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Causation

The document discusses approaches for studying disease etiology, including observational studies like ecological, cohort, and case-control studies as well as randomized trials. It also examines how evidence for a causal relationship between a factor and disease has been established through a sequence of studies, from initial clinical observations to randomized trials. Key figures in establishing causal relationships for various diseases are also mentioned, such as Alton Ochsner's work linking smoking to lung cancer and Barry Marshall and J. Robin Warren's discovery of H. pylori's role in peptic ulcers. Guidelines for determining causation, such as those from the Surgeon General and Bradford Hill, are also reviewed.

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Dr. Vipin K Ravi
• “I have no wish nor the skill to embark upon a philosophical discussion of the meaning causation ”
Approaches available for studying disease etiology. 1.Determine the association b/w exposure and disease Ecological study Cohort ,Case control study 2.Whether the observed association is a causal one ?
Sequences of studies in human population Clinical observation Available data Case control studies Cohort studies Randomized trials 9/1/2016 5
• Alton Ochsner
• Dr. Alton Ochsner observed almost every person he operated for lung cancer gave a history of smoking • He was among the first to suggest a causal relationship
Sequences of studies in human population Clinical observation Available data Case control studies Cohort studies Randomized trials 9/1/2016 8
Mc Mahon Is ita real /spurious
Real and Spurious Association • McMahon’s study: observed association of coffee consumption with risk of pancreatic cancer Coffee Drinking Pancreatic Cancer Causal association Coffee Drinking Smoking Pancreatic Cancer Non-causal association (due to confounding 9/1/2016 10
SMOKING in antinatal period leads to lowbirth weight
BW of infants to % of smoker and non smoker mothers
Mean BW to week of gestation smoker and nonsmoker mom S
Percentage of pregnancies to LBW infant,
Jacob Yerushalmy believed smoking as confonder SMOKING LOW BIRTH WEIGHT BABIES
Types of causal relationships 9/1/2016 16
Types of causal relationships Necessary – Association is necessary Sufficient – Association itself is sufficient NECESSARY and SUFFICIENT NECESSARY but NOT SUFFICIENT SUFFICIENT but NOT NECESSARY NEITHER SUFFICIENT NOR NECESSARY 9/1/2016 17 N & S
Types of causal relationships cont. • Necessary and sufficient – Without that factor the diseases never develops, and in its presence the disease always develops – This situation rarely occurred Factor A Disease 9/1/2016 18
Types of causal relationships cont. • Necessary, but not sufficient – Factor is necessary but not sufficient to produce the disease e.g. Tubercle bacillus – Multiple factors are required, often in a specific temporal sequence Factor A + Factor B + Factor C Disease 9/1/2016 19
Types of causal relationships cont. • Sufficient, but not necessary – The factor alone can produce the disease, but so can other factors • Radiation, benzene – either can produce leukemia • Cancer does not develop in everyone who has experienced radiation or benzene exposure Factor A or Factor B or Factor C Disease 9/1/2016 20
Types of causal relationships cont. • Neither sufficient nor necessary – More complex model – Probably most accurately represents the causal relationships that operate in most chronic diseases Factor A + Factor B or Factor C + Factor D or Factor E + Factor F Disease 9/1/2016 21
Friedrich Gustav Jakob Henle (9 July 1809 – 13 May 1885) • Loop of Henle • Crypts of Henle • Hassall-Henle bodies • Henle's fissure • Henle's ampulla • Henle's layer • Henle's ligament • Henle's membrane • Henle's sheath • Henle's spine
• Founded evidence for germ theory of disease. Infective microorganisms as the cause of the diseases . He did not find a special species of bacteria himself – this was achieved by his student Robert Koch.
ROBERT KOCH
Evidence for a causal relationship • Infectious diseases: 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) • Towards the middle of 20th century issues9/1/2016 26
To establish the relationship between smoking and lung cancer, the U.S. Surgeon General had appointed an expert committee . • 1964 The committee developed a set of guidelines, which have been revised over the years.
SURGEON GENERALS REPORT(1964) 1. Consistency 2.Strength -Dose response 3.Specificity 4.Temporarily 5.Coherence
The Bradford Hill criteria, Austin Bradford Hill (1897–1991) in 1965
Bradford Hill criteria(1965) 1. Consistency 2. Specificity: 3. Strength 4. Temporality 5. Biological gradient: 6. Plausibility 7. Coherence: 8. Experiment: 9. Analogy
SURGEON GENERALS REPORT(1964) 1. Consistency 2.Strength -Dose response 3.Specificity 4.Temporarily 5.Coherence HILL’S CRITERIA (1965) 1. Strength 2. Consistency 3. Specificity: 4. Temporality 5. Biological gradient: 6. Plausibility 7. Coherence: 8. Experiment: 9. Analogy
Guidelines for judging whether an association is causal 1. Temporal association 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 35
Guidelines for judging whether an association is causal 1. Temporal association 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association Bradford Hill criteria 1. Strength 2. Consistency 3. Specificity: 4. Temporality 5. Biological gradient: 6. Plausibility 7. Coherence: 8. Experiment: 9. Analogy:
Sequences of studies in human population Clinical observation Available data Case control studies Cohort studies Randomized trials 9/1/2016 38
Types of causal relationships 9/1/2016 39
Types of causal relationships Necessary – Association is necessary Sufficient – Association itself is sufficient NECESSARY and SUFFICIENT NECESSARY but NOT SUFFICIENT SUFFICIENT but NOT NECESSARY NEITHER SUFFICIENT NOR NECESSARY 9/1/2016 40
Guidelines for judging whether an association is causal 1. Temporal association 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 41
“I have no wish nor the skill to embark upon a philosophical discussion of the meaning causation ” Austin Bradford Hill (1897– 1991)
REFERENCES  Park K, Textbook of Preventive and Social medicine, 23nd edition, Chp 3, P 80-84.  Gordis, Leon. Textbook of Epidemiology, 5rd Edition, Elsevier, Chp 14, P 243-260.  Report of advisory committee to surgeon general of public health  BMJ, Proceedings of the Royal Society of Medicine  Fletcher, Robert. Clinical Epidemiology, 4rd edition, Chp 11, P 237-239. ( contributors- Dr.Shabna ,Dr.Sreekanth and Dr.Abin )
Thank u … (to be continued…..)
