2Framework Definitions Introduction Historical theories of causation of diseaseCurrent conceptsFactors in causationFrom association to causationHow to establish the cause of a disease?Analytical approachModern concept of causation
3DefinitionsAssociation: define as occurrence of two variable more often than would be expected by chanceCausal association: when cause and effect relation is seen.
4Historical Theories “Supernatural causes”& Karma Theory of humors (humor means fluid)The miasmatic theory of diseaseTheory of contagionGerm theoryKoch’s postulates
5Koch’s postulatesThe organism must be present in every case of the disease;The organism must be able to be isolated and grown in pure culture;The organism must, when inoculated into a susceptible animal, cause the specific disease;The organism must then be recovered from the animal and identified.
6Limitations of Koch postulate Non communicable diseaseOne to one relation are rare biology.Disease production may require co cofactors.Always it is not possible to isolate organism from disease personViruses cannot be cultured like bacteria because viruses need living cells in which to grow.Always infection does not produce diseasePathogenic microbes may be present without clinical disease (sub sub-clinical infections, carrier states).
7Single or Multiple cause? One to one association Epidemiological triad Sufficient & Necessary cause(Specificity) Multi factorial causationWeb of causationInteraction
9Epidemiological triad Agent FactorsPhysical AgentsChemical AgentsBiological AgentsNutritional agentsAgent FactorsPhysical Agents : (as heat, cold, vibrations, electricity,mechanical forces etc.).Chemical Agents : (as acids, alkalies, heavy metals, allergens,etc.).Biological Agents : (as viruses, bacteria, parasites, etc.).Nutritional agents : These are truly a part of chemical agentsbut often described as a separate category because of theHost FactorsSocio-demographic Factors : Such as age, sex, occupation,education, marital status, etc.Psycho-social Factors : Such as attitudes, practices,behavioural patterns, life style, etc.Intrinsic Characteristics : Intrinsic Characteristics or the“biological, Immunological and Genetic factors” in a humanbeing - e.g. genetic factors, HLA types, biochemical andphysiological characteristics, etc.Environmental FactorsPhysical Environment : Such as seasons, climate, altitude,rainfall, etc.Biological Environment : e.g. arthropod vectors of diseaseslike mosquitoes, animal reservoirs like canines and rodents,etc.Social Environment : e.g. community attitudes, beliefs,practices and cultural factors affecting disease; level of socioeconomicdevelopment; availability of health services, etc.Environmental FactorsPhysical EnvironmentBiological EnvironmentSocial EnvironmentHost FactorsSocio-demographic FactorsPsycho-social FactorsIntrinsic Characteristics
10From association to causation Spurious associationB. Indirect associationC. Direct (Causal) association1. One –to- one causal association2. Multifactorial causationSufficient & necessary causeWeb of causation (Interaction)
11Spurious association Not real e.g. More perinatal deaths in hospital delivery than home delivery.The cause of spurious association is poor control of Biases in study.
12Direct Vs indirect cause F508 PolymorphismHigh cholesterolArtery thickeningHemostatic factorsMyocardial infarctionCystic Fibrosis
13Indirect association: Statistical association due to presence of another factor, known or unknown that is common both the characteristics & disease i.e. Confounding factors.ExampleSmokingPancreatic cancere.g. 1. Altitude & endemic goiter2. Sucrose & CHDCoffee drinking
14Direct ( Causal) association One –to- one causal association2. Multifactorial causationSufficient & necessary causeWeb of causation (Interaction)
15One-to-one causal association A causing Be.g. MeaslesCriticsStreptococal tonsilitisScarlet feverErysipelasHaemolytic Streptococci
16ii) Multifactorial causation Multiple factor leads to the diseasesCommon in non-communicable diseasese.g.SmokingAir pollution Reaction at cellular level Lung cancerExposure to asbestos
17b. Interaction of multiple individual causes Smoking+Air pollution Reaction at cellular level Lung cancerExposure to asbestosTable 1: Age-standardized lung cancer death rates (per population) inrelation to tobacco use and occupational exposure to asbestos dust
18Web of causation Change in life style Stress Abundance of food Smoking Emotional Aging & D Disturbance other factorObesity Lack of physical activity HypertensionHyperlidemia Increase catacholamine Changes in walls of arteriesthrombotic activityCoronory atherosclerosisCoronary occlusionMyocardial Infarction
21 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 dsNecessary causes + Component causes = Sufficient causeNecessary cause: necessary is factor without this disease/outcome never develops.Each sufficient cause has a necessary cause as a component.Sufficient cause: A cause is termed sufficient when it inevitably produces or initiates an outcome, that is in the presence of this factor disease always develops.
22 Sufficient & necessary cause U BC NKnown components (causes) – A, B, C, NUnknown component (cause)- UN – Necessary causeKnown components + Unknown component cause + Necessary cause = Sufficient cause
23Figure 1: Causes of tuberculosis Susceptible hostInfectionTubercu-losis
24There may be number of sufficient causes for single disease in various combination of component causes, necessary causesAU BE NAU DC NAU BC NUA BUA BUA EDisease
25How to establish the cause of a disease? OBSERVED ASSOCIATION?Could it be due to selection or measurement bias?NoCould it be due to confounding?NoCould it be a result of chance?Probably notCould it be causal?Apply guidelines and make judgment
26Appling guidelines (Hills criteria/Guidelines for causation) and making judgment regarding causation Temporal relationDoes the cause precede the effect? (essential)PlausibilityIs the association consistent with other knowledge? (mechanism of action; evidence from experimental animals)ConsistencyHave similar results been shown in other studies?StrengthWhat is the strength of the association between the cause and the effect? (relative risk)Dose–response relationshipIs increased exposure to the possible cause associated with increased effect?ReversibilityDoes the removal of a possible cause lead to reduction of disease risk?Study designIs the evidence based on a strong study design?Judging the evidenceHow many lines of evidence lead to the conclusion?
