Causal and non-causal
associations
Biases, confounding,
confusion
How to decide if a finding is
real
Ora Paltiel October 26, 2014
Causation
Importance of studying causation
1. Clinical medicine
Advice to patients
Prevention
2. Social/environmental
Compensation
3. Population
Screening
prevention
“Cause”
A factor which, if altered is followed by
a change in the frequency or
character of a disease.
Probabilistic approach: X is a cause of
Y if the probability that Y occurs is
increased as a consequence of X.
Problems: risk factor vs cause
risk marker vs risk factor
‫‪Models‬‬
‫המשולש האפידמיולוגי‬
‫המאכסן‬
‫הסביבה ‪Environment‬‬
‫‪Triangle‬‬
‫‪Host‬‬
‫מחולל המחלה ‪Agent‬‬
Web of causation
Association and cause
Explanation
Finding
Association
Bias in selection
or measurement
Chance
Confounding
Cause
Yes
No
Likely
Unlikely
Yes
No
Cause
Types of association
Positive vs inverse
Linear, exponential, quadratic (U or J
shaped)
Two factors:
additive
multiplicative
Effect modification
Relationship between asbestos
exposure (particle-years) and relative
risk of lung cancer
Wisconsin Card Sorting Test number of categories in early-onset, late-onset and control
groups use of marijuana.
Fontes M A et al. BJP 2011;198:442-447
Annual mortality (per 1000 men) from
all causes related to alcohol
consumption
Ischaemic heart disease
Age-standardized lung cancer death rates
(per 100000 population) in relation to
cigarette smoking and occupational
exposure to asbestos dust
Exposure to
asbestos
History of
cigarette
smoking
Lung cancer
death rate per
100000
No
No
11
Yes
No
58
No
Yes
123
Yes
Yes
602
Effect modification
Prevalence of Actinic Keratoses in
Psoriatics and Controls by Hair Colour
Odds
Psoriatics
ratio
Controls
Black
Brown
Blonde/red
Effect modification
Prevalence of Actinic Keratoses in
Psoriatics and Controls by propensity
to sunburn
5
4
Odds
ratio
Psoriatics
3
Controls
2
1
0
Never
Often/always
Association and cause
Explanation
Finding
Association
Bias in selection
or measurement
Chance
Confounding
Cause
Yes
No
Likely
Unlikely
Yes
No
Cause
Definition of bias
“Any process at any stage of inference
which tends to produce results or
conclusions that differ systematically
from the truth”
Stages of research in which
bias can occur:
1. In reading-up on the field
2. In specifying and selecting the study
sample
3. In executing the experimental
maneuvre (or exposure)
4. In measuring exposures and
outcomes
5. In analyzing the data
6. In publishing the results
Membership bias
Membership in a group (the
employed, joggers, etc…) may
imply a degree of health which
differs systematically from that
of the general population.
Selection bias
Confirmation by randomized trial of
observed effect in non-randomized
trial: Salk vaccine for poliomyelitis
Type of study
Poliomyelitis cases/total
(rate per 100,000)
Odds ratio
(95% CI)
Vaccine
Control
Nonrandomized
60/231902
(26)
391/725173
(54)
0.55 (0.44-0.68)
Randomized
57/200745
(28)
142/201229
(71)
0.43 (0.32-0.56)
External Validity
Confirmation by randomized trial of
observed effect in non-randomized
trial: Salk vaccine for poliomyelitis
Type of study
Poliomyelitis cases/total
(rate per 100,000)
Odds ratio
(95% CI)
Vaccine
Control
Nonrandomized
60/231902
(26)
391/725173
(54)
0.55 (0.44-0.68)
Randomized
57/200745
(28)
142/201229
(71)
0.43 (0.32-0.56)
Cumulative mortality from verified
colorectal cancer in the control
and screened groups
Cause specific mortality rates (per 1000
person years) in the intervention and
control groups by faecal occult blood
testing
Social approval bias
Social approval bias
Interventionletter, nutrition
survey, benefits of
fruits and veggies.
5-a day sticker
Control- letter,
nutrition
survey,
Referral bias
Admission rate (Berkson) bias
When combination of exposure and
disease leads to higher rate of
hospitalization, the relation between
exposure and disease will become
distorted in hospital based studies.
Measurement bias/ information
bias esp.in case-control studies
a) presence of the outcome directly affects the
exposure. E.g. endometrial cancer and
estrogen
b) presence of the outcome affects the
recollection of the exposure “recall bias”.
E.g. birth defects and drug exposure
c) presence of the outcome affects the
measurement or recording of the exposure.
