Causation Epid

Causation ConceptPrinciples of Epidemiology

Irwin Aras, M.D

Natural History of DiseaseNatural history of disease = progression of disease in an individual over timeWhen considering a single cause, we look at 4 stages SusceptibilitySub-clinicalClinicalRecovery, disability or death

Henle-Koch PostulatesSometimes called pure determinism

The agent is present in every case of the diseaseIt does not occur in any other disease as a chance or nonpathogenic parasite (one agent one disease)It can be isolated and if exposed to healthy subjects will cause the related disease

then it can no longer be a random accident of the disease, but between the parasite and the disease can be conceived no relation except that the parasite is the cause of the disease -- Robert Koch (1890)

Natural History of Disease (Fig 2.1, p. 34)

Natural History of HIV/AIDSFig 2.3 (p. 37)

CauseCause is not easily definedDefinitions are metaphysicalRothman & Greenlands (1998) definition:any event, act, or condition preceding diseasewithout which disease would not have occurred or would have occurred at later time

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

Causal Pies (Fig. 2.8, p. 43)Note: there is more than one sufficient mechanism for a given ailment

Sufficient / Component Cause (Causal Pies)A necessary cause - a factor found in all casesContributing cause a non-necessary factor that is needed in some cases Sufficiency combination of factors that make disease inevitable completed pie (see next slide)

Sufficient / Component Cause (cont.)The effect of a factor in a population depends on prevalence of causal complementsThe effect of Mycobacterium exposure in a fully immune population is nil (increases risk by 0%)The effect of Mycobacterium exposure in a fully susceptible population is 100%We cannot talk about cause in isolation

Types of Causal RelationshipsNecessary and sufficient without the factor, disease never developsWith the factor, disease always develops (this situation rarely occurs)Necessary but not sufficient the factor in and of itself is not enough to cause diseaseMultiple factors are required, usually in a specific temporal sequence (such as carcinogenesis)Sufficient but not necessary the factor alone can cause disease, but so can other factors in its absence Benzene or radiation can cause leukemia without the presence of the otherNeither sufficient nor necessary the factor cannot cause disease on its own, nor is it the only factor that can cause that diseaseThis is the probable model for chronic disease relationships

Factors in CausationAll may be necessary but rarely sufficient to cause a particular disease or statePredisposing age, sex or previous illness may create a state of susceptibility to a disease agentEnabling low income, poor nutrition, bad housing or inadequate medical care may favor the development of diseaseConversely, circumstances that assist in recovery or in health maintenance may be enablingPrecipitating exposure to a disease or noxious agentReinforcing repeated exposure or undue work or stress may aggravate an established disease or state

Causal ComplementA causal complement is a factor or set of factors that complete a sufficient causal mechanism (pie) e.g., Consider tuberculosisThe agent (Mycobacteria sp.) is necessary Susceptibility is complementary

Multi-CausalityEvery cause is interdependent on other causal factors.Cause is the cumulative effects of multiple factors acting together (causal interaction)Causal factors almost never act aloneMulti-causality requires a more sophisticated view of incubation

Multi-causal incubationInduction period = time between causal action and disease initiation Latency period = time between disease initiation and detectionEmpirical induction period = induction + latency

Genetic + Environmental Factors in Causing a Heart Attack (Fig 2.5, p. 38)

Iceberg PhenomenonSpectrum of illness most ailments have a broad range manifestations & severities We often detect only the tip of the iceberge.g., dog bite injuries:

Henle-Koch PostulatesSometimes called pure determinism

The agent is present in every case of the diseaseIt does not occur in any other disease as a chance or nonpathogenic parasite (one agent one disease)It can be isolated and if exposed to healthy subjects will cause the related disease


Hills PostulatesStrength of Association the stronger the association, the less likely the relationship is due to chance or a confounding variableConsistency 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)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 causationTemporality the exposure of interest must precede the outcome by a period of time consistent with any proposed biologic mechanismBiologic Gradient there is a gradient of risk associated with the degree of exposure (dose-response relationship)

Source: Hill, Sir Austin Bradford (1965)

Hills Postulates (cont)Biologic Plausibility there is a known or postulated mechanism by which the exposure might reasonably alter the risk of developing the diseaseCoherence the observed data should not conflict with known facts about the natural history and biology of the diseaseExperiment the strongest support for causation may be obtained through controlled experiments (clinical trials, intervention studies, animal experiments)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

Web of Causation for the Major Cardiovascular Diseases

Web of Causation for the Major Cardiovascular Diseases. (Source: Stallones, R.A. (1966). Prospective epidemiologic studies of cerebrovascular disease. Public Health Monograph No. 76, Washington, DC: U.S. Government Printing Office. p. 53.)

Causation Web ModelUpstream causesDownstream causesIndividual level causes

Agent, Host, & Environment

Epidemiologic Variables Person Place Time

I keep six honest serving men(They taught me all I know); Their names are what and why and whenAnd how and where and who. (Kipling)

Person VariablesExample of a person variables: age and sex in relation to recreational injuries (Fig 2.13, p. 50). Rates are per 1000 per year.

PlaceIllustrative example: Regional Differences in Breast Cancer Mortality (Table 2.14, p. 52) Fig. 2.14 (p. 52) shows large regional difference in breast cancer ratesRate in U.S. = 20 per 100,000 in 1962Rate in Japan = 4 per 100,000 in 1962What is not shown: rates in Japanese-Americans women increase with each generationConclusion: environment plays large role in determine breast cancer risk

Time Table 2.5: Examples of time variablesFig 2.15

ReferencesProceeding : Epidemiology Kept Simple, Chapter 2; Causal Concepts.Proceeding : Dona Schneider, Ph.D, MPH, FACE; Showing Cause, Intriduction to Study Design; Lecture 4.Rothman, K. J : Epidemiology An Introduction; 2002.Murti, B : Prinsip dan Metode Riset Epidemiologi; Edisi ke-2; 2003.


then it can no longer be a random accident of the disease, but between the parasite and the disease can be conceived no relation except that the parasite is the cause of the disease -- Robert Koch (1890)Source: Hill, Sir Austin Bradford (1965)

Web of Causation for the Major Cardiovascular Diseases. (Source: Stallones, R.A. (1966). Prospective epidemiologic studies of cerebrovascular disease. Public Health Monograph No. 76, Washington, DC: U.S. Government Printing Office. p. 53.)

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Causation Epid