Epidemiology MPH 531 Disease Causation (CAUSALITY) Mpundu MCK MSc Epidemiology and Biostatistics, BSc Nursing, RM, RN

Learning objectives What is disease causation Define and Explain common terms used in Epidemiology Discuss Causal Models in contemporary epidemiology

Common Terms in Epidemiology Disease A pattern of response by a living organism to some form of invasion by a foreign substance or injury which causes an alteration of the organisms normal functioning An abnormal state in which the body is not capable of responding to or carrying on its normally required functions

Common Terms in Epidemiology Pathogens Organisms such as bacteria, viruses, or parasites that are capable of producing diseases Pathogenesis the development, production, or process of generating a disease

Common Terms in Epidemiology Pathogenic Disease causing or producing Pathogenicity Potential ability and strength of a pathogenic substance to cause disease Invasiveness the ability to get into a susceptible host and cause a disease within the host The capacity of a microorganism to enter into and grow in or upon tissues of a host

Common Terms in Epidemiology Infective disease Disease which the pathogen or agent has the capability to enter, survive, and multiply in the host Virulence the extent of pathogenicity or strength of different organisms the ability of the pathogen to grow, thrive and to develop all factor into virulence the capacity and strength of the disease to produce severe and fatal cases of illness

Common Terms in Epidemiology Aetiology Factors contributing to the source of or causation of a disease Toxins A poisonous substance that is a specific product of the metabolic activities of a living organism and is usually very unstable notably toxic when introduced into the tissues, and typically capable of inducing antibody formation

Common Terms in Epidemiology Agent A factor, such as a micro-organism, chemical, radiation whose presence, absence or relative absence is essential for the occurrence of disease Association Statistical relationship between two or more events, characteristic or other variables Cause of disease A factor (character, behaviour, event, etc that directly influences the occurrence of disease. Reduction in the factor in pop should lead to reduction in occurrence of disease

Common Terms in Epidemiology Epidemic Occurrence of one specific disease from a single source, in a group population, community or geographical area in excess of the usual level of expectancy The occurrence of more cases of disease than expected in a given area or among a specific group of people over a particular time Endemic The constant presence of a disease or infectious agent within a given geographic area or population group. The ongoing, usual prevalence of or constant presence of a disease within such area in a given population

Common Terms in Epidemiology Pandemic Epidemic that is widespread across a country, continent or large pop, possible worldwide. eg. HIV/AIDS An epidemic occurring over a very wide area (several countries or continents) and usually affecting a large proportion of population

Common Terms in Epidemiology Epidemic period A time when the number of cases of disease reported is greater than expected Holoendemic A disease that is highly prevalent in a population and is commonly acquired early in life in most all of the children of the population

Common Terms in Epidemiology Hyperendemic Persistent level of disease beyond or above the expected prevalence A disease that is constantly present at high incidence and or prevalence rate Incidence Extent that people, within a population who do not have a disease, develop the disease during a specific time period

Common Terms in Epidemiology Prevalence Number of people within a population who have a certain disease at a given point in time Point prevalence Number cases of a disease exist in a group of people at that moment prevalence relies on 2 factors How many people have had the disease in the past Duration of the disease in the population

Overview of Causation Cause of Disease Accepted models of causation require interaction of factors and conditions before disease/ health outcome can occur Association is not equal to causation. All association between exposure and disease are casual relations Cause of Disease A factor (characteristic, behaviour, event, etc) that influence the occurrence of a disease An increase in factor leads to increase increse in disease A reduction in factor leads to reduction in disease Consider the following statement: If the rooster crows at the break of dawn, then the rooster caused the sun to rise???

