3 Causal Models

Part I: Sufficient Causes

Matthew Fox
Advanced Epidemiology

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 Review of This Morning
 “Modern” epidemiology
 Goal of etiologic research
– Valid and precise estimate of the effect of exposure
on disease
 Why not everything is as we were taught
– Statistics
 Review of study designs, measure of effect
– Odds ratios and case-control sampling
– Hopefully changed a few minds (and set the tone)

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 This Session
 Why are we in this business?
– What is the goal of epi investigations?
 Things may have missed in intro epi
– How causal models and causal inference
helps clarify what we do and how we do it
 Sufficient Causes Model
– Rothman’s Model (Sufficient Cases Model)

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 I turn on a light switch and the light
doesn’t go on. The globe (bulb?) is
burned out.

What prevented the

light from going on?

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 I turn on a light switch and the
light does go on.

What caused the light

to go on?

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 Is there any disease for which
all cases are attributable to one
and only one cause?

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 Smoking causes lung cancer.
So why doesn’t every smoker get lung
cancer?
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 Is the occurrence of disease
deterministic or random within
what we know?

Is a coin flip random?

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 What is a “strong” risk factor?
What determines strength?

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 Why study causal models?
 Helps understand why we do what we do
– What do we mean when we say that smoking
causes lung cancer?
 Gives meaning to our measures of effect
– Theoretical and practical
 Helps clarify important epidemiologic
concepts

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 A definition of a cause
 An antecedent event, characteristic, or
condition that was necessary for the
occurrence of disease at the time it
occurred all other things being fixed
– Antecedent
– Necessary
– At the time it occurred
– Other things fixed

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 The Sufficient Cause Model

U Ken Rothman
C

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 History

 Goes back to John Leslie Mackie (1964)

 Necessary causes:
– If x is a necessary cause of y, then y necessarily implies x
– x does not imply y will occur
 Sufficient causes:
– If x is a sufficient cause of y, then x necessarily implies y
– Since other things can cause y, y does not imply x
 Typical use of cause refers to:
– Insufficient and non-redundant parts of unnecessary but
sufficient causes (INUS)
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 The Sufficient Cause Model

 Lots of ways to get a disease

– Think of each way as a pie
– Called a sufficient cause
 Mechanisms exist independent of us A

– But we’re susceptible to them if we

acquire the components B

 Go through life picking up U

exposures and filling in pies C

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 The Sufficient Cause Model

 Person is susceptible to multiple diseases

– Diseases have multiple sufficient causes
– Each sufficient cause has
multiple component causes
– Each component cause
has attributes
– Shared components
between sufficient causes
– It is theoretically possible every
case of outcome has a unique pie
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 Take home message 1:
All disease causation is multifactoral
and mechanisms are complex

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 Sufficient Causes
 Minimally sufficient
– Each sufficient cause has a unique set of components and
none is extraneous
 Necessary cause
– Component cause appearing in all sufficient causes for a
disease
– Poole proposes “universally necessary”
 Complementary component causes
– Set of component causes required to complete a sufficient
cause, aside from one (exposure)

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 How much do we know?

 U is often largest piece of a sufficient cause

– We understand poorly disease causation
 But if we could specify the mechanisms
perfectly, could we predict all disease?
– Deterministic
– Might be infinite combinations
 In risk factor epidemiology, we focus on
one component and ignore the complement

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 So what might HIV infection look
like?
 One SCM (pie) might be:
– Exposed to HIV through sex
– Unvaccinated (OK for now), no natural immunity
– No condom use
– Why doesn’t everyone exposed through sex get HIV? U
 Circumcision? STDs? Genetic factors? No use of microbicide?
 Is each component necessary?
– If so, take away one and you prevent disease
– Must be more causes than just the HIV virus
 Other SCMs exist
– Mother to child, transfusion, needle stick, etc.

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 The Sufficient Cause Model

 Components can be positive or negative

– Lack of vaccination
 Component causes should be specific A

– Can be identical except for timing

 Don’t need to understand B

entire pie to prevent U

– Removing one piece C

renders the pie incomplete

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 Disease and Causation

 The sufficient cause acts when all of the

component causes have been gathered
 Disease occurs at completion of temporally
last component cause
– Model is deterministic
 Each disease occurrence has a latency
– Time between its occurrence and its detection

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 Component Causes (Exposures)
 Component causes (i.e. exposures we
might want to study) have attributes
– Dose
– Duration
– Induction period (NOT LATENCY)
 Specifying the attributes
improves the resolving
power of the study

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 Does smoking cause lung
cancer?
 Smoking is too imprecise
– How much for how long? What type?
– Starting at what age?
 Infinite combinations
– Each might have a different risk
 Ignoring the attributes means we are lump all
exposures (from 1 lifetime cigarette to a 10
packs a day) together as exposed
– This biases towards no effect!

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 Dose attributes

 Time weighted average dose

– Grams of fat per day
 Maximum dose
– Highest adult body weight
 Body weight or surface area scaled
– Grams of alcohol per kilogram body weight
 Cumulative dose
– Pack years of cigarettes

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 Duration attributes
 Total time of exposure
– years employed
 Biologically relevant time of exposure
– Smoking before first pregnancy
 Time of exposure beyond a minimum
– Years of driving after age 25
 Time of exposure after gathering another
component cause
– HIV infection after HPV infection
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 Take home message 2:
To study effects of exposures, the
exposures must be precisely defined

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 Induction period attributes

 Induction period is the time between

completion of a COMPONENT cause (i.e. the
exposure of interest) and completion of the
SUFFICIENT cause (i.e. disease occurrence)
– Induction period doesn’t characterize disease
– Characterizes component cause-disease pair
– Every disease has a component cause with zero
induction time
– Failure to exclude induction time from person time biases
towards the null
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 Take home message 3:
Diseases don’t have induction times

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 Induction Time Example
 Diethylstilbestrol, adenocarcinoma of the vagina
– A synthetic non-steroidal estrogen, given to pregnant women to prevent
miscarriage (’40s-’70s)
– Exposure is known to have occurred during gestation
– Cancer occurs in the offspring between 15-30 years of age
 Other processes assumed to occur in the interim
– Other components in the causal pie still occur
– Adolescent hormonal activity may be one
 If outcome can’t occur before 10 years, don’t include 1st
10 years of person-time
– Similar to immortal person-time

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 What about promoters or
catalysts?
 Catalyst of diseases
– Anything that speeds up (or slows down) the
occurrence of a disease that would occur anyway
 Are they causes of disease?
– Remember the “at the time it occurred” part of the
definition of a cause
– Does it matter to you?

