association to causation ...Leon gordis review

2. Dr. Vipin K
Ravi

3. • “I have no wish nor the skill to embark
upon a philosophical discussion of the
meaning causation ”

4. 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 ?

5. Sequences of studies in human
population
Clinical observation
Available data
Case control studies
Cohort studies
Randomized trials
9/1/2016 5

6. • Alton Ochsner

7. • 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

8. Sequences of studies in human
population
Clinical observation
Available data
Case control studies
Cohort studies
Randomized trials
9/1/2016 8

9. Mc Mahon
Is ita real /spurious

10. 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

11. SMOKING in antinatal
period leads to lowbirth
weight

12. BW of infants to % of smoker and non
smoker mothers

13. Mean BW to week of gestation
smoker and nonsmoker mom
S

14. Percentage of pregnancies to LBW
infant,

15. Jacob Yerushalmy believed smoking as
confonder
SMOKING LOW BIRTH
WEIGHT
BABIES

16. Types of causal relationships
9/1/2016 16

17. 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

18. 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

19. 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

20. 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

21. 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

23. 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

24. • 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.

25. ROBERT KOCH

26. 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

27. 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.

29. SURGEON GENERALS
REPORT(1964)
1. Consistency
2.Strength
-Dose response
3.Specificity
4.Temporarily
5.Coherence

32. The Bradford Hill criteria, 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
-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

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
9/1/2016 35

36. 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:

38. Sequences of studies in human
population
Clinical observation
Available data
Case control studies
Cohort studies
Randomized trials
9/1/2016 38

39. Types of causal relationships
9/1/2016 39

40. 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

41. 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

42. “I have no wish 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 …
(to be continued…..)

45. Continuing ……..
Vipin K Ravi
31/08/2016

46. "(e)veryone was against me, but I knew I
was right."

49. The Nobel Prize in
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. H.Pylori

53. 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

54. T S
D R s
BIG
CONSIDERAO
N is
CESSATION of
CONSISTENCY
in SPECIALITY

55. 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

56. Temporal relationship cont.
9/1/2016 56

57. 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

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 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

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 relationship cont.
9/1/2016 61

62. 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

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 different populatios
and in different studies

65. 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

66. 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

68. 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

69. 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

70. Consideration of alternate
explanations
SMOKING
LOW BIRTH
WEIGHT
BABIES
WHISKY,
COFFEE

71. 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

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 exposure cont.
Eosinophilia myalgia syndrome caused by L-
tryptophan9/1/2016 73

74. 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

75. Consistency with other knowledge
• If a relationship is causal, we would expect
the findings to be consistent with other
data
9/1/2016 75

76. 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

77. 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

78. 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

79. DERIVING CAUSAL INFERENCES
Peptic Ulcers and Gastric Cancer in
Relation
to Infection with Helicobacter pylori

80. H.Pylori

81. 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

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 of Helicobacter 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 different populatios
and in different studies

86. 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

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. Consideration of alternate
explanations
H.PYLORI PEPTIC ULCER
SMOKIN
G

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
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

93. 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

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 of Marshall’s abstract from
the Gastroenterogical Society of Australia
meeting held in Perth, 1983.

98. "(e)veryone was against me, but I knew I
was right.“
Barry James
Marshall
(Nobel laureate 2005 for
Medicine)

99. "(e)veryone was against me, but I knew I
was right.“

101. thanQ..
Vipin

104. 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

105. • Stage II: Guidelines for Evaluating the
Evidence of a Causal Relationship. (In
each category, studies are listed in
descending priority order)
.

106. • 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

107. • 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

108. • 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

109. 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

110. • 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