Criteria in the 1964 Guidelines (7/9)

What is Specificity, and Why Is It Limited?

One exposure is associated with one disease

• It is limited because a single exposure may cause multiple diseases

Nine Criteria in the 1964 Guidelines (8/9)

What is Coherence in Causal Inference?

Findings agree with other established scientific knowledge, while allowing for new discoveries

Nine Criteria in the 1964 Guidelines (9/9)

How does HPV demonstrate Disease Causation?

HPV infection precedes cervical cancer, shows strong and consistent associations, has biological evidence, and can be prevented through vaccination

What are the Four Criteria in the 1986 Guidelines?

1. Temporality

2. Biological plausibility

3. Consistency

4. Lack of confounding

What Is Confounding?

A distortion of an exposure–disease association caused by another factor associated with both

Why are Ecological and Social Determinants Important?

They influence exposure, susceptibility, access to prevention, and overall disease outcomes

What are Predisposing Factors?

Factors that increase an individual's susceptibility to developing disease

• Distant

• Social determinants

What are Enabling and Precipitating Factors?

• Enabling factors → Facilitate disease development

  • Intermediate

  • Risk factors

• Precipitating factors → Help trigger disease occurrence

  • Proximate

  • Direct or final cause

What is the Difference between Necessary and Sufficient Causes?

• Necessary: Must be present

• Sufficient: Complete cause or combination that produces disease

What is a Necessary Cause?

A factor that must be present for a particular disease to develop but may not produce disease by itself

What is a Sufficient Cause?

A complete factor or combination of factors capable of producing a disease outcome

What is a Component Cause?

An individual contributing factor that forms part of a sufficient causal mechanism

What is the Causal Pie Model?

A model illustrating how different combinations of component causes can produce the same disease

How can Causal Pies help identify prevention opportunities?

Interrupting a component cause can prevent completion of a sufficient causal pathway

How do Epidemiologists move from Observations to Understanding Disease Causation?

They identify disease patterns, investigate exposures and determinants, evaluate associations, and assess evidence using causal frameworks

Koch's Postulates vs. 1964 vs. 1986 Causal Frameworks SUMMARY

Framework	Main Criteria	Limitations
Koch's Postulates (1880)	Presence → Isolation → Reproduction → Re-isolation	Does not explain many viruses, asymptomatic carriers, or noninfectious disease
1964 Guidelines	9 criteria evaluating associations	Some criteria, such as specificity, are not always applicable
1986 Guidelines	Temporality, biological plausibility, consistency, lack of confounding	Requires evaluation of multiple lines of evidence
Modern Multifactorial Model	Interacting component causes, risk factors, and environmental influences	Complex causal relationships can be difficult to isolate

Remember: Temporality is essential across causal inference frameworks.

Nine Criteria of Causation (1964) SUMMARY

Criterion	Meaning
Temporality	Exposure must occur before disease develops
Strength	Stronger associations provide greater support for causation
Dose-response	Disease risk changes with increasing exposure
Experiment	Removing an exposure may reduce disease risk
Consistency	Findings are repeated across different studies or populations
Biological plausibility	A reasonable biological mechanism explains the relationship
Alternate explanations	Other explanations, including confounding, must be considered
Specificity	An exposure is associated with a particular disease
Coherence	Evidence agrees with existing scientific knowledge

Important: Temporality is essential. The other criteria strengthen causal evidence but are not all required in every case.

Necessary vs. Sufficient vs. Component Causes SUMMARY

Cause	Definition	Key Point
Necessary	Must be present for disease to occur	Required but may not be enough
Sufficient	Complete combination of factors capable of producing disease	Enough to produce disease
Component	Individual factor contributing to a sufficient cause	One piece of the causal pie

Remember: Multiple combinations of component causes can produce the same disease.

Epidemiologic Triad SUMMARY

Agent	Host	Environment
Infectiousness	Age	Housing
Virulence	Immune status	Climate
Exposure dose	Genetics	Population density
Survival outside host	Reproductive status	Water availability
Exposure duration	Behavior	Vectors
Potency (noninfectious)	Stress	Species mixing
Degradation	Susceptibility	Environmental contamination

Remember: Disease outcomes are influenced by interactions among agent, host, and environmental determinants.

Types of Disease Factors SUMMARY

Factor	Definition	Example
Predisposing	Increases susceptibility to disease	Genetic susceptibility
Enabling	Facilitates disease development	Crowded housing
Precipitating	Helps trigger disease	Exposure to an infectious agent
Protective	Reduces disease risk	Vaccination

Important: A risk factor is associated with increased disease risk, but association alone does not establish causation.

How Do We Go from Patient Observations to Understanding Disease Causation? SUMMARY

1. Observe Disease Patterns

   • Identify unusual disease occurrence in patients or populations

2. Identify Potential Determinants

   • Investigate agent, host, environment, and risk factors

3. Evaluate Associations

   • Determine whether exposures are associated with disease

4. Apply Causal Frameworks

   • Evaluate temporality, plausibility, consistency, and confounding

5. Establish Causal Understanding

   • Integrate evidence and identify opportunities for disease prevention