Faculty of Medicine Introduction to Community Medicine Course

(31505201)

Disease Causation

By

Hatim Jaber MD MPH JBCM PhD

29- 11- 2017

1

World AIDS Day, 1 December 2017

We can End Polio!

• Polio cases worldwide:

1988: 350000 2016: 27

• Since 1988, we have reduced polio cases by

99.9%.

3

Post midterm

• Week 8 Unit 6: Demography and Data • Week 9 Midterm assessment (Exams.)15-11-2017 • Week 10 Unit 8 Introduction to Epidemiology. • Week 11 Unit 9: Prevention and Control of Diseases

Causation • Week 12 Unit 10: Health Education and Communication • Week 13 Unit 11: Public Health Surveillance and Screening • Week 14 Unit 12: Health Administration and healthcare management • Week 15 Unit 13: Revision and Health Research

• Week 16 Final assessment (Exams.)

Presentation outline

Time

Epidemiology and causation 08:00 to 08:15

Cause , Risk, factor, confounder and effect 08:15 to 08:30

Necessary and sufficient cause 08:30 to 08:45

Application of guidelines/criteria to associations

08:45 to 09:00

Confounders 09:00 to 09:15

5

Epidemiology

• Epi = upon

• Demos = population

• Logos = study of

Definition

• The study of the distribution and determinants of health related states or events in specified human populations and its application to the control of health problems

• Last, 1988

6

Epidemiological Principles

• •Diseases (or other health events) don’t occur at random

• •Diseases (or other health events) have causal and preventive factors which can be identified

• Diseases and health have a distribution

• Epidemiology focuses on populations rather than individual persons, tissues or organs.

7

• « The art of epidemiological thinking is to

draw conclusions from imperfect data”

• George W. Comstock

• Based on what ??????

8

Determinants of Prevention

• Successful prevention depends upon:

– a knowledge of causation – dynamics of transmission,

– identification of risk factors and risk groups,

– availability of prophylactic or early detection and treatment measures,

– an organization for applying these measures to appropriate persons or groups, and

– continuous evaluation of and development of procedures applied

9

Preventable Causes of Disease

BEINGS Biological factors and Behavioral Factors

Environmental factors

Immunologic factors

Nutritional factors

Genetic factors

Services, Social factors, and Spiritual factors

[JF Jekel, Epidemiology, Biostatistics, and Preventive Medicine, 1996]

10

Epidemiologic triad

Host

Agent Environment •Biological agents •Physical agents •Chemical agents •Nutrient agents •Mechanical agents •Social agents

•Physical environment •Biological environment •Social environment

•Demographic characteristics •Biological characteristics •Socioeconomic characteristics

11

• Hazard is something with the

potential to cause harm, such as a substance, a piece of equipment, a form of energy, a way of working or a feature of the environment.

• Harm includes death and major

injury and any form of physical or mental ill health.

• Risk it is a measure of the

probability that the hazard (defined previously) will manifest some degree of harm.

12

Risk • Risk is the likelihood of an event occurring. In

health care events, we usually consider a negative consequence arising from exposure to a hazard.

• Types of risk – Absolute: incidence of disease in any population

– Relative: ratio of the incidence rate in the group exposed to the hazard to the incidence rate in the non-exposed group

– Attributable: Difference in incidence rates between exposed and non-exposed groups.

13

Cause and effect

• Cause and effect understanding is the highest form of achievement of scientific knowledge.

• Causal knowledge permits rational plans and actions to break the links between the factors causing disease, and disease itself.

• Causal knowledge can help predict the outcome of an intervention and help treat disease.

• Quote Hippocrates "To know the causes of a disease and to understand the use of the various methods by which the disease may be prevented amounts to the same thing as being able to cure the disease".

14

cause?

• The first and difficult question is, what is a cause?

• A cause is something which has an effect.

• In epidemiology a cause can be considered to be something that alters the frequency of disease, health status or associated factors in a population.

15

Cause - Definition

• “ It t is an antecedent event, condition or characteristic that is necessary for the occurrence of the disease at the movement it occurs, given that the other conditions are fixed.”

