Association and causation
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This document discusses approaches for studying disease causation through epidemiological studies. It outlines the difference between association and causation, describing various types of causal relationships like necessary vs sufficient. It also discusses guidelines for assessing causality, including temporal relationship, strength of association, biological plausibility, consistency of findings, and consideration of alternative explanations. The document uses examples like the relationship between Helicobacter pylori and duodenal ulcers to demonstrate how these guidelines can be applied to evaluate evidence for a causal inference.
Association and causation
- 1. From association to causation deriving inference from epidemiological studies Sima Naderi, 2th year of MPH−department of epidemiology & biostatistics, Kabul university of medical science
- 2. Presentation outline • Introduction • Approaches for studying disease etiology • Type of Association • Causal relationship • Type of causal relationship • Guidelines to asses causality • Causal inference and conclusion • Reference 2/27/2020 2
- 3. Why to know cause of events/disease • As human being, Enable each of us to navigate our complex world • As a doctor, why to know cause of disease? • As a researcher? • As an academic org member? 2/27/2020 3
- 4. Introduction • Ascertainment of cause and effect relationships is one of the central and most difficult tasks of all scientific activities • Epidemiological principles stand on 2 basic assumption: • Human disease does not occur at random. • The disease and its cause as well as preventive factors can be identified by a thorough investigation of population. • Identification of relation (association, causation) between disease and suspected risk factors forms major part of epidemiological research. 2/27/2020 4
- 5. Historical theories of disease causation • Supernatural cause of “ and Karma • Theory of humors (humor means fluid) • The miasmatic theory of disease • Theory of contagion • Germ theory • Koch`s postulations 2/27/2020 5
- 6. Approaches for studying disease etiology • Expose animals to risk factors such as carcinogens in control lab • Control the exposure dose • Control other environmental conditions and genetic factors • Keep lost to follow up to minimum • Can we extrapolate data across species and from animal to human population? 2/27/2020 6
- 7. Approaches for studying disease etiology • Epidemiology build on unplanned or natural experiments • People exposes to risk factor for non- study purposes • E.g. exposure to atomic bomb radiation in Hiroshima and Nagasaki 1945 2/27/2020 7
- 8. Approaches for studying disease etiology • Sequence of study in human population 2/27/2020 8 Randomized trial Cohort studies Case control studies Available data Clinical observation
- 9. Approaches for studying disease etiology 1.Determining association b/n an exposure and disease Studies of group characteristics: ecologies studies Studies of individual characteristics: case-control, cohort 2.If association exist Causal Non causal 2/27/2020 9
- 10. Association • Concurrence of two variable more often, than would be expected by chance. • Correlation indicates the degree of Association. 2/27/2020 10
- 11. Type of association • Spurious or artificial • Real • Non causal • causal 2/27/2020 11
- 12. Spurious association • Spurious association arise because of bias, when 2 variables are improperly compared. • E.g. • Conclusion: prenatal mortality in hospital delivery is higher compared to home delivery • This conclusion results due to bias in study 2/27/2020 12 Study in England 5174 home delivery 11156 hospital delivery Prenatal MR= 5.4/1000 Prenatal MR= 27.8/1000
- 14. Non causal association • McMahon`s study: observed an association of coffee consumption with risk of pancreatic cancer. Causal association 2/27/2020 14 Coffee Drinking Pancreatic Cancer Coffee Drinking smoking pancreatic cancer Non Causal association (due to confounding)
- 15. Type of causal association Direct Indirect 2/27/2020 15 factor disease factor diseaseStep 2 Step 1
- 16. Evidence for causal relationship • Infectious disease: Henle assumptions 1840 which was expanded by Koch in 1880s: • The organism is always found with the disease • The organism is not found with any other disease • The organism, isolated from one who has the disease, and cultured through several generations, produces the disease( in experimental animals) • NCDs, no organism to detect and culture causal relationship more complex 2/27/2020 16
- 17. Type of causal association • Necessary and sufficient, (one to one relation, based on Koch theory) Without that factor the disease never develops, and in its presence the disease always develops This situation rarely occurred 2/27/2020 17 Factor A disease HIV AIDS
- 18. Type of causal association • Necessary, not sufficient • Factor is necessary but not sufficient to produce the disease • Multiple factors are required, often in a specific temporal sequence 2/27/2020 18 Factor A + Factor B + Factor C Disease
- 19. Necessary, not sufficient 2/27/2020 19 initiator + promoter + trigger cancer
- 20. Type of causal association • Sufficient, but not necessary • The factor alone can produce the disease, but so can other factor • Radiation, benzene – either can produce leukemia • Cancer does not develop in everyone who has experienced radiation or benzene exposure 2/27/2020 20 Factor A or Factor B or Factor C Disease
- 21. Sufficient, but not necessary 2/27/2020 21 radiation or Benzene exp or smoking leukemia
- 22. Type of causal association • Neither necessary nor Sufficient • More complex model (independent.v=risk factor) • Probably most accurately represents the causal relationships that operate in most chronic disease 2/27/2020 22 Factor A + factor B or Factor C + factor D or Factor E + factor F Disease
- 23. . • Diabetics are most likely at risk of myocardial infarction than non diabetics 2/27/2020 23 2 matched groups Myocardial infraction Risk factor Non diabeticsdiabetics diabetes
- 24. Guidelines for judging whether an association is causal 2/27/2020 24