Continuing …….. Vipin K Ravi 31/08/2016
"(e)veryone was against me, but I knew I was right."
The Nobel Prize in Physiology or Medicine 2005 Barry J. Marshall and J. Robin Warren
Until the 1980s, the major causes of peptic ulcer disease were considered to be stress and lifestyle factors, including smoking
DERIVING CAUSAL INFERENCES: EXAMPLE 1. In 1984, Australian physicians Drs. Barry J. Marshall and J. Robin Warren reported that they had observed small curved bacteria colonizing the lower part of the stomach in patients with gastritis and peptic ulcers • After several attempts, Marshall succeeded in cultivating a hitherto unknown bacterial species (later) from several of these biopsies
H.Pylori
Guidelines for judging whether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 53
T S D R s BIG CONSIDERAO N is CESSATION of CONSISTENCY in SPECIALITY
Temporal relationship • Exposure to the factor must occurred before the disease developed • It is easy to establish a temporal relationship in a prospective cohort study than case control and retrospective cohort • Length of the interval between the exposure and disease (asbestos in lung cancer) 9/1/2016 55
Temporal relationship cont. 9/1/2016 56
Guidelines for judging whether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 57
Strength of association • Strength of association is measured by Relative Risk or Odds Ratio • The stronger the association, the more likely the relation is causal 9/1/2016 58
Guidelines for judging whether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 59
Dose response relationship • As the dose of exposure increase, 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 does not necessarily rule out a causal relationship • In some cases a threshold may exist 9/1/2016 60
Dose response relationship cont. 9/1/2016 61
Guidelines for judging whether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 62
Replication of findings • If the relationship is causal, we would expect to find it consistently in different studies and in different population • It is expected to be present in subgroups of the population 9/1/2016 63
consistently in different populatios and in different studies
Guidelines for judging whether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 65
Biologic plausibility • Coherence with the current body of biologic knowledge • Sometimes, epidemiological observation preceded biologic knowledge – 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 9/1/2016 66
Guidelines for judging whether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 68
Consideration of alternate explanations • Explanation of a relationship as causal or due to confounding • The extent to which the investigators have taken other possible explanations into account and the extent to which they have ruled out such explanations are important considerations 9/1/2016 69
Consideration of alternate explanations SMOKING LOW BIRTH WEIGHT BABIES WHISKY, COFFEE
Guidelines for judging whether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 71
Cessation of exposure • If a factor is a cause of a diseases, the risk of the disease to decline when exposure to the factor is reduced or eliminated 9/1/2016 72
Cessation of exposure cont. Eosinophilia myalgia syndrome caused by L- tryptophan9/1/2016 73
Guidelines for judging whether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 74
Consistency with other knowledge • If a relationship is causal, we would expect the findings to be consistent with other data 9/1/2016 75
Guidelines for judging whether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 76
Specificity of the association • An association is specific when a certain exposure is associated with only one disease – The weakest point of the guideline – should be removed – When specificity of an association is found, it provides additional support for a causal inference – With a dose response relationship, absence of specificity in no way negates a causal relationship9/1/2016 77
Specificity of the association Smoking is linked with lung, pancreatic & bladder cancers; hearth disease, emphysema … SMOKIN G LUNG CANCER 9/1/2016 EMPHYSEMA C/a Urinary Bladder CAD
DERIVING CAUSAL INFERENCES Peptic Ulcers and Gastric Cancer in Relation to Infection with Helicobacter pylori
H.Pylori
1.Temporal relationship Helicobacter pylori is clearly linked to chronic gastritis. • Marshall and Warren described spiral or curved bacilli in histologic sections from 58 of 100 consecutive biopsies of human gastric antral mucosa
2.Strength of the association • Helicobacter pylori is found in at least 90% of patients with duodenal ulcer.
3.Dose-response relationship • Density of Helicobacter pylori per square millimeter of gastric mucosa is higher in patients with duodenal ulcer than in patients without duodenal ulcer.
4.Replication of the findings • Many of the observations regarding Helicobacter pylori have been replicated repeatedly • The genus Helicobacter presently comprises 18 validly named species • In at least one population reported to lack duodenal ulcers, a northern Australian aboriginal tribe that is isolated from other people.
consistently in different populatios and in different studies
7.Cessation of exposure • Long-term ulcer recurrence rates were zero after Helicobacter pylori was eradicated using triple-antimicrobial therapy, compared with a 60% to 80% relapse rate often found in patients with duodenal ulcers treated with histamine receptor antagonists
6.Consideration of alternate explanations • Data suggest that smoking can increase the risk of duodenal ulcer in Helicobacter pylori–infected patients but is not a risk factor in patients in whom Helicobacter pylori has been eradicated
Consideration of alternate explanations H.PYLORI PEPTIC ULCER SMOKIN G
5 Biologic plausibility • Although originally it was difficult to envision a bacterium that infects the stomach antrum causing ulcers in the duodenum, it is now recognized that Helicobacter pylori has binding sites on antral cells and can follow these cells into the duodenum. • Helicobacter pylori also induces mediators of inflammation. • Helicobacter pylori–infected mucosa is weakened and is susceptible to the damaging effects of acid.