(contemporary epidemiologist) Definition of Cause Definition of “cause” Any event, act or condition preceding disease or Illness without which disease would not have occurred or would have occurred at a later time Ken Rothman (contemporary epidemiologist)

Characteristics of a cause Must precede the effect proximate vs. distant 2. Can be either host or environmental factors e.g. characteristics, conditions, actions, behaviour, life style, events, natural, social or economic phenomena 3. Positive (presence of a causative exposure) or negative (lack of a preventive exposure)

Causal Relationships A causal pathway may be direct or indirect In direct causation, A causes B without intermediate effects In indirect causation, A causes B, but with intermediate effects In human disease, intermediate steps are virtually always present in any causal process

Causal Relationship Exposure Disease Smoking Risk of Lung Cancer Causal Association Exposure Disease Smoking Risk of Lung Cancer

“Risk Factor” The term is commonly used to describe factors that are positively associated with the risk of development of a disease but that are not sufficient to cause the disease. The concept has proved useful in several practical prevention programmes. Some risk factors (such as tobacco smoking) are associated with several diseases, and some diseases

Factors in Causation All factors may be necessary but rarely sufficient to cause a particular disease or state Predisposing Factors Factor that may create a state of susceptibility to a disease agent e.g age, sex or previous illness Precipitating Factors Factors that may trigger the disease exposure to a disease or noxious agent Aggravating factors Factors that may worsen the disease

Factors in Causation Reinforcing factors Enabling Factors Repeated exposure or undue work or stress may aggravate an established disease or state Enabling Factors Factors that may favor the development of disease E.g. Low income, poor nutrition, bad housing or inadequate medical care Circumstances that assist in recovery or in health maintenance may be enabling

Comparing Rules of Evidence Criminal Law Disease Causation Criminal present at scene of crime Agent present in the disease Premeditation Causal events precede onset of disease Accessories involved in the crime Cofactors and/or multiple causality involved Severity of crime related to state of victim Susceptibility and host response determine severity Motivation – there must be gain to the criminal The role of the agent in the disease must make biologic and common sense No other suspect could have committed the crime No other agent could have caused the disease under the circumstances given Proof of guilt must be established beyond a reasonable doubt Proof of causation must be established beyond reasonable doubt or role of chance

Disease Causation Theories and Models

SUPERNATURAL THEORY Early past, disease was thought be due to Divine retribution/punishment for sins Curse of God Devil force the demons and evil 10% in developed and 30% in developing countries still believe in supernatural origin of disease Today superstitions are becoming a major obstacle to disease control

Miasma Theory of Disease Causation Miasma - bad or malodorous air as a cause of disease Pleasant or strong smelling agents were thought to be protective Public health efforts concentrated on finding the source of bad smells

Understanding causal mechanisms Understanding causal mechanisms is essential for effective public health intervention Consider the case of miasmas and cholera “For want of knowledge, efforts which have been made to oppose Cholera have often had contrary effect.” – John Snow

Germ or contagion theory Developed in early 1800’s Infection spread by random contacts between infected and susceptible people (or animals) 1860’s: Louis Pasteur demonstrated existence of pathogenic organisms 1880’s: Robert Koch: isolated and cultured Vibrio cholerae.

Sufficient-Component Cause Model (Kenneth Rothman) Admits causes are neither specific nor strictly necessary for their effect Made up of a number of components, no one is sufficient to cause disease on its own When all the components are present, a sufficient cause is formed More than one of the components may be sufficient for the same effect, thus a diseases may have multiple causes

Sufficient-Component Cause Model Necessary cause A component cause that is a member of every sufficient cause. Sufficient cause A set of conditions without any one of which the disease would not have occurred. (This is one whole pie.) Component cause Any one of the set of conditions which are necessary for the completion of a sufficient cause. (This is a piece of the pie.)