271.Temporal relationship (Relationship with time) Cause must precede the effect. (Essential)Which is cart & Which hourse?Drinking contaminated water occurrence of diarrheaHowever many chronic cases, because of insidious onset and ignorance of precise induction period, it become hard to establish a temporal sequence as which comes first -the suspected agent or disease.
282. . Plausibility ( Biological plausibility) Consistent with biological knowledge of daySmoking causing lung cancerSmoking causes skin cancer?Lack of plausibility may simply reflect lack of scientific knowledge
293. Consistency of association Different persons, in Different places, in Different circumstances & times by Different method (by various types studies) is established the Same result by several studies.Cigarette smoking and lung cancer. More than 50 retrospective studies and at least nine prospective studies
30Meta-analysis of the relative risk of cleft palate in the offspring of mothers who smoked during pregnancy compared with the offspring of mothers who did not smoke
314 . Strength of association Relative risks/Odds ratio greater than 2 can be considered strongRisk ratioInterpretation< 1ProtectiveNo associationWeak Causal associationmoderate causal association>2.6Strong causal association
325. Dose – response relationship ( The Biological gradient ) Death rates from lung cancer (per 1000) by number of cigarettes smoked, British male doctors, –1961
33 6. Specificity One to one association Critics Haemolytic Streptococal tonsilitisStreptococci Scarlet feverErysipelas
347. ReversibilityFig 7: Stopping works: cumulative risk of lung cancer mortalityCriticseg Infection of HIV/ AIDS
358. Study designRelative ability of different types of study to “prove” causation
369. Analogy (= Similarity, = reasoning from parallel cases) Judging by analogyknown effect of drug thalidomide & rubella in pregnancyaccepting slighter but similar evidence with another drug or another viral disease
3710. Coherence of association & Judging the evidence Based on available evidence or should be coherence with known facts that are thought to be relevant: uncertainty always remainsCorrect temporal relationship is essential; then greatest weight may be given to plausibility, consistency and the dose–response relationship. The likelihood of a causal association is heightened when many different types of evidence lead to the same conclusion.
38Critics on Hill’s guideline on causation Criteria Vs Guidelines Vs considerationExcept for temporality, none of the Hill’s criteria is absolute for establishing a causal relation
39Measures of association /strength of association Analytical MethodsMeasures of association /strength of associationTesting hypothesis of associationControlling confounders
40Measures of association / strength of association 1. Ratio measures- Relative risk- Odds ratio2. Difference measures-Attributable risk-Population Attributable risk
41Testing hypothesis of association Null HypothesisRejecting AcceptedCausal association Not causal association
42Controlling confounders At time designing of epidemiological study or while carrying studyRandomizationRestrictionMatchingAt analysis stageStratificationAdjustmentStatistical modeling
43Modern concepts in causation Counterfactual ModelCausal diagram
44Counterfactual model (Potential outcome model) When we are interested to measure effect of a particular cause, we measureeffect in a population who are exposedImagine amount of effect which would have been observed, if the same population would not have been exposed to that cause, all other conditions remaining identical.We calculate risk ratios & risk differences based on this modelThe difference of the two effect measures is the effect due the cause we are interested in.
45ExampleWill smoking ban decrease the rate of lung cancer in 10 yrs beyond what can be expected in absence of ban?
47Causal DiagramConfounding is complex phenomenon – Need to understand relationUseful for analysis of confoundersConceptual definition of variable involvedDirectionality of causal associationNeed some level of understanding (Knowledge & hypothetical) – relation between risk factor, confounders & outcome.Directed Acyclic Graph (DAG)
50X Y Z U Causal Assumption Independency Marginal association Conditional associationX & Y are each direct cause of Y(Direct with respect to other variable in Diagram)X & Y are independent (only path between them is blocked by the collider)X & Y are associatedX & U are associated conditional on Y(Conditional on a collider unblocks the path)Y is direct cause of ZX & Y are independent conditioned on Y (Conditioning on Y blocks the path between X & Z)U & Y are associatedX & U are associated conditional on Z (Z is a descendent of collider)X is not a direct cause of Z, but X is an indirect cause of Z via YU & Z are independent conditional on YY & Z are associatedNo 2 variable in diagram(X,U, Y, Z) share prior cause not shown in the diagram eg. No variable causes both X & Y, or both X & UX & Z are associatedU & Z are associated
51References :Hill AB. The environment and disease: association or causation? Proc R Soc Med1965;58:Hill AB. Bradford Hill’s Principle of Medical statistics. Ed first Indian addition NewDelhi: B. I. Publication pvt limited.Detels R, McEwen J, Beaglhole R, Tanaka H. Oxford textbook of public health. 4th ed.New York: Oxford university press; 2004.Beaglehole R, Bonita R. Basic epidemiology. Delhi: AITBS publisher & distributor;2006.Park K. Park’s textbook of preventive & social medicine. 19th ed. Jabalpur: M/sBhanarsidas Bhanot publishers; 2007.Galea S, Riddle M, Kaplan GA. Causal thinking & complex system approach inepidemiology. International journal of epidemiology Feb; 39(1):Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. New Delhi:Wolter kluwar (India) pvt; 2009.