Confounding

Dr. Zabiullah Azizi MD

Infectious diseases department AFAMS
 Learning objectives

By end of this presentation , the reader will be able to:

 Define and provide examples of confounding.

 Describe the methods for assessing the presence of
confounding.
 Describe the methods for controlling confounding.
 What do we mean by confounding ?

• In a study of whether factor A is a cause of diseases B we say that a third

factor, factor X is a confounder if the following are true:

1- Factor X is a known risk factor for disease B.

2- Factor X is associated with factor A, but is not a result of factor A.

• An alternate explanation for observed association between an exposure

and disease.
• A mixing of effects. The association between exposure and disease is
distorted because it is mixed with the effect of another factor that is
associated with the disease.
 An example:
Who can run faster, men or women?
• Exposure = gender Outcome = speed
• Null Hypothesis: average speed of men = average speed of
women
• All men and women in one town invited to participate in a
road race. On race day, both men and women came and race.
• The average running time for the men is faster than the
women.
• CONCLUSION: Men run faster than women because of their
gender.
 But Wait!
• Someone notices that women with young children
did not race. In fact, women who ran the race
were, on average, older than men who ran.
• For example, the average age of women was 50
years while the average age of men was 25 years.
• CONCLUSION: Perhaps men were faster not
because of their gender, but because they were
younger.
 An example:
Who can run faster, men or women?
• So another race is held, this time making sure
ages in the two compared groups (men and
women) are comparable. That is, the men and
women have same distribution of ages.
• Race result: Once again, men are faster.
• CONCLUSION: Controlling for age, men are
still faster than women.
 BUT WAIT!
• Someone points out that the men are, on
average, taller than the women.
• CONCLUSION: Perhaps men were faster not
due to their gender, but because their legs are
longer.
• So another race is held, this time making sure
heights and ages in the two groups (men and
women) are comparable.
• Race result: Once again, men are faster.
 BUT WAIT!
• Someone points out that 50% of the women
had hair longer than their shoulders, and only
5% of the men did!

• CONCLUSION??? Long hair made the women

run slower. Is this a reasonable conclusion?
 Lessons from the road race:
Criteria for a characteristic to be a confounder
• In general, for a characteristic to be a potential
confounder, it must be associated with both
the disease (outcome) and the exposure
under study.
(Why are age and height competing explanations, but not hair length?)
 Confunding-1

The mixing of effects between an exposure , an

outcome, and a third extraneous variable known
as confounder.

Exposure Disease

Confounder
 Confounding - 2
• Key term in epidemiology
• Most important explanation for associations
• Always look for confounding factors

coffee Cancer of pancreas

Smoking
Downs’ syndrome by birth order

Cases of Down syndroms by birth order

Cases per 100 000
live births
180
160
140
120
100
80
60
40
20
0
1 2 3 4 5

Birth order
 Find confounders
“ third , fourth and fifth child are more often
affected by Downs’ syndrome.”

Many children Downs’

Maternal age
Downs’ syndrome by maternal age

Cases of Down Syndrom by age groups

1000
Cases per
900
100000 live 800
births 700
600
500
400
300
200
100
0
< 20 20-24 25-29 30-34 35-39 40+

Age groups
 Find confounders

”The Norwegian comedian Marve Fleksnes once

stated: I am probably allergic to leather because
every time I go to bed with my shoes on, I wake up
with a headache the next morning.”

Sleep with shoes Headache

Alcohol
 Find confounders
“A study has found that small hospitals have lower
rates of nosocomial infections than the large
university hospitals. The local politicians use this as
an argument for the higher quality of local
hospitals.”

Small hosp Few infections

Well patients
 A variable can be a confounder if all the following
conditions are met:

• It is associated with the exposure of interest

• It is causally related to the outcome.

• AND ... It is not part of the exposure 

outcome causal pathway
Modest Alcohol Consumption HDL Reduced risk of IHD

Example: Age and height are associated with speed regardless of

gender. Taller people (both men and women) have greater speed.
Younger people (both men and women) have greater speed.
 Decision Tree for Determining if a Variable is a
• 1
Confounder
Evaluate association between confounder and disease
(Overall and separately among exposed and
unexposed)

If association is present, If association is absent

confounding is possible no confounding

Evaluate association between

confounder and exposure

If association is present,
If association is absent no confounding
confounding is possible
 Ways to assess if confounding is present:

1. Does the variable meet the criteria to be a confounder

(relation with exposure and outcome)?