8.Consistency with other knowledge. • Prevalence of Helicobacter pylori infection is the same in men as in women. • The incidence of duodenal ulcer, has been equal in recent years. • The prevalence of ulcer disease was peaked in the latter part of the 19th century, and the prevalence of Helicobacter pylori is is much higher in developing countries.
9.Specificity of the association • Prevalence of Helicobacter pylori in patients with duodenal ulcers is 90% to 100%. However, it is found in some patients even in asymptomatic individuals.
MODIFICATIONS OF THE GUIDELINES FOR CAUSAL INFERENCES • 1. The Process for Using the Evidence in Developing Recommendations on the Effectiveness of Prenatal Interventions • 2. the U.S. Preventive Services Task Force, for developing clinical practice guidelines for prevention and screening
CONCLUSION  The Causal inferences resulted from the Epidemiological Studies are very important tool for Public health experts for planning and evaluation of health strategies . The criteria along with reasonable judgment about evidence is needed in making decision about causation
REFERENCES  Park K, Textbook of Preventive and Social medicine, 23nd edition, Chp 3, P 80-84.  Gordis, Leon. Textbook of Epidemiology, 5rd Edition, Elsevier, Chp 14, P 243-260.  Report of advisory committee to surgeon general of public health 250 HELICOBACTER CONNECTIONS Nobel Lecture, December 8, 2005 Fletcher, Robert. Clinical Epidemiology, 4rd edition, Chp 11, P 237-238  ( contributors-Dr.Anuja (Addl Professor) ,Dr.Aneesh T S (Asst. Professor) Dr.Shabna ,Dr.Sreekanth and Dr.Abin )  BMJ, Proceedings of the Royal Society of Medicine 
Rejection letter of Marshall’s abstract from the Gastroenterogical Society of Australia meeting held in Perth, 1983.
"(e)veryone was against me, but I knew I was right.“ Barry James Marshall (Nobel laureate 2005 for Medicine)
"(e)veryone was against me, but I knew I was right.“
thanQ.. Vipin
Stage I: Categorizing the Evidence by the Quality of Its Source. (In each category, studies are listed in descending order of quality.) • 1. Trials (planned interventions with contemporaneous assignment of treatment and nontreatment) • a. Randomized, double-blind, placebo-controlled with sufficient power appropriately analyzed. • b. Randomized, but blindness not achieved. • c. Nonrandomized trials with good control of confounding, that are well conducted in other respects. • d. Randomized, but with deficiencies in execution or analysis (insufficient power, major losses to follow- up, • suspect randomization, analysis with exclusions). • e. Nonrandomized trials with deficiencies in execution or analysis. • 2. Cohort or case-control studies • a. Hypothesis specified before analysis, good data, confounders accounted for. • b. As above, but hypothesis not specified before analysis. • c. Post hoc, with problem(s) in the data or the analysis. • 3. Time-series studies • a. Analyses that take confounding into account. • b. Analyses that do not consider confounding. • 4. Case-series studies: Series of case reports without any specific comparison group • Among other issues that must be considered in reviewing the evidence are the precision of definition of the • outcome being measured, the degree to which the study methodology has been described, adequacy of the sample • size, and the degree to which characteristics of the population studied and of the intervention being evaluated • have been described. • A study can be well designed and carried out in an exemplary fashion (internal validity), but if the population • studied is an unusual or highly selected one, the results may not be generalizable (external validity
• Stage II: Guidelines for Evaluating the Evidence of a Causal Relationship. (In each category, studies are listed in descending priority order) .
