EPID 600; Class 10

Effect measure modification

University of Michigan School of Public Health

1
 Effect measure modification

Situation where measure of effect changes over the value

of some other variable
Stated another way, where the effect of interest (as typically
expressed by a measure of association) is heterogenous
over a third variable

2
 Graphically

Exposure Disease

Third factor

Note that like confounding, effect measure modification is about a

“third variable” involved in the basic relation between a single
“exposure” and a single disease

3
 Why effect “measure” modification?

The notion of effect modification is meaningless unless we

specify what is being modified
Therefore, the exact effect measure (e.g., RR, RD) between
exposure E and outcome D that is being modified by “effect
measure modifier” F needs to be specified in order for us to
meaningfully understand effect measure modification
This is particularly of interest when we compare absolute (i.e.,
difference measures, RD, IRD) and relative (i.e., RR, IRR)
measures
Remember...absolute measures are on an additive scale
while relative measures are on a multiplicative scale

4
 Example

A cohort study is conducted that collects information on smoking,

exposure to ceramic dust, and subsequent lung cancer. The table
below gives the risk of developing lung cancer (over 1 year and
expressed per 100,000 persons) derived from the study

No exposure to Exposure to
ceramic dust ceramic dust
Smokers 10 50

Non-smokers 5 5

5
 Example

A cohort study is conducted that collects information on smoking,

exposure to ceramic dust, and subsequent lung cancer. The table
below gives the risk of developing lung cancer (over 1 year and
expressed per 100,000 persons) derived from the study

No exposure to Exposure to
ceramic dust ceramic dust
Smokers 10 50

Non-smokers 5 5

among those not exposed to ceramic dust, RR of lung

cancer among smokers vs. non-smokers is 10/5, i.e., 2
6
 Example

A cohort study is conducted that collects information on smoking,

exposure to ceramic dust, and subsequent lung cancer. The table
below gives the risk of developing lung cancer (over 1 year and
expressed per 100,000 persons) derived from the study

No exposure to Exposure to
ceramic dust ceramic dust
Smokers 10 50

Non-smokers 5 5

among those exposed to ceramic dust, RR of lung cancer

among smokers vs. non-smokers is 50/5, i.e., 10
7
 Therefore...

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)?

RD among those unexposed to ceramic dust = 10-5=5/100,000

RD among those exposed to ceramic dust=50-5=45/100,000

So here we have modification on both scales (absolute and relative)

8
 An alternate example

A cohort study is conducted that collects information on drinking,

exposure to ceramic dust, and subsequent liver cancer. The table
below gives the risk of developing liver cancer (over 1 year and
expressed per 100,000 persons) derived from the study

Exposure to No exposure to
ceramic dust ceramic dust
Drinkers 10 50

Non-drinkers 1 5

9
 Example

A cohort study is conducted that collects information on drinking,

exposure to ceramic dust, and subsequent liver cancer. The table
below gives the risk of developing liver cancer (over 1 year and
expressed per 100,000 persons) derived from the study

No exposure to Exposure to
ceramic dust ceramic dust
Drinkers 10 50

Non-drinkers 1 5

among those not exposed to ceramic dust, RR of liver

cancer among drinkers vs. non-drinkers is 10/1, i.e., 10
10
 Example

A cohort study is conducted that collects information on drinking,

exposure to ceramic dust, and subsequent liver cancer. The table
below gives the risk of developing liver cancer (over 1 year and
expressed per 100,000 persons) derived from the study

No exposure to Exposure to
ceramic dust ceramic dust
Drinkers 10 50

Non-drinkers 1 5

among those exposed to ceramic dust, RR of liver cancer

among drinkers vs. non-drinkers is 50/5, i.e., 10
11
 Therefore...

Now, there is no modification of the risk ratio describing the

association between drinking and liver cancer by exposure
to ceramic dust
However, there clearly remains effect modification of the
absolute scale, since RD between risk of liver cancer
among drinkers vs. non-drinkers, among those not exposed
to ceramic dust is 10-1=9/100,000 and among those
exposed to ceramic dust is 50-5=45/100,000

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 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”?

Interaction is a statistical term that refers to deviation from

underlying model form
In epidemiology the term “interaction” has been used
congruently with “effect measure modification”
This is incorrect...let’s not do that 13
 From a causal heuristic perspective

A B A U B U U U

Disease

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 Conceptually, statistical interaction (1)

Statistical interaction then refers to deviation from the way we are

specifying our relation between variables of interest

A. Positive statistical interaction refers to the situation where the

association between two variables is greater than might be expected
given the way a model is specified
Note, put another way, the third variable accentuates the relation
between exposure and outcome

B. Negative statistical interaction refers to a situation where the

association between two variables is less than might be expected

Note, put another way, the third variable diminishes the relation
between exposure and outcome

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 Conceptually, statistical interaction (2)

Given that statistical interaction depends on how we are specifying the

“model” that describes the relation between variables of interest, then
statistical interaction can come in two forms, both dependent on
comparing expected vs. observed joint effects of our variables acting
independently or together

A. Additive interaction is when the joint effect of exposure and third

variable is not equivalent to the arithmetic sum of the independent
effects (component effects) measured by the RD or IRD

B. Multiplicative interaction is when the joint effect of exposure and

third variable is not equivalent to the multiplication of the independent
effects (component effects) measured by the RR or IRR
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 Mathematically, statistical interaction,
multiplicative
Remember that to determinate statistical interaction we want to
compare observed vs. expected joint effects

Therefore, three steps

1. Calculate measure of disease occurrence (R, IR) for combination of

presence and absence of exposure (A) and third variable (B)