• Alternatively the particular disease will not occur if those antecedent event, condition or characteristic are different in a specified way.

16

Association and Causation

• Association is defined as “ Occurrence of two variables more frequently than expected”.

• Association between suspected cause and effect

does not always mean a causal association.

17

From association to causation

A. Spurious association

B. Indirect association

C. Direct (Causal) association

1. One –to- one causal association

2. Multifactorial causation

Sufficient & necessary cause

Web of causation (Interaction)

Types of Association

Association may be grouped into following three types; 1. Spurious Association : When the observed association

between suspected cause and effect may not be real. Example- Perinatal mortality being high in hospital deliveries than home deliveries implying hospital is unsafe.

2. Indirect Association : It is a statistical association between a factor of interest and a disease due to presence of another factor known as Confounding Factor. Example-Iodine deficiency and Altitude association with Endemic Goitre.

3. Direct Causal Association : One to one and multifactorial

20

Direct Vs indirect cause

High cholesterol

Artery thickening

Hemostatic factors

Myocardial infarction

Indirect

F508 Polymorphism

Cystic Fibrosis

Direct

Interaction of multiple individual causes

Smoking

+

Air pollution Reaction at cellular level Lung cancer

+

Exposure to asbestos

Table 1: Age-standardized lung cancer death rates (per 100 000 population) in

relation to tobacco use and occupational exposure to asbestos dust

Web of causation

Change in life style Stress Abundance of food Smoking Emotional Aging & D Disturbance other factor Obesity Lack of physical activity Hypertension Hyperlidemia Increase catacholamine Changes in walls of arteries thrombotic activity Coronory atherosclerosis Coronary occlusion Myocardial Infarction Myocardial Infarction

Direct (Causal ) Association

1. One to one causal Association : • Two variables /factors are considered to be causally related

if any change in one is followed by a change in the other.

• The initial criteria used by Henle and Koch to distinguish causal association from indirect and spurious ones were applied to infective disease and included ;

1. The causative agent must be recovered from all diseased individuals.

2. The agent recovered from diseased individuals must be grown in pure culture.

3. The organism grown in culture must replicate the disease when introduced in susceptible animals.

24

Koch's Postulates • 1. The specific organism should be shown to be present in

all cases of animals suffering from a specific disease but should not be found in healthy animals.

• 2. The specific microorganism should be isolated from the diseased animal and grown in pure culture on artificial laboratory media.

• 3. This freshly isolated microorganism, when inoculated into a healthy laboratory animal, should cause the same disease seen in the original animal.

• 4. The microorganism should be reisolated in pure culture from the experimental infection.

26

Direct (Causal ) Association ….contd.

2. Multifactorial Causation :

– Single causation theory does not explain causation of Non-Communicable diseases where multiple factors are involved in causation of disease viz; CHD and Ca-Lung.

– Two models presented below may explain multifactorial causation mechanism ;

1. 2.

Factor –A Factor –A

Factor- B Cellular reaction Factor- B

Factor -C Factor-C

Disease

27

Recent Concepts of Causation

• Sufficient Cause : Sufficient cause imply a complete causal mechanism, a minimal set of conditions and events that are sufficient are sufficient to cause disease or outcome to occur.

• Component Cause & Necessary Cause

ABCD

Unknown 29

Hill’s criteria

1. Strength of association

2. Temporal relationship

3. Distribution of the disease

4. Gradient (dose-response effect)

5. Consistency

6. Specificity

7. Biological plausability

8. Experimental models

9. Preventive trials

30

Temporal Association

• Exposure to causative factor must occur before the onset of disease.

• This criteria is basic to the causal association. • Establishment of temporal association is easy in acute

communicable diseases • It is difficult to establish temporal sequence in chronic

insidious non communicable diseases as to which came first.

• The consumption of cigarette smoking preceded by 30 years to the increase in the death rates due to lung cancer. Theses observations are compatible with the long latent period pathogenesis of carcinogenesis .

31

Strength of Association

• The larger the Relative Risk the more likely the association is causal.

• Likelihood of causal association is strengthened if there is dose and duration response relationship.