• 2. Other considerations • a. Dose-response relationship: If a factor is indeed the cause of a disease, usually (but not invariably) the • greater the exposure to the factor, the greater the risk of the disease. Such a dose-response relationship may • not always be seen because many important biologic relationships are dichotomous, and reach a threshold • level for observed effects. • b. Strength of the association: The strength of the association is usually measured by the extent to which the • relative risk or odds depart from unity, either above 1 (in the case of disease-causing exposures) or below 1 • (in the case of preventive interventions). • c. Cessation effects: If an intervention has a beneficial effect, then the benefit should cease when it is removed • from a population (unless carryover effect is operant
• 2. Other considerations • a. Dose-response relationship: If a factor is indeed the cause of a disease, usually (but not invariably) the • greater the exposure to the factor, the greater the risk of the disease. Such a dose-response relationship may • not always be seen because many important biologic relationships are dichotomous, and reach a threshold • level for observed effects. • b. Strength of the association: The strength of the association is usually measured by the extent to which the • relative risk or odds depart from unity, either above 1 (in the case of disease-causing exposures) or below 1 • (in the case of preventive interventions). • c. Cessation effects: If an intervention has a beneficial effect, then the benefit should cease when it is removed • from a population (unless carryover effect is operant
• 1. Major criteria • a. Temporal relationship: An intervention can be considered evidence of a reduction in risk of disease or • abnormality only if the intervention was applied before the time the disease or abnormality would have • developed. • b. Biological plausibility: A biologically plausible mechanism should be able to explain why such a relationship • would be expected to occur. • c. Consistency: Single studies are rarely definitive. Study findings that are replicated in different populations • and by different investigators carry more weight than those that are not. If the findings of studies are • inconsistent, the inconsistency must be explained. • d. Alternative explanations (confounding): The extent to which alternative explanations have been explored is • an important criterion in judging causality
U.S. Preventive Services Task Force Levels of Certainty Regarding Net Benefit • HIGH The available evidence usually includes consistent results from well-designed, well-conducted • studies in representative primary care populations. These studies assess the effects of the • preventive service on health outcomes. This conclusion is therefore unlikely to be strongly • affected by the results of future studies. • MODERATE The available evidence is sufficient to determine the effects of the preventive service on health • outcomes, but confidence in the estimate is constrained by such factors as: • • The number, size, or quality of individual studies. • • Inconsistency of findings across individual studies. • • Limited generalizability of findings to routine primary care practice. • • Lack of coherence in the chain of evidence. • As more information becomes available, the magnitude or direction of the observed effect • could change, and this change may be large enough to alter the conclusion. • LOW The available evidence is insufficient to assess effects on health outcomes. Evidence is • insufficient because of: • • The limited number or size of studies. • • Important flaws in study design or methods. • • Inconsistency of findings across individual studies. • • Gaps in the chain of evidence. • • Findings not generalizable to routine primary care practice. • • A lack of information on important health outcomes. • More information may allow an estimation of effects on health outcomes
• A similar approach, ranking studies by the • quality of the study and its evidence, is used by • the U.S. Preventive Services Task Force, which is • responsible for developing clinical practice guidelines • for prevention and screening (Table 14-4).13 • The Task Force is an independent committee • of experts supported by the U.S. Government. • Members include experts in primary care, prevention, • evidence-based medicine, and research • methods. Various clinical areas and experience in • preventive medicine, public health, and health
Causation
Causation
Causation

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Causation

  • 2.
  • 3.
    • “I haveno wish nor the skill to embark upon a philosophical discussion of the meaning causation ”
  • 4.
    Approaches available forstudying disease etiology. 1.Determine the association b/w exposure and disease Ecological study Cohort ,Case control study 2.Whether the observed association is a causal one ?
  • 5.
    Sequences of studiesin human population Clinical observation Available data Case control studies Cohort studies Randomized trials 9/1/2016 5
  • 6.
  • 7.
    • Dr. AltonOchsner observed almost every person he operated for lung cancer gave a history of smoking • He was among the first to suggest a causal relationship
  • 8.
    Sequences of studiesin human population Clinical observation Available data Case control studies Cohort studies Randomized trials 9/1/2016 8
  • 9.
    Mc Mahon Is itareal /spurious
  • 10.
    Real and SpuriousAssociation • McMahon’s study: observed association of coffee consumption with risk of pancreatic cancer Coffee Drinking Pancreatic Cancer Causal association Coffee Drinking Smoking Pancreatic Cancer Non-causal association (due to confounding 9/1/2016 10
  • 11.
    SMOKING in antinatal periodleads to lowbirth weight
  • 12.
    BW of infantsto % of smoker and non smoker mothers
  • 13.
    Mean BW toweek of gestation smoker and nonsmoker mom S
  • 14.
  • 15.
    Jacob Yerushalmy believedsmoking as confonder SMOKING LOW BIRTH WEIGHT BABIES
  • 16.
    Types of causalrelationships 9/1/2016 16
  • 17.
    Types of causalrelationships Necessary – Association is necessary Sufficient – Association itself is sufficient NECESSARY and SUFFICIENT NECESSARY but NOT SUFFICIENT SUFFICIENT but NOT NECESSARY NEITHER SUFFICIENT NOR NECESSARY 9/1/2016 17 N & S
  • 18.
    Types of causalrelationships cont. • Necessary and sufficient – Without that factor the diseases never develops, and in its presence the disease always develops – This situation rarely occurred Factor A Disease 9/1/2016 18
  • 19.
    Types of causalrelationships cont. • Necessary, but not sufficient – Factor is necessary but not sufficient to produce the disease e.g. Tubercle bacillus – Multiple factors are required, often in a specific temporal sequence Factor A + Factor B + Factor C Disease 9/1/2016 19
  • 20.
    Types of causalrelationships cont. • Sufficient, but not necessary – The factor alone can produce the disease, but so can other factors • Radiation, benzene – either can produce leukemia • Cancer does not develop in everyone who has experienced radiation or benzene exposure Factor A or Factor B or Factor C Disease 9/1/2016 20
  • 21.
    Types of causalrelationships cont. • Neither sufficient nor necessary – More complex model – Probably most accurately represents the causal relationships that operate in most chronic diseases Factor A + Factor B or Factor C + Factor D or Factor E + Factor F Disease 9/1/2016 21
  • 23.
    Friedrich Gustav JakobHenle (9 July 1809 – 13 May 1885) • Loop of Henle • Crypts of Henle • Hassall-Henle bodies • Henle's fissure • Henle's ampulla • Henle's layer • Henle's ligament • Henle's membrane • Henle's sheath • Henle's spine
  • 24.
    • Founded evidencefor germ theory of disease. Infective microorganisms as the cause of the diseases . He did not find a special species of bacteria himself – this was achieved by his student Robert Koch.
  • 25.
  • 26.
    Evidence for acausal relationship • Infectious diseases: 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) • Towards the middle of 20th century issues9/1/2016 26
  • 27.