Types of Causal Relationships Necessary and sufficient Without the factor, disease never develops With the factor, disease always develops (this situation rarely occurs) Necessary but not sufficient The factor in and of itself is not enough to cause disease Multiple factors are required, usually in a specific temporal sequence (such as carcinogenesis)

Types of Causal Relationships Sufficient but not necessary The factor alone can cause disease, but so can other factors in its absence Radiation can cause leukemia without the presence of the other Neither sufficient nor necessary The factor cannot cause disease on its own, nor is it the only factor that can cause that disease This is the probable model for chronic disease relationships

GENERAL MODEL OF CAUSATION (CAUSAL PIES) Causal complement = the set of factors that completes a sufficient causal mechanism Example: tuberculosis Necessary agent Mycobacterium tuberculosis Causal complement “Susceptibility”

GENERAL MODEL OF CAUSATION (CAUSAL PIES) This illustration shows a disease that has 3 sufficient causal complexes, each having 5 component causes. A is a necessary cause since it appears as a member of each sufficient cause. B, C, and F are not necessary causes since they fail to appear in all 3 sufficient causes. Adapted from Kenneth Rothman

Causal Pies Necessary cause = found in all cases Contributing cause = needed in some cases Sufficient cause = the constellation of necessary and contributing causes that make disease inevitable in an individual A given disease can have multiple sufficient mechanisms

Sufficient-Component Cause Model (Multicausality) A disease can be caused by more than one casual factor and every factor involves the joint action of multitude of component causes Most identified causes are neither necessary nor sufficient to produce disease A cause need not be either necessary or sufficient for its removal to result in disease prevention One does not need to identify every component cause to prevent some cases of disease

Adopted from Prof Kamiji Phiri

Sufficient-Component Cause Model (Sum of attributable Fractions) Each single cause of diseases has an associated attributable proportion. This measure is the proportion of all cases of disease that would not have occurred had the cause been eliminated The fraction of disease that can be attributed to each of the causes of disease in all the casual mechanism has no upper limit because of the interaction between component causes

Sufficient-Component Cause Model (Interaction among causes) Several causal components act in concert to produce an effect (Disease), “Acting in concert” This does not necessarily imply factors must act at the same time e.g. Person sustains head injury Later develops imbalance Years later, falls and sustains a fracture Disease results from the cumulative effects of multiple causes acting together (causal interaction)

Necessary and Sufficient factors of Causality Necessary causes A condition without which the effect/disease will not occur If the disease does not develop without the factor being present, the causative factor is termed “ necessary” Sufficient causes Number of components, no one of which is sufficient on its own, but together are sufficient to cause a disease If the disease is always results from the factor, the causative factor is termed “sufficient” Exposure to mycobacterium tuberculosis is “necessary” for TB to develop, but not “sufficient” because not everyone infected develops the disease

Summary of Necessary and Sufficient causal factors Without a factor, the disease never develops With the factor, the disease always Necessary but not sufficient Each factor necessary, but not itself sufficient to cause the disease Multiple factors are required, usually a specific temporal sequence

Summary of Necessary and Sufficient causal factors Sufficient but not necessary Factor alone can cause disease, but so other factors in its absence Not all risk factors necessary in disease causation Neither necessary nor sufficient The factor can not cause disease on its own, nor is it the only factor that can cause that disease

Adopted from Kenneth Rothman

The Epidemiological Triangle or Triad of Disease causation According to this theory, every one is exposed to disease agent did not contract the disease It means the causative agent that is responsible for disease , but there are another factors also, related to man a associated causative factors and environment which contribute to disease Applicable to some NCDs, because of multiple etiology Helps to understand various associated causative factors, priotise and plan preventive measures to control the disease

Components of Epidemiological Triangle or Triad of Disease causation A traditional model of infectious disease causation Epi Triad has three components An external agent A susceptible host Environment that brings the host and agent together, causing the disease to occur in the host A vector, an organism which transmits infection by conveying the pathogens from one host to another causing disease, may be part of the infectious process

The Epidemiologic Triad

The Epidemiology Triangle

The Epidemiology Triangle Time accounts for incubation periods, life expectancy of the host or pathogen, duration of the course of illness or condition. Time

The Epidemiology Triangle The role of the epidemiologist is to break one of the legs of the triangle, which disrupts the connection between environment, host, and agent, stopping the continuation of disease or an outbreak. The goals of public health are the control and prevention of disease. By breaking one of the legs of the triangle, public health intervention can partially realize these goals and stop diseases/epidemics A disease/epidemic can be stopped when one of the elements of the triangle is interfered with, altered, changed or removed from existence.