• In the absence of experimental evidence in humans, the causal association between cigarette smoking and lung cancer has been based on following ; – Relative Risk

– Dose response relationship

– Decrease in risk on cessation of smoking

32

Dose Response Relationship

• Dose Response Relationship :

– More intense and longer exposure should result into more frequent and severe disease.

– This has been clearly established in the relationship of smoking and lung cancer.

• Dose and Duration Response Relationship

– The cumulative effect of dose and duration has also been well established in relationship of smoking and lung cancer.

33

Specificity of Association

• The concept of specificity implies a “ one to one” relationship between the cause and effect

• The causal factor should produce one specific disease or effect . • In recent past, the controversy over cigarette smoking and lung cancer

relationship has centered around specificity of the association. • Cigarette smoking is linked with lung cancer and several other conditions

such as CHD, Chronic Respiratory conditions and Ca-Cervix etc. • Lack of specificity can be explained by the fact that tobacco smoke contains

several harmful substances such as nicotine, carbon monoxide, benzpyrene, tar and other particulate matters with possible additive and synergistic actions.

34

Consistency of Association

• The result from single study is seldom sufficient to establish causal association.

• An association has to be replicated and confirmed by different investigators, in different populations using different design in order to be established as causal association.

• More than fifty retrospective studies and at least nine prospective studies in different countries have shown a consistent association between cigarette smoking and subsequent development of lung cancer has lent support to a causal association.

35

Biological Plausibility

• Causal association is substantiated if biological plausibility is present.

• The notion that food intake and cancer is interrelated is an old concept.

• The positive association of intestine, colon and rectum with food intake is biologically plausible.

• The cigarette smoking and lung cancer is also biologically plausible as it is well established that tobacco contains carcinogen which cause Ca-lung

36

How to establish the cause of a disease?

Could it be due to selection or measurement bias?

Could it be due to confounding?

Could it be causal?

Could it be a result of chance?

No

Probably not

Apply guidelines and make judgment

OBSERVED ASSOCIATION?

No

Appling guidelines (Hills criteria/Guidelines for causation) and making judgment regarding causation

Temporal relation Does the cause precede the effect? (essential)

Plausibility Is the association consistent with other knowledge?

(mechanism of action; evidence from experimental

animals)

Consistency Have similar results been shown in other studies?

Strength What is the strength of the association between the

cause and the effect? (relative risk)

Dose–response

relationship

Is increased exposure to the possible cause associated

with increased effect?

Reversibility Does the removal of a possible cause lead to

reduction of disease risk?

Study design Is the evidence based on a strong study design?

Judging the

evidence

How many lines of evidence lead to the

conclusion?

Causal Inference in Epidemiology

Bridging the gap between our ideas and our observations.

Criteria:

Strength of association

Consistency of findings

Specificity of association

Temporality (lack of ambiguity)

Biologic gradient (dose-response effect)

Biologic plausibility of the hypothesis

Coherence of evidence

Experimental evidence

39

Confounding: A Fundamental Problem of

Causal Inference

Confounding is bias due to inherent (unobservable) differences in risk between exposed and unexposed populations, i.e., a lack of comparability.

Confounding is usually not a major source of bias in randomized trials (assuming sample size is large enough) because randomization tends to equalize inherent risks between treatment groups

(treated group = exposed, untreated = unexposed)

40

Confounding

May lead to observation of association when

none exists

May obscure an association that exists

Information on potential confounders should be

collected in the study and used in analysis,

otherwise they cannot be excluded as alternate

explanations for findings

Confounding factors must be considered during

study design

41

Confounding

Mixing of the effect of the exposure on disease with the effect of another factor that is associated with the exposure

Bias in estimating the effect of exposure (E) on disease (D) occurrence, due to the lack of comparability between exposed and unexposed populations

Risk among exposed ≠ Risk among exposed if they had been unexposed

42

Properties of Confounders

3 Criteria for a variable to be a confounder (C):

C must be a risk factor for the disease (D) in the

unexposed population

C must be associated with exposure (E) in the

population from which the cases arose

The association between C and E must not be

due entirely to the effect of E on C (meaning C

cannot be an intermediate step between E and D)

43

Physical Activity Colorectal Cancer

Body Mass Index

Obesity

Confounding or Intermediate Effect?