    To establish therelationship between smoking and lung cancer, the U.S. Surgeon General had appointed an expert committee . • 1964 The committee developed a set of guidelines, which have been revised over the years.
  • 29.
    SURGEON GENERALS REPORT(1964) 1. Consistency 2.Strength -Doseresponse 3.Specificity 4.Temporarily 5.Coherence
  • 32.
    The Bradford Hillcriteria, Austin Bradford Hill (1897–1991) in 1965
  • 33.
    Bradford Hill criteria(1965) 1.Consistency 2. Specificity: 3. Strength 4. Temporality 5. Biological gradient: 6. Plausibility 7. Coherence: 8. Experiment: 9. Analogy
  • 34.
    SURGEON GENERALS REPORT(1964) 1. Consistency 2.Strength -Doseresponse 3.Specificity 4.Temporarily 5.Coherence HILL’S CRITERIA (1965) 1. Strength 2. Consistency 3. Specificity: 4. Temporality 5. Biological gradient: 6. Plausibility 7. Coherence: 8. Experiment: 9. Analogy
  • 35.
    Guidelines for judgingwhether an association is causal 1. Temporal association 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 35
  • 36.
    Guidelines for judging whetheran association is causal 1. Temporal association 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association Bradford Hill criteria 1. Strength 2. Consistency 3. Specificity: 4. Temporality 5. Biological gradient: 6. Plausibility 7. Coherence: 8. Experiment: 9. Analogy:
  • 38.
    Sequences of studiesin human population Clinical observation Available data Case control studies Cohort studies Randomized trials 9/1/2016 38
  • 39.
    Types of causalrelationships 9/1/2016 39
  • 40.
    Types of causalrelationships Necessary – Association is necessary Sufficient – Association itself is sufficient NECESSARY and SUFFICIENT NECESSARY but NOT SUFFICIENT SUFFICIENT but NOT NECESSARY NEITHER SUFFICIENT NOR NECESSARY 9/1/2016 40
  • 41.
    Guidelines for judgingwhether an association is causal 1. Temporal association 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 41
  • 42.
    “I have nowish nor the skill to embark upon a philosophical discussion of the meaning causation ” Austin Bradford Hill (1897– 1991)
  • 43.
    REFERENCES  Park K,Textbook of Preventive and Social medicine, 23nd edition, Chp 3, P 80-84.  Gordis, Leon. Textbook of Epidemiology, 5rd Edition, Elsevier, Chp 14, P 243-260.  Report of advisory committee to surgeon general of public health  BMJ, Proceedings of the Royal Society of Medicine  Fletcher, Robert. Clinical Epidemiology, 4rd edition, Chp 11, P 237-239. ( contributors- Dr.Shabna ,Dr.Sreekanth and Dr.Abin )
  • 44.
    Thank u … (tobe continued…..)
  • 45.
  • 46.
    "(e)veryone was againstme, but I knew I was right."
  • 49.
    The Nobel Prizein Physiology or Medicine 2005 Barry J. Marshall and J. Robin Warren
  • 50.
    Until the 1980s,the major causes of peptic ulcer disease were considered to be stress and lifestyle factors, including smoking
  • 51.
    DERIVING CAUSAL INFERENCES: EXAMPLE 1.In 1984, Australian physicians Drs. Barry J. Marshall and J. Robin Warren reported that they had observed small curved bacteria colonizing the lower part of the stomach in patients with gastritis and peptic ulcers • After several attempts, Marshall succeeded in cultivating a hitherto unknown bacterial species (later) from several of these biopsies
  • 52.
  • 53.
    Guidelines for judgingwhether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 53
  • 54.
    T S D Rs BIG CONSIDERAO N is CESSATION of CONSISTENCY in SPECIALITY
  • 55.
    Temporal relationship • Exposureto the factor must occurred before the disease developed • It is easy to establish a temporal relationship in a prospective cohort study than case control and retrospective cohort • Length of the interval between the exposure and disease (asbestos in lung cancer) 9/1/2016 55
  • 56.
  • 57.
    Guidelines for judgingwhether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 57
  • 58.
    Strength of association •Strength of association is measured by Relative Risk or Odds Ratio • The stronger the association, the more likely the relation is causal 9/1/2016 58
  • 59.
    Guidelines for judgingwhether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 59
  • 60.
    Dose response relationship •As the dose of exposure increase, 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 does not necessarily rule out a causal relationship • In some cases a threshold may exist 9/1/2016 60
  • 61.
    Dose response relationshipcont. 9/1/2016 61
  • 62.
    Guidelines for judgingwhether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 62
  • 63.
    Replication of findings •If the relationship is causal, we would expect to find it consistently in different studies and in different population • It is expected to be present in subgroups of the population 9/1/2016 63
  • 64.
    consistently in differentpopulatios and in different studies
  • 65.
    Guidelines for judgingwhether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 65
  • 66.
    Biologic plausibility • Coherencewith the current body of biologic knowledge • Sometimes, epidemiological observation preceded biologic knowledge – 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 9/1/2016 66
  • 68.
    Guidelines for judgingwhether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 68
  • 69.
    Consideration of alternateexplanations • Explanation of a relationship as causal or due to confounding • The extent to which the investigators have taken other possible explanations into account and the extent to which they have ruled out such explanations are important considerations 9/1/2016 69
  • 70.
    Consideration of alternate explanations SMOKING LOWBIRTH WEIGHT BABIES WHISKY, COFFEE
  • 71.
    Guidelines for judgingwhether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 71
  • 72.