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 Applications of the sufficient cause
model

 The effect of the index condition, relative

to the reference condition:
– The number of completed sufficient causes among
those with index condition
– Minus number of completed sufficient causes
among those with reference condition
 Interaction between component causes
– Arises when one or more sufficient causes
contains both component causes
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 Take home message 4:
Interaction is ubiquitous

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 Strength is Determined by
Complements

 Strength of a risk factor

– Typically measured on the relative scale
 Is determined by the relative
prevalence in the population of the
causal complements
– Also affected by the competing risks of other
sufficient causes for the same disease

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 Imagine a gene-environment
interaction

G
U U
E
Phenylketonuria (PKU) - a genetic disorder characterized by a deficiency
in the enzyme to metabolize the amino acid phenylalanine. Untreated, it can
cause problems with brain development. However, PKU is a rare genetic
diseases that can be controlled by diet, one low in phenylalanine.
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 Imagine a gene-environment
interaction

 Imagine a population where:

– 10% get disease through U no matter what
– 60% of the population has U and G completed
– If we randomly assigned the exposure (diet), would
the relative risk be high or low?

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 Imagine a gene-environment
interaction

Randomized to get E Randomized to not get E

U U

Exposed
70% get disease Unexposed
G G (10% U + G G 10% get disease
U E U E U U (10% U)
60% U/G/E)
G G G G
U E U E U U
G G G G
U E U E U U

RR = 70%/10% = 7
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 Imagine a gene-environment
interaction

 Imagine a population where:

– 10% get disease through U no matter what
 Same as 1st example
– 10% of the population has U and G completed
– If we randomly assigned the exposure, would the
relative risk be high or low?

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 Imagine a gene-environment
interaction

Randomized to get E Randomized to not get E

U U

Exposed
20% get disease Unexposed
(10% U + 10% get disease
10% U/G/E) (10% U)

G G
U E U

RR = 20%/10% = 2.0
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 Imagine a gene-environment
interaction

 Imagine a population where:

– 40% get disease through U no matter what
– 10% of the population has U and G completed
 Same as last
– If we randomly assigned the exposure, would the
relative risk be high or low?

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 Imagine a gene-environment
interaction

Randomized to get E Randomized to not get E

U U U U

Exposed
U U
50% get disease
U U Unexposed
(10% U + 40% get disease
40% U/G/E) (40% U)

G G
U E U

RR = 50%/40% = 1.25
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 Another example
 Vaccines are usually extremely protective
– What we often call a strong protective effect
 But what if we tested our vaccine in a population
where everyone had natural immunity?
– Lack of natural immunity is a piece in the pie (causal
complement)
– When it is common, the effect appears strong
– When it is rare, the effect appears weak

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 Take home message 5:

“Strength” of an exposure’s effect is a

function of:

1) prevalence of causal complements

(what we usually ignore)

and

2) the % of all disease that goes through

mechanisms without the exposure
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(U for short)
 Illustrates arbitrariness of effects:
Effect of folic acid on: Spina bifida

0.85
0.9
0.8 Assume same sample
% with spina bifida

0.7 0.65
0.55 size (N=100)
0.6
0.5 Folic Acid
0.35
0.4
0.25 No FA
0.3
0.2
0.05
0.1
RD = 0.2
0
RR=0.2 RR=0.63 RR=0.75

A B C
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 Illustrates arbitrariness of effects:
Effect of FA on: Neural tube closure

0.95
1
% with neural tube closure

0.9
0.75
0.8
0.65
0.7
0.6
0.45
0.5 Folic Acid
0.35
0.4 No FA
0.3
0.15
0.2
0.1
RD = 0.2
0
RR=1.3 RR=1.4 RR=2.3

Same A B C
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 Take home message 6:

We are often best studying rare

occurrences when possible

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 Proportion of disease caused by…

 What % of all cases are caused by genes?

 What % of are caused by environment
(dietary phenalynine)?
G
U
E

Phenketunuria - 100% of all cases

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 Take home message 7:
The % of all cases of a disease
attributable to different causes can
(and will) sum to > 100%

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 Advantages of the SCM
 Applies to disease mechanisms in
individuals
– Tells us about how disease occurs, not just what
caused it
 Illustrates:
– How component causes act together
– Attributes of component causes
– How strength is function of complements
– The ubiquity of interaction
– Process of causation, although not complete
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 Disadvantages of the SCM
 Cannot easily apply to populations
– Though our examples show can be used this way
 Deterministic in nature
– Assumes no randomness to disease causation
– Doesn’t easily deal with continuous variables
 Obscures importance of reference group
definition
– Comparison is between those with component cause
and those without the component cause under study

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 Disadvantages of the SCM
 Difficult to assess validity of measures of
association
– No easy definition of bias
 No distinction between mutable, immutable
variables
– Can sex can be a component cause?
 Does not include temporal sequence
– Could be revised to do so
 Mechanisms cannot be fully articulated

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