?

44

Clues

Stable in incidence

Clusters in families

Clues

Incidence varies rapidly over

time or between genetically

similar populations

Is the disease predominantly genetic or environmental?

Genetic Environmental

46

Down’s syndrome

Phenylketonuria

Sickle cell disease

Diabetes

Asthma

Coronary heart disease

Stroke

Lung cancer

Road traffic

accidents

Genetic Environmental

47

Example of judging causality: lung cancer Question

Does the supposed cause precede

the disease (effect)

(temporality)

Yes, clearly so

By how much does exposure to

the cause raise the incidence of

disease?

(strength)

Greatly and as much as 20 to 30

fold in smokers of 20 or more

cigarettes per day

Does varying exposure lead to

varying disease?

(does-response)

Yes, there is clear relationship

and more smoking causes more

disease

Does the cause lead to a rise in a

few relevant diseases?

(specificity)

No. Numerous diseases show an

association with smoking

48

causality: lung cancer Is the association consistent across

different studies and between

groups?

Yes. The association is

demonstrable in men and

women, and across social

groups.

Is the way that the cause exerts its

effect on disease understood?

(biological plausibility)

Only partly. The tar in

cigarettes contains important

carcinogens

Does manipulating the level of

exposure to the cause change

disease experience?

(experimental confirmation)

Yes. Reducing consumption of

cigarettes reduces risk.

Persuading people to smoke

more would be unethical.

Tobacco is carcinogenic to

animals

Overall judgement Originally, bitterly contested,

now accepted as causal

49

The pyramid of associations 1 Causal and mechanisms

understood

2 Causal

3 Non-causal

4 Confounded

5 Spurious / artefact

6 Chance

50

Summary • Cause and effect understanding is the

highest form of scientific knowledge.

• Epidemiological and other forms of causal thinking shows similarity.

• An association between disease and the postulated causal factors lies at the core of epidemiology.

• Demonstrating causality is difficult because of the complexity and long natural history of many human diseases and because of

ethical restraints on human experimentation.

51

Summary

• All judgements of cause and effect are

tentative. • Be alert for error, the play of chance and bias.

• Causal models broaden causal perspectives.

• Apply criteria for causality as an aid to thinking.

• Look for corroboration of causality from other scientific frameworks.

52

Definitions • Association (relationship): statistical dependence

between two or more events, characteristics or other variables. Positive association implies a direct relationship, while negative association implies an inverse one. The presence of a statistical association alone does not necessarily imply a causal relationship.

• Causality (causation / cause-effect relationship): relating causes to the effects they produce.

• Cause: an event, condition, characteristic (or a combination) which plays an important role / regular / predicable change in occurrence of the outcome (e.g. smoking and lung cancer)

• Causes may be “genetic” and / or “environmental” (e.g. many NCDs including: diabetes, cancers, COPD, etc)

Sufficient & necessary cause

Necessary cause is without this disease/outcome never develops. Sufficient cause: presence of this factor disease always develops. Component cause: Supporting causes, per se they can not develop ds

Necessary causes + Component causes = Sufficient cause

Necessary Condition

• Must be there for the effect, the charge, to be true

• If absent, cannot occur.

• No oxygen, no combustion.

• No seeds, no plants to grow

• Car runs only if gas in tank.

55

Sufficient Condition

• Whenever A is present, B will follow-decapitation is sufficient for death.

• Getting a B in the course is sufficient for passing.

• Necessary cause: must always PRECEDE the effect. This effect need not be the sole result of the one cause

• Sufficient cause: inevitably initiates or produces an effect

56

Necessary & Sufficient

• Something can serve as both necessary and sufficient- “You will get Malaria if and only if you are bitten by a mosquito carrying the germ. Malaria ≈ Mosquito (germ)

• If you have Malaria you must have been bitten by the mosquito with the germ.

57

Causes of tuberculosis

Infection

Tubercu-losis

Susceptible

host