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
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
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
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
22.
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.
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.
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:
37.
38. Sequences of studies in human
population
Clinical observation
Available data
Case control studies
Cohort studies
Randomized trials
9/1/2016 38
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 )
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
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
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
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
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
67.
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
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
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
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.
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
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.
96.
97.
98. "(e)veryone was against me, but I knew I
was right.“
Barry James
Marshall
(Nobel laureate 2005 for
Medicine)
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
Editor's Notes
Good morning mam.. Dear frnds welcom to todays presatation ..
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
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
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
Smoking VS Lung Cancer – Ochsner surgeon example
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
Mac Mahan who studied assiciation between coffee drinking and pancreatic cancer ..coffee as observed association
Likely to be causal due to the confonder smoking
If the association is causal 4 types of realationship b/w expossure and disease are possible
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]
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]
The germ theory was proposed by Girolamo Fracastoro in 1546, 1 Miasma theory
TS DR. BIG CONSIDERATION IS CESSATION OF CONSISTENCY in speciality
Smoking VS Lung Cancer – Ochsner surgeon example
Smoking VS Lung Cancer – Ochsner surgeon example
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
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
Some diseases are irreversible: Emphysema --- smoking --- but smoking cessation its progression is reduced
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.