Eg DVT and oral contraceptives
Association and cause
Explanation
Finding
Association
Bias in selection
or measurement
Chance
Confounding
Cause
Yes
P value
No
Likely
Unlikely
Yes
No
Cause
Association and cause
Explanation
Finding
Association
Bias in selection
or measurement
Chance
Confounding
Cause
Yes
No
Likely
Unlikely
Yes
No
Cause
Confounding
Confounding: coffee drinking, cigarette
smoking, and coronary heart disease
EXPOSURE
(coffee drinking)
DISEASE
(heart disease)
CONFOUNDING
VARIABLE
(cigarette smoking)
Locations of potential bias
02 in cohort
studies 16
57
40
80
21
65
02
74
16
08
57
40
80
21
65
74
08
Association and cause
Explanation
Finding
Association
Bias in selection
or measurement
Chance
Confounding
Cause?
Yes
No
Likely
Unlikely
Yes
No
Cause
Criteria for causation
1. Is there evidence from true
experimentation in humans?
2. Is the association strong?
3. Is the association consistent from study
to study?
4. Is the temporal association correct?
5. Is there a dose-response gradient?
6. Does the association make biological
sense?
7. Is the association specific?
(Adapted from Bradford Hill)
The isotretinoin dysmorphic syndrome
Lancet, March 3 1984
Sir, - we describe here a case of human
teratogenicity that confirms the need for
the drug isotretinoin to be avoided in
pregnancy.
Post-mortem examination revealed a
dysmorphic syndrome, with
malformations of the ears, heart, and
brain….This is the 1st case of human
isotretinoin teratogenicity to be described
in detail.
The isotretinoin teratogen
syndrome
Two infants with prominent frontal bossing,
hydrocephalus, microphthalmia, and small
malformed, low-set, undifferentiated ears were
born to mothers, who had taken isotretinoin in
the first trimester of pregnancy. A Dandy-Walker
malformation, microcephaly, hypertelorism, small
ear canals, cleft palate, small mouth, and
congenital heart disease were also observed.
Isotretinoin is a potent teratogen in many.
Maternal ingestion early in pregnancy, leads to a
distinct clinical pattern of anomalies.
JAMA 1984; 251:3267-69.
Coherence
Retinoic acid, an analogue of vitamin A, is known to be
teratogenic in laboratory animals and has recently been
implicated in a few clinical case reports. To study the
human teratogenicity of this agent, we investigated 154
human pregnancies with fetal exposure to isotretinoin, a
retinoid prescribed for severe recalcitrant cystic acne. The
outcomes were 95 elective abortions, 26 infants without
major malformations, 12 spontaneous abortions, and 21
malformed infants. A subset of 36 of the 154 pregnancies
was observed prospectively.
Specificity
The outcomes in this cohort were 8 spontaneous abortions, 23
normal infants, and 6 malformed infants. Exposure to
isotretinoin was associated with an unusually high relative
risk for a group of selected major malformation (relative
risk = 25.6; 95% CI 11.4-57.5).
Among the 21 malformed infants we found a characteristic
pattern of malformation involving craniofacial, cardiac,
thymic, and central nervous system structure.
Further criterion:
• Reversibility -rarely applicable
Relative risk for developing lung cancer by time
since stopping smoking and total duration of
smoking habit
Time since
stopping
smoking
(years)
Men
0
1-4
5-9
>10
Women
0
1-4
5-9
>10
Duration of smoking habits (years)
1-19
20-39
40-49
>50
1.0
1.1
0.4
0.3
2.2
2.1
1.5
1.0
2.8
2.3
2.2
1.6
3.0
3.8
2.8
2.7
1.0
1.0
0.4
0.4
2.1
2.3
2.0
0.8
2.7
2.1
1.1
2.3
5.2
7.1
1.7
Level
Source of Evidence
I
Evidence obtained from at least one properly
designed randomized controlled trial
II-1
Evidence obtained from well-designed
controlled trials without randomization
II-2
Evidence obtained from well-designed cohort
or case-control analytic studies, preferably
from more than one center or research group
II-3
Evidence obtained from multiple time series with or
without the intervention. Dramatic results in
uncontrolled experiments (such as the results of the
introduction of penicillin treatment in the 1940s)
could also be regarded as this type of evidence
III
Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees
Hierarchy of study methods to
assess causation
Hierarchy of study methods to
assess causation
Remember: Evidence based medicine means
making decisions on BEST EVIDENCE,
not IDEAL or PERFECT evidence