2. If the effect of that variable (on exposure and outcome) is

controlled for (e.g., by stratification or adjustment) does the
association change?
 Strategy #1: Does the variable meet
the criteria to be a confounder?

Hypothetical case-control study of risk factors for Malaria.

150 cases, 150 controls; gender distribution.
Cases Controls
Males 88 68
OR= [88 x 82] ÷ [68 x 62] =
Females 62 82
1.71
150 150
Question:
Is male gender causally related to the risk of malaria?

Yes
No
 Further study is needed
Confounder for a male gender-Malaria association?

Male
gender

?
?

Malaria
Confounder for a male gender-malaria association?

Male
gender

Outdoor ?
occupation

Malaria
 First criterion:
Is the putative confounder associated with exposure?

Male
gender
?

Outdoor ?
occupation

Malaria
 First criterion:
Is the putative confounder associated with exposure?

Males Females
N (%) N (%)
OR=7.8
Outdoor 68 (43.5) 13 (9.0)
Indoor 88 131
156 (100) 144 (100)

Question:
Is outdoor occupation associated with male gender?

 Yes
No
 Second criterion:
Is the putative confounder associated with the outcome
(case-control status)?

Male
gender

Outdoor ?
occupation

?
Malaria
 Second criterion:
Is the putative confounder associated with case-
control status?
. Malaria
Cases Controls
N (%) N (%)
Outdoor 63 (42.0) 18 (12.0) OR=5.3
Indoor 87 132
150 (100) 150 (100)
Question:
Is outdoor occupation (or something for which this
variable is a marker of --e.g., exposure to mosquitoes)
causally related to malaria?

 Yes
No
 Third criterion:
Is the putative confounder in the causal pathway
exposure  outcome?
. Male
gender
?

Outdoor Yes, it could be

?
occupation  Probably not

Malaria

Note: Judgment and knowledge about the socio-

cultural context are critical to answer this question
Question:
Provided that:
• Crude association between male gender and malaria: OR=1.71
and
• ... Outdoor occupation is more frequent among males, and
• ... Outdoor occupation is associated with greater risk of malaria …

What would be the expected magnitude of the association between

male gender and malaria after controlling for occupation (i.e.,
assuming the same degree of outdoor occupation in males and
females)?

 The (adjusted) association estimate will be smaller than 1.71

The (adjusted) association estimate will =1.71
The (adjusted) association estimate will greater than 1.71
 Strategy #2: Does controlling for the putative
confounder change the magnitude of the exposure-
outcome association?
Malaria
Cases Controls
Males 88 68
Females 62 82 OR=1.71
150 150

Outdoor Indoor
occupation occupation

Ca
se
sCo
nt
rol
s Ca
se
sCo
nt
rol
s
Ma
les 5
3 15 Ma
les 3
5 53
F
em
ales 1
0 3 F
em
ales 5
2 79
6
3 18 8
7 1
32

OR=1.06 OR=1.00
 Ways to control for confounding

• During the design phase of the study:

– Randomization
– Restriction
– Matching

• During the analysis phase of the study:

– Stratification
– Adjustment
 Randomization

• Randomization achieve baseline comparability of the

patients
• Randomization will control for variables that study
investigators are unable to measure
• There are numerous advantages and no disadvantages
• It can be used only in experimental study
 Restriction
• Restriction of the study to a subgroup that is homogenous for
the possible confounder( Means admisibility criteria for study
subjects are limited).
• E.g. Confounding by age can be reduced by restricting a study to
individuals within a narrow age range , say from 25 to 35,
• Limiting the study population to one gender or only one race
• Always possible, but reduces the size of the study.
 Advantages and Disadvantages of Restriction

Advantages Drawback

• Simplicity • It make it difficult to

• Convenience find enough study
• Low expense subjects
• Effectiveness • It limits generazability
of the study
 Restriction
We study only mothers of a certain age

Many children Downs’

35 year old
mothers
 Matching
“The process of making a study group and a
comparison group comparable with respect to
extraneous factors.”

Exercise Colone Cancer

Age, sex and

Obesity
 Types of matching
 Simple matching (individual)
Frequency matching (group)
 Disadvantages of matching
• It is difficult and expensive to find subjects who
are appropriate matches.
• It is possible to” over match” on a confounder
in a case-control study
• Cannot study whether matched factor has a
causal effect
• More difficult to find controls
– Therefore: Special ”matched” analysis needed
– More complicated analysis
 Stratified analysis
• Calculate crude odds ratio with whole data set
• Divide data set in strata for the potential confounding
variable and analyse these separately
• Calculate adjusted (OR adj) