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
Triangle האפידמיולוגי המשולש
Host המאכסן
Agent המחלה הסביבה Environment מחולל
Web of causation
Association and cause
Explanation Finding
Association
Bias in selection Yes No
or measurement
Chance Likely Unlikely
Confounding Yes No
Cause 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 toasbestos
History ofcigarettesmoking
Lung cancerdeath rate per
100000
No
Yes
No
Yes
No
No
Yes
Yes
11
58
123
602
0
2
4
6
8
Black Brown Blonde/red
Psoriatics
Controls
Prevalence of Actinic Keratoses in Psoriatics and Controls by Hair Colour
Effect modification
Odds
ratio
Prevalence of Actinic Keratoses in Psoriatics and Controls by propensity
to sunburn
Effect modification
0
1
2
3
4
5
Never Often/always
Psoriatics
ControlsOdds ratio
Association and cause
Explanation FindingAssociation
Bias in selection Yes Noor measurement
Chance Likely Unlikely
Confounding Yes No
Cause 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 field2. In specifying and selecting the study
sample3. In executing the experimental
maneuvre (or exposure)4. In measuring exposures and outcomes5. In analyzing the data6. 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
Non-randomized
Randomized
60/231902
(26)
57/200745
(28)
391/725173
(54)
142/201229
(71)
0.55 (0.44-0.68)
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
Non-randomized
Randomized
60/231902
(26)
57/200745
(28)
391/725173
(54)
142/201229
(71)
0.55 (0.44-0.68)
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
Intervention- letter, 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 Yes No
or measurement
Chance Likely Unlikely
Confounding Yes No
Cause Cause
P value
Association and cause
Explanation Finding
Association
Bias in selection Yes No
or measurement
Chance Likely Unlikely
Confounding Yes No
Cause Cause
Confounding
Confounding: coffee drinking, cigarette smoking, and coronary heart disease
EXPOSURE DISEASE
(coffee drinking) (heart disease)
CONFOUNDING
VARIABLE
(cigarette smoking)
Locations of potential bias in cohort Locations of potential bias in cohort studiesstudies
021657408021657408
021657408021657408
Association and cause
Explanation Finding
Association
Bias in selection Yes No
or measurement
Chance Likely Unlikely
Confounding Yes No
Cause? 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 syndromeLancet, 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.
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.
Coherence
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.
Specificity
Further criterion:
• Reversibility -rarely applicable
Time sincestoppingsmoking(years)
Duration of smoking habits (years)
1-19 20-39 40-49 >50
Men01-45-9>10Women01-45-9>10
1.01.10.40.3
1.01.00.40.4
2.22.11.51.0
2.12.32.00.8
2.82.32.21.6
2.72.11.12.3
3.03.82.82.7
5.27.11.7
Relative risk for developing lung cancer by time since stopping smoking and total duration of
smoking habit
Level Source of EvidenceI 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