Components of Epidemiological Triad 1. The Agent Factors Bacterial Virus Parasite Fungi Other microbes These agents are necessary, but not sufficient to cause the disease The concept of agent has been broaden to include: Physical (temp, radiation, trauma) Chemical (acids, alkalis, poisons, tobacco) Environmental (allergens) Nutritional (under or over nutrition) This model does not work well for some NCDs because it may not be clear whether a particular factor should be classified as an agent or as an environmental factor such as chemical contaminants physical, pyschological causes This model does not work well for some NCDs

Components of Epidemiological Triad Host Factors These are intrinsic factors that influence an individual’s exposure, susceptibility or response to causative agent. Includes Personal Characteristics Age, gender, socio-economic status, Personal behaviour : Life style, diet, smoking, exercise, alcohol/drug use, sexual practices, beliefs and practices Genetic composition Immunologic state Presence of disease or medications Psychological make up

Components of Epidemiological Triad Environmental factors These are extrinsic factors which affect the agent and the opportunity for exposure. Includes Physical factors Geology, climate (temperature, humidity, rain) Biological factors insects that transmit an agent( e.g. Mosquito) Socio-economic factors overcrowding, sanitation and availability of health services Agent, host and environmental factors interrelate in a variety of complex ways to produce a disease in humans The balance and interaction are different for different diseases. In casual relationship, analyse all the three components interactions to find practical and effective prevention and control measures

Bradford Hill 1897–1991

Causal "guidelines" suggested by Sir Hill (1965) Purpose: Guidelines to help determine if associations are causal. Should not be used as rigid criteria to be followed slavishly. Hill stated that he did not intend for these "viewpoints" to be used as “hard and fast rules.”

Bradford Hill criteria of disease causation 1. Strength of Association The stronger the association, the less likely the relationship is due to chance or a confounding variable Consistency of the Observed Association The association been observed by different persons, in different places and times circumstances. Consistency ≡ similar conclusions from diverse methods of study in different populations under a variety of circumstances Example: The association between smoking and lung cancer was supported by ecological, cohort, and case-control done by independent investigators on different continents. Source: Hill, Sir Austin Bradford (1965)

Bradford Hill criteria of disease causation 3. Specificity One factor can only cause one disease and that cause is not associated with other diseases Cause single effect/disease, not multiple Specificity ≡ the exposure is linked to a specific effect or mechanism 4. Temporality The exposure of interest must precede the outcome by a period of time consistent with any proposed biologic mechanism Example: Smoking is not specific for lung cancer (it causes many other ailments, as well)

Bradford Hill criteria of disease causation 5. Biologic Gradient (Dose response)  risk of outcome with increased exposure lack of dose response doesn’t mean no causality exposure (dose-response relationship) threshold effect there is a gradient of risk associated with the degree of association 6. Biologic Plausibility There is a known mechanism by which the exposure might reasonably alter the risk of developing the disease Plausibility = appearing worthy of belief. The mechanism must be plausible in the face of known biological facts. However, all that is plausible is not always true

Bradford Hill criteria of disease causation 7. Coherence of association. There should not conflict with known facts about the natural history and biology of the disease Experiment (Reversibility) Removal of exposure/factor leads to reduction in risk

Bradford Hill criteria of disease causation 9. Analogy Factor A can cause disease D, similarly, factor E can cause disease D “With the effects of rubella , it is fair to accept slighter but similar evidence with another viral disease in pregnancy” Example: Before the HIV was discovered, epidemiologists noticed that AIDS and Hepatitis B had analogous risk groups, suggesting similar types of agents and transmission

Hill concludes… “Here then are nine different viewpoints from all of which we should study association before we cry causation.... None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or lesser strength, is to help us make up our minds on the fundamental question – is there any other way of explaining the set of facts before us, is there any other answer equally or more, likely than cause and effect?”