    Cessation of exposure •If a factor is a cause of a diseases, the risk of the disease to decline when exposure to the factor is reduced or eliminated 9/1/2016 72
  • 73.
    Cessation of exposurecont. Eosinophilia myalgia syndrome caused by L- tryptophan9/1/2016 73
  • 74.
    Guidelines for judgingwhether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 74
  • 75.
    Consistency with otherknowledge • If a relationship is causal, we would expect the findings to be consistent with other data 9/1/2016 75
  • 76.
    Guidelines for judgingwhether an association is causal 1. Temporal relationship 2. Strength of association 3. Dose response relationship 4. Replication of findings 5. Biologic plausibility 6. Consideration of alternate explanations 7. Cessation of exposure 8. Consistency with other knowledge 9. Specificity of the association 9/1/2016 76
  • 77.
    Specificity of theassociation • An association is specific when a certain exposure is associated with only one disease – The weakest point of the guideline – should be removed – When specificity of an association is found, it provides additional support for a causal inference – With a dose response relationship, absence of specificity in no way negates a causal relationship9/1/2016 77
  • 78.
    Specificity of theassociation Smoking is linked with lung, pancreatic & bladder cancers; hearth disease, emphysema … SMOKIN G LUNG CANCER 9/1/2016 EMPHYSEMA C/a Urinary Bladder CAD
  • 79.
    DERIVING CAUSAL INFERENCES PepticUlcers and Gastric Cancer in Relation to Infection with Helicobacter pylori
  • 80.
  • 81.
    1.Temporal relationship Helicobacter pyloriis clearly linked to chronic gastritis. • Marshall and Warren described spiral or curved bacilli in histologic sections from 58 of 100 consecutive biopsies of human gastric antral mucosa
  • 82.
    2.Strength of the association •Helicobacter pylori is found in at least 90% of patients with duodenal ulcer.
  • 83.
    3.Dose-response relationship • Density ofHelicobacter pylori per square millimeter of gastric mucosa is higher in patients with duodenal ulcer than in patients without duodenal ulcer.
  • 84.
    4.Replication of the findings •Many of the observations regarding Helicobacter pylori have been replicated repeatedly • The genus Helicobacter presently comprises 18 validly named species • In at least one population reported to lack duodenal ulcers, a northern Australian aboriginal tribe that is isolated from other people.
  • 85.
    consistently in differentpopulatios and in different studies
  • 86.
    7.Cessation of exposure • Long-termulcer recurrence rates were zero after Helicobacter pylori was eradicated using triple-antimicrobial therapy, compared with a 60% to 80% relapse rate often found in patients with duodenal ulcers treated with histamine receptor antagonists
  • 87.
    6.Consideration of alternate explanations •Data suggest that smoking can increase the risk of duodenal ulcer in Helicobacter pylori–infected patients but is not a risk factor in patients in whom Helicobacter pylori has been eradicated
  • 88.
  • 89.
    5 Biologic plausibility •Although originally it was difficult to envision a bacterium that infects the stomach antrum causing ulcers in the duodenum, it is now recognized that Helicobacter pylori has binding sites on antral cells and can follow these cells into the duodenum. • Helicobacter pylori also induces mediators of inflammation. • Helicobacter pylori–infected mucosa is weakened and is susceptible to the damaging effects of acid.
  • 90.
    8.Consistency with other knowledge. •Prevalence of Helicobacter pylori infection is the same in men as in women. • The incidence of duodenal ulcer, has been equal in recent years. • The prevalence of ulcer disease was peaked in the latter part of the 19th century, and the prevalence of Helicobacter pylori is is much higher in developing countries.
  • 91.
    9.Specificity of the association •Prevalence of Helicobacter pylori in patients with duodenal ulcers is 90% to 100%. However, it is found in some patients even in asymptomatic individuals.
  • 92.
    MODIFICATIONS OF THE GUIDELINESFOR CAUSAL INFERENCES • 1. The Process for Using the Evidence in Developing Recommendations on the Effectiveness of Prenatal Interventions • 2. the U.S. Preventive Services Task Force, for developing clinical practice guidelines for prevention and screening
  • 93.
    CONCLUSION  The Causalinferences resulted from the Epidemiological Studies are very important tool for Public health experts for planning and evaluation of health strategies . The criteria along with reasonable judgment about evidence is needed in making decision about causation
  • 94.
    REFERENCES  Park K,Textbook of Preventive and Social medicine, 23nd edition, Chp 3, P 80-84.  Gordis, Leon. Textbook of Epidemiology, 5rd Edition, Elsevier, Chp 14, P 243-260.  Report of advisory committee to surgeon general of public health 250 HELICOBACTER CONNECTIONS Nobel Lecture, December 8, 2005 Fletcher, Robert. Clinical Epidemiology, 4rd edition, Chp 11, P 237-238  ( contributors-Dr.Anuja (Addl Professor) ,Dr.Aneesh T S (Asst. Professor) Dr.Shabna ,Dr.Sreekanth and Dr.Abin )  BMJ, Proceedings of the Royal Society of Medicine 
  • 95.
    Rejection letter ofMarshall’s abstract from the Gastroenterogical Society of Australia meeting held in Perth, 1983.
  • 98.
    "(e)veryone was againstme, but I knew I was right.“ Barry James Marshall (Nobel laureate 2005 for Medicine)
  • 99.
    "(e)veryone was againstme, but I knew I was right.“
  • 101.
  • 104.