2. Calculate a relative measure of association (RR, IRR) between each

combination (AB) with reference category being absence of both (U)

3. Expected RRAB = Observed RRA * Observed RRB

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 Example, multiplicative statistical
interaction
RR (A-) RR (A+) Joint expected RR=6.0

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
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Aside…what my data looks like
A B Disease

+ + +

+ - -

- + +

- - +

- - -

+ + -

+ - -

- + +

- - +

- - +

+ + -

+ - -

- + -

- - +

- - +

+ + -

++ - -

- + +

- - +

- - -

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Aside…what my data looks like
A B Disease

+ + +

+ - -

- + +

- - +

- - -

+ + -

+ - -

+ + +

- - +

- - +

+ + -

+ - -

- + -

- + +

- - +

+ + -

+ - -

- + +

- - +

- - -

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 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

Therefore, three steps

1. Calculate measure of disease occurrence (R, IR) for combination of

presence and absence of exposure (A) and third variable (B)

2. Calculate an absolute measure of association (RD, IRD) between

each combination (AB) with reference category being absence of both
(U)

3. Expected RDAB = Observed RDA + Observed RDB

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 Example, additive statistical interaction

RD (A-) RD (A+) Joint expected RD=30

RD(A+B-)+RD(A-B+)=20+10=30
RD (B-) 0 20
Therefore, no interaction assuming
RD (B+) 10 30 an additive risk model

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

For multiplicative interaction

RRAB > RRA * RRB there is greater than multiplicative effect
RRAB < RRA * RRB there is less than multiplicative effect
For additive interaction
RDAB > RDA + RDB there is greater than additive effect
RDAB < RDA + RDB there is less than additive effect
All the above can also be calculated for IRRs

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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

Smoking 32 168 200

Non-Smoking 15 185 200

Total 47 353 400

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

Among alcohol drinkers

MI No MI Total RR=1.4
Smoking 14 126 140 RD=4

Non-Smoking 10 130 140

Total 24 256 280

Among non-alcohol drinkers

MI No MI Total RR=3.6
Smoking 18 42 60 RD=13

Non-Smoking 5 55 60

Total 23 97 120 27
 Example, step 3

Among alcohol drinkers

MI No MI Total RR=1.4
Smoking 14 126 140 RD=4

Non-Smoking 10 130 140

interaction on
Total 24 256 280 both additive
and
multiplicative
scales
Among non-alcohol drinkers
MI No MI Total RR=3.6
Smoking 18 42 60 RD=13

Non-Smoking 5 55 60

Total 23 97 120 28
 A final note...there is almost always
statistical interaction

Rothman KJ. Epidemiology: An Introduction. Oxford, 2002. 29

 Stroke: geography or race?

8 southern US states are consistently found to have higher

stroke mortality, and termed the “stroke belt”
Stroke mortality rates are about 50% higher in blacks as
compared to whites
Is it black race or southern geography that explain stroke
patterns in the US? Or do these two trends both interact in
some way?

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

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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?

Among men aged 65-74, the effect of living in the south

on stroke mortality is heterogeneous over 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

South ratio : North 1.21 [Black : White 21%

ratio South] : [Black :
White North]

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?

We have now summarized the notion of statistical

interaction which shows clearly that statistical interaction
depends primarily on choice of specification of effect
measure
However, earlier we introduced the notion of biologic
interaction
Biologic interaction between component causes A and B
means that the effect of A on an individual depends on the
presence/absence (or level of) B
There might then be merit to understand the implications of
biologic interaction, and how they are (or are not) different
than those of statistical interaction
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 Understanding biologic interaction

Assume we are interested in two variables A and B

Assume that a particular disease can be caused by variables A and B
and a set of other unspecified variables U
Therefore, there are 4 ways in which the disease can be produced,
that is ABU, AU, BU, and U
This has clear analogs in sufficient cause model
If we buy above argument that disease production is a function of four
causes (ABU, AU, BU, and U) then surely disease production is all
explained by the addition of these 4 causes
Hence, departure from additivity on the risk scale for two exposures is
an indication of biologic interaction in the population

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 Defining biologic interaction

Interaction risk = R AB -(R A -R U )-(R B -R U )-R U

for no interaction, interaction risk=0
therefore
0=R AB -(R A -R U )-(R B -R U )-R U
0=R AB -R A +R U -R B +R U -R U
0=R AB -R A -R B +R U
or
R AB =R A +R B -R U
and
(R AB -R U )=(R A -R U )+(R B -R U )
or
RD AB =RD A +RD B
therefore, when there is no interaction, risk differences are additive 36
 Continuing

if we divide both sides by R U

R AB -R U R A -R U R B -R U
= +
RU RU RU
or
R AB R U R A R U R B R U
- = - + -
RU RU RU RU RU RU
or
(RR AB -1)=(RR A -1)+(RR B -1)

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 Quantifying biologic interaction

A cohort study is conducted that collects information on coffee

drinking (A), smoking (B), and subsequent brain cancer. The table
below gives the risk of developing brain cancer (over 1 year and
expressed per 100,000 persons) derived from the study

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?

Since RU = 1, RA = 5, RB = 10, RAB = 50

and RA + RB − RU = 10 + 5 − 1 = 14
therefore, out of all the 50 cases that make up RAB
14, or 14 / 50, or 28%, are not due to interaction
so, the majority of cases ( 72%) here are due to biologic
interaction
Caveat: This is very much a simplification. Even assuming no bias, from
a causal perspective it is a simplification to attribute all the observed
mathematical interaction to biologic interaction

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 Assess measure of association within strata

Are stratum specific measures same?

Yes No

Crude measure=stratum specific? Statistical interaction; report

stratum specific measures

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