1
Effect measure modification
2
Graphically
Exposure Disease
Third factor
3
Why effect “measure” modification?
4
Example
No exposure to Exposure to
ceramic dust ceramic dust
Smokers 10 50
Non-smokers 5 5
5
Example
No exposure to Exposure to
ceramic dust ceramic dust
Smokers 10 50
Non-smokers 5 5
No exposure to Exposure to
ceramic dust ceramic dust
Smokers 10 50
Non-smokers 5 5
The risk ratio (i.e., the relative measure) describing the difference in
risk of lung cancer between smokers and non-smokers is
heterogenous in groups of those exposed to vs. not exposed to
ceramic dust
Therefore, there is effect modification of the risk ratio measure by
exposure to ceramic dust
But what about the absolute measure (i.e. risk difference)?
Exposure to No exposure to
ceramic dust ceramic dust
Drinkers 10 50
Non-drinkers 1 5
9
Example
No exposure to Exposure to
ceramic dust ceramic dust
Drinkers 10 50
Non-drinkers 1 5
No exposure to Exposure to
ceramic dust ceramic dust
Drinkers 10 50
Non-drinkers 1 5
12
So, what’s going on?
The difference in effect modification between scales is
typically referred to as a reflection of a statistical
interaction, which is to be differentiated from biological
interaction
Pause...what is “interaction”?
A B A U B U U U
Disease
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Conceptually, statistical interaction (1)
Note, put another way, the third variable diminishes the relation
between exposure and outcome
15
Conceptually, statistical interaction (2)
RR (B-) 1 3
RR(A+B-)*RR(A-B+)=2*3=6
RR (B+) 2 6
Therefore, there is no interaction
assuming a multiplicative risk
model
RR (A-) RR (A+)
Joint expected RR=6.0
RR (B-) 1 3 RR(A+B-)*RR(A-B+)=2*3=6<9
RR (B+) 2 9 Therefore, there is positive
interaction assuming a
multiplicative risk model
18
Aside…what my data looks like
A B Disease
+ + +
+ - -
- + +
- - +
- - -
+ + -
+ - -
- + +
- - +
- - +
+ + -
+ - -
- + -
- - +
- - +
+ + -
++ - -
- + +
- - +
- - -
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Aside…what my data looks like
A B Disease
+ + +
+ - -
- + +
- - +
- - -
+ + -
+ - -
+ + +
- - +
- - +
+ + -
+ - -
- + -
- + +
- - +
+ + -
+ - -
- + +
- - +
- - -
20
Aside…what my data looks like
A B Disease
+ + +
+ - -
- + +
AB (blue) - - +
- - -
+ + -
+ - -
+ + +
- - +
UU (red) - - +
+ + -
+ - -
- + -
- + +
- - +
+ + -
+ - -
- + +
- - +
- - -
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Mathematically, statistical interaction,
additive
Remember that to determinate statistical interaction we want to
compare observed vs. expected joint effects
RD (A-) RD (A+)
Joint expected RD=30
RD(A+B-)+RD(A-B+)=20+10=30<50
RD (B-) 0 20
Therefore, there is positive
RD (B+) 10 50 interaction assuming an additive risk
model
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Summary
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Another way to consider homogeneity of
effects
1. Calculate the appropriate measure of effect between
exposure and outcome
2. Calculate the appropriate measure of effect within strata
of the third variable
3. Compare the measures of effects within strata of the
third variable
4. If there are differences in the measures of effect within
strata, there is effect modification
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Example, step 1
MI No MI Total
32
200 0.16
RR = = = 2.13
15 0.075
200
32 15
RD = − = 17 cases per 200 exp osed
200 200
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Example, step 2
Non-Smoking 5 55 60
Total 23 97 120 27
Example, step 3
Non-Smoking 5 55 60
Total 23 97 120 28
A final note...there is almost always
statistical interaction
30
Howard et al. Regional differences in African American’s high risk for stroke: the remarkable burden of stroke for southern African Americans. Ann Epidemiol.
2007; 17: 689-696.
Stroke: geography or race?
Set up:
Stroke mortality rates were calculated for sex and age
strata on the basis of US vital statistics 1997-2001
Investigators looked at the patterns in southern vs non-
southern states
They compared the ratio of white and black mortality rates
They compared the “excess” mortality in the south vs. non-
south for each race
They compared the difference in the excess between the
two races
31
Howard et al. Regional differences in African American’s high risk for stroke: the remarkable burden of stroke for southern African Americans. Ann Epidemiol.
2007; 17: 689-696.
Stroke: geography or race?
32
Howard et al. Regional differences in African American’s high risk for stroke: the remarkable burden of stroke for southern African Americans. Ann Epidemiol.
2007; 17: 689-696.
Stroke: geography or race?
Mortality Mortality
ratio Excess
Black : White in the 1.81 South :. North among 14%
North Whites
Black : White in the 2.19 South : North among 36%
South Blacks
33
Howard et al. Regional differences in African American’s high risk for stroke: the remarkable burden of stroke for southern African Americans. Ann Epidemiol.
2007; 17: 689-696.
What about biologic interaction?
35
Defining biologic interaction
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Quantifying biologic interaction
Non-smokers Smokers
No coffee drinking 1 5
Coffee drinking 10 50
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Is there biologic interaction?
RU = 1, RA = 5, RB = 10, RAB = 50
then, RDA = 5 − 1 = 4
and RDB = 10 − 1 = 9
and RDAB = 50 − 1 = 49
and 49 > 9 + 4, i.e., RDAB > RDA + RDB
and, RRA = 5 / 1 = 5
and, RRB = 10 / 1 = 10
and, RRB = 50 / 1 = 50
and 50 − 1 > (10 − 1) + (5 − 1) = 13, i.e., RRAB − 1 > (RRA − 1) + (RRB − 1)
So, biologic interaction is present and can be calculated
using both RD and RR
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Can we quantify biologic interaction?
40
Assess measure of association within strata
Yes No
Caveat: this is a
Yes No
simplification; stratum-
specific estimates of effect
are almost never the same
Presumably no confounding Confounding and even if there is
or interaction report measure
adjusted for heterogeneity, sometimes it
Report crude measure
confounding is still appropriate to
combine strata 41