    Stage I: Categorizingthe Evidence by the Quality of Its Source. (In each category, studies are listed in descending order of quality.) • 1. Trials (planned interventions with contemporaneous assignment of treatment and nontreatment) • a. Randomized, double-blind, placebo-controlled with sufficient power appropriately analyzed. • b. Randomized, but blindness not achieved. • c. Nonrandomized trials with good control of confounding, that are well conducted in other respects. • d. Randomized, but with deficiencies in execution or analysis (insufficient power, major losses to follow- up, • suspect randomization, analysis with exclusions). • e. Nonrandomized trials with deficiencies in execution or analysis. • 2. Cohort or case-control studies • a. Hypothesis specified before analysis, good data, confounders accounted for. • b. As above, but hypothesis not specified before analysis. • c. Post hoc, with problem(s) in the data or the analysis. • 3. Time-series studies • a. Analyses that take confounding into account. • b. Analyses that do not consider confounding. • 4. Case-series studies: Series of case reports without any specific comparison group • Among other issues that must be considered in reviewing the evidence are the precision of definition of the • outcome being measured, the degree to which the study methodology has been described, adequacy of the sample • size, and the degree to which characteristics of the population studied and of the intervention being evaluated • have been described. • A study can be well designed and carried out in an exemplary fashion (internal validity), but if the population • studied is an unusual or highly selected one, the results may not be generalizable (external validity
  • 105.
    • Stage II:Guidelines for Evaluating the Evidence of a Causal Relationship. (In each category, studies are listed in descending priority order) .
  • 106.
    • 2. Otherconsiderations • a. Dose-response relationship: If a factor is indeed the cause of a disease, usually (but not invariably) the • greater the exposure to the factor, the greater the risk of the disease. Such a dose-response relationship may • not always be seen because many important biologic relationships are dichotomous, and reach a threshold • level for observed effects. • b. Strength of the association: The strength of the association is usually measured by the extent to which the • relative risk or odds depart from unity, either above 1 (in the case of disease-causing exposures) or below 1 • (in the case of preventive interventions). • c. Cessation effects: If an intervention has a beneficial effect, then the benefit should cease when it is removed • from a population (unless carryover effect is operant
  • 107.
    • 2. Otherconsiderations • a. Dose-response relationship: If a factor is indeed the cause of a disease, usually (but not invariably) the • greater the exposure to the factor, the greater the risk of the disease. Such a dose-response relationship may • not always be seen because many important biologic relationships are dichotomous, and reach a threshold • level for observed effects. • b. Strength of the association: The strength of the association is usually measured by the extent to which the • relative risk or odds depart from unity, either above 1 (in the case of disease-causing exposures) or below 1 • (in the case of preventive interventions). • c. Cessation effects: If an intervention has a beneficial effect, then the benefit should cease when it is removed • from a population (unless carryover effect is operant
  • 108.
    • 1. Majorcriteria • a. Temporal relationship: An intervention can be considered evidence of a reduction in risk of disease or • abnormality only if the intervention was applied before the time the disease or abnormality would have • developed. • b. Biological plausibility: A biologically plausible mechanism should be able to explain why such a relationship • would be expected to occur. • c. Consistency: Single studies are rarely definitive. Study findings that are replicated in different populations • and by different investigators carry more weight than those that are not. If the findings of studies are • inconsistent, the inconsistency must be explained. • d. Alternative explanations (confounding): The extent to which alternative explanations have been explored is • an important criterion in judging causality
  • 109.
    U.S. Preventive ServicesTask Force Levels of Certainty Regarding Net Benefit • HIGH The available evidence usually includes consistent results from well-designed, well-conducted • studies in representative primary care populations. These studies assess the effects of the • preventive service on health outcomes. This conclusion is therefore unlikely to be strongly • affected by the results of future studies. • MODERATE The available evidence is sufficient to determine the effects of the preventive service on health • outcomes, but confidence in the estimate is constrained by such factors as: • • The number, size, or quality of individual studies. • • Inconsistency of findings across individual studies. • • Limited generalizability of findings to routine primary care practice. • • Lack of coherence in the chain of evidence. • As more information becomes available, the magnitude or direction of the observed effect • could change, and this change may be large enough to alter the conclusion. • LOW The available evidence is insufficient to assess effects on health outcomes. Evidence is • insufficient because of: • • The limited number or size of studies. • • Important flaws in study design or methods. • • Inconsistency of findings across individual studies. • • Gaps in the chain of evidence. • • Findings not generalizable to routine primary care practice. • • A lack of information on important health outcomes. • More information may allow an estimation of effects on health outcomes
  • 110.
    • A similarapproach, ranking studies by the • quality of the study and its evidence, is used by • the U.S. Preventive Services Task Force, which is • responsible for developing clinical practice guidelines • for prevention and screening (Table 14-4).13 • The Task Force is an independent committee • of experts supported by the U.S. Government. • Members include experts in primary care, prevention, • evidence-based medicine, and research • methods. Various clinical areas and experience in • preventive medicine, public health, and health

Editor's Notes

  • #2 Good morning mam.. Dear frnds welcom to todays presatation ..