- 25. . Guidelines for inference causal association temporal Biological plausibility Alternative explanation Consistency and replication Cessation effects Specificity of the association Strength of association Dose- response 2/27/2020 25 Major criteria Minor criteria Austin Bradford hill 1965
- 26. Temporal relationship • Exposure to the factor must occurred before the disease developed • Length of the interval between the exposure and outcome (asbestos in lung cancer__15-20 year) • Temporal relationship easily established in prospective cohort than in case-control and retrospective cohort as The only criteria that is inarguable 2/27/2020 26
- 28. Dose-response relationship • As dose of exposure increases, the risk of disease also increases • If a dose-response relationship is present, it is strong evidence for a causal relationship • Absence of dose-response relationship dose not necessarily rule out a causal relationship • In some cases threshold may exist 2/27/2020 28
- 29. 2/27/2020 29
- 30. Strength of association • Measured by • OR • RR • The stronger association the more likely it is that the relation is causal 2/27/2020 30
- 31. Biological plausibility • Coherence with the current body of biologic knowledge • Sometimes, epidemiological observation preceded biologic knowledge (mechanism of action, evidence from animal experiment) • E.g. Gregg`s observation on rubella and congenital cataracts preceded any knowledge of teratogenic viruses • If epidemiological findings are not consistent with the existing knowledge-interpreting the meaning of observed association might be difficult 2/27/2020 31
- 32. Consideration of alternate explanation • Explanations of relationship as a causal or due to confounding • The extent to which the investigators have taken other possible explanation into account and the extent to which they ruled out such explanation are important considerations 2/27/2020 32
- 33. Cessation of exposure • If a factor is a cause of a disease, the risk of disease is decline when exposure to the factor is reduced or eliminated 2/27/2020 33
- 34. Consistency & Replication of findings • If the relationship is causal, we would expect to find it consistency in different studies (cohort, case-control) and in different populations. • Causal association b/n smoking and lung cancer is found consistently in: • 50 retrospective studies • 9 prospective studies • Some times there are good reasons why study results differ. For example, one study may have looked at low level exposure while another looked at high level exposure. 2/27/2020 34
- 35. Specificity of the association • Specificity implies a one to one relationship between the exposure and outcome (weakest criteria). • Not everyone who smokes develop lung cancer • Not everyone who develops cancer has smoked • Lack of specificity does not negate causation 2/27/2020 35
- 36. Additional model for causality • Kennet rothman`s component cause theory: describe the circumstances leading to a health outcome as being parts of one pie chart, or a “causal pie”. without each component in place, the disease or health outcome would not have occurred at that specific point in time 2/27/2020 36
- 37. Slip on an icy sidewalk and break the wrist 2/27/2020 37 Causal pie calcium intake impaired balance type of shoe Icy path fall
- 38. Directed acyclic graph • One method used to create a conceptual diagram that maps the relationship between the main exposure, outcome of intrest, and all potential confounders for a given study. • Confounders should identified for: • Adjusting, less biased association 2/27/2020 38 Covariates exposure outcome
- 39. Observed association & causal inference • Could it be due to bias No • Could it be confounding no • Could it be result of chance No • Could it be causal relation yes • Apply guidelines and make judgment 2/27/2020 39
- 40. conclusion • The causal inference resulted from the epidemiological studies are very important to public health and provide inputs for political and judicial decisions. • E.g. the causal association b/n smoking and lung cancer has resulted in labeling of cigarette packets and increased campaign ads. 2/27/2020 40
- 41. Wrong Causal inference • Suppose a study find an association b/n paternal silk tie ownership and infant mortality • On the back of this, the government implements a program in which 5 silk ties are given to all men aged 18-45 with a view to reducing infant mortality. • We would all agree that this is madness • This is because we understand the difference b/n association and causation 2/27/2020 41
- 42. Assessment of the evidence suggesting helicobacter pylori as a causative Agent of Duodenal ulcer 1. Temporal relationship About 11% of chronic gastritis patients duodenal occurs over a 10 year period 2. Strength of association H.Pylori found - 90% of patients with duodenal ulcer 3. Dose-response R Density of H.Pylori per mm2 of gastric mucosa – higher in duodenal ulcer patients 4. Replication of the findings Many of the observation – H.pylori – replicated repeatedly 5. Biological possibility • Earlier- difficult to invasion bacterium infecting the stomach antrum causing ulcers in the duodenum, now recognized – H.pylori- binding sites on antral cell. • Induces mediators of inflammation • Infected mucosa – weakened, susceptible to damaging effects of acid 2/27/2020 42
- 43. Assessment of the evidence suggesting helicobacter pylori as a causative Agent of Duodenal ulcer 6. Cessation of exposure • Eradication – heals duodenal ulcers at the same rate as histamine receptor antagonists • Long-term ulcers recurrence rate – zero after H.pylori was eradicated using triple – anti microbial therapy 7. Specific of association Prevalence of H.pylori in duodenal ulcers patients – 90% to 100% 8. Consistency with other knowledge High prevalence of ulcer disease in later part of 19th century – consistent with high prevalence of H.pylori due to poor living condition at the same period 9. Consideration of alternative explanation Smoking risk of duodenal ulcer – H.pylori infected patients but not a risk factor – H.pylori eradicated patients 2/27/2020 43
- 44. Reference • Gordis leon. Textbook of epidemiology, 5th edition, chp 14, P243-260 2/27/2020 44