  • #3 Today we r moving on to chaptr 14 of leon gordis ‘from association to causation” this chapter dealing with disease etiology..that is causation of a disease
  • #4 These are the words of a persolity who contributed a lot to the science of epidemiology espacially causation ..any guesses……no problem….lets move on to todays session
  • #5 This is a two step process..first we need to determine the association b/n a particular risk fact\or and a disease ..secondly we need to find out the observed associatioN S C
  • #6 Smoking VS Lung Cancer – Ochsner surgeon example
  • #9 Smoking VS Lung Cancer – Ochsner surgeon example .clinical observations r the initial step..then we need case control study..cohort finally randomized trial never used for the study of putative toxin or carcinogen
  • #10 Mac Mahan who studied assiciation between coffee drinking and pancreatic cancer ..coffee as observed association
  • #11 Likely to be causal due to the confonder smoking
  • #18 If the association is causal 4 types of realationship b/w expossure and disease are possible
  • #23 Crypts of Henle: Microscopic pockets located in the conjunctiva of the eye. Hassall-Henle bodies: Transparent growths in the periphery of the Descemet membrane of the eye. Henle's fissure: Fibrous tissue between the cardiac muscle fibers. Henle's ampulla: Ampulla of the uterine tube. Henle's layer: Outer layer of cells of root sheath of a hair follicle. Henle's ligament: Tendon of the transversus abdominis muscle. Henle's membrane: Bruch’s layer forming inner boundary of the choroid of the eye. Henle's sheath: Connective tissue which supports outer layer of nerve fibres in a funiculus. Henle's spine: The supra-meateal spine that serves as a landmark in the mastoid area.[3]
  • #24 Crypts of Henle: Microscopic pockets located in the conjunctiva of the eye. Hassall-Henle bodies: Transparent growths in the periphery of the Descemet membrane of the eye. Henle's fissure: Fibrous tissue between the cardiac muscle fibers. Henle's ampulla: Ampulla of the uterine tube. Henle's layer: Outer layer of cells of root sheath of a hair follicle. Henle's ligament: Tendon of the transversus abdominis muscle. Henle's membrane: Bruch’s layer forming inner boundary of the choroid of the eye. Henle's sheath: Connective tissue which supports outer layer of nerve fibres in a funiculus. Henle's spine: The supra-meateal spine that serves as a landmark in the mastoid area.[3]
  • #25 The germ theory was proposed by Girolamo Fracastoro in 1546, 1 Miasma theory
  • #37 TS DR. BIG CONSIDERATION IS CESSATION OF CONSISTENCY in speciality
  • #39 Smoking VS Lung Cancer – Ochsner surgeon example
  • #41 Smoking VS Lung Cancer – Ochsner surgeon example
  • #52 Life and research In 1979, Marshall was appointed as a Registrar in Medicine at the Royal Perth Hospital. He met Robin Warren, a pathologist interested in gastritis, during internal medicine fellowship training at Royal Perth Hospital in 1981. Together, the pair studied the presence of spiral bacteria in association with gastritis. In 1982, they performed the initial culture of H. pylori and developed their hypothesis related to the bacterial cause of peptic ulcer and gastric cancer.[7] It has been claimed that the H. pylori theory was ridiculed by the establishment scientists and doctors, who did not believe that any bacteria could live in the acidic environment of the stomach. Marshall has been quoted as saying in 1998 that "(e)veryone was against me, but I knew I was right."[10] On the other hand, it has also been argued that medical researchers showed a proper degree of scientific scepticism until the H. pylori hypothesis could be supported by evidence.[11] After failed attempts to infect piglets in 1984, Marshall, after having a baseline endoscopy done, drank a Petri dish containing cultured H. pylori, expecting to develop, perhaps years later, an ulcer. He was surprised when, only three days later, he developed vague nausea and halitosis (due to the achlorhydria, there was no acid to kill bacteria in the stomach, and their waste products manifested as bad breath), noticed only by his mother. On days 5–8, he developed achlorydric (no acid) vomiting. On day eight, he had a repeat endoscopy, which showed massive inflammation (gastritis), and a biopsy from which H. pylori was cultured, showing it had colonised his stomach. On the fourteenth day after ingestion, a third endoscopy was done, and Marshall began to take antibiotics.[12] Interestingly, Marshall did not develop antibodies to H. pylori, suggesting that innate immunity can sometimes eradicate acute H. pylori infection. Marshall's illness and recovery, based on a culture of organisms extracted from a patient, fulfilled Koch's postulates for H. pylori and gastritis, but not for peptic ulcer. This experiment was published in 1985 in the Medical Journal of Australia[13] and is among the most cited articles from the journal.[14] After his work at Fremantle Hospital, Marshall did research at Royal Perth Hospital (1985–86) and at the University of Virginia, USA (1986–Present), before returning to Australia while remaining on the faculty of the University of Virginia.[2] He held a Burnet Fellowship at the University of Western Australia (UWA) from 1998–2003.[15] Marshall continues research related to H. pylori and runs the H. pylori Research Laboratory at UWA.[16] In 2007, Marshall accepted a part-time appointment at the Pennsylvania State University.[17
  • #56 The temporal relationship of exposure and disease is important not only for clarifying the order in which the two occur but also in regard to the length of the interval between exposure and disease. For example, asbestos has been clearly linked to increased risk of lung cancer, but the latent period between the exposure and the appearance of lung cancer is at least 15 to 20 years. Therefore, if, for example, lung cancer develops after only 3 years since the asbestos exposure, it is safe to conclude that the lung cancer was not a result of
  • #74 Some diseases are irreversible: Emphysema --- smoking --- but smoking cessation its progression is reduced
  • #76 The absence of such consistency would not completely rule out this hypothesis , if we observed rising lung cancer rates after a period of declining cigarette sales, for example, we would need to explain how this observation could be consistent with a causal hypothesis. Parallel trendsbetween cigarette consumption and lung cancer in men (two curves on left) and in women(two curves on right), in Englandand Wales.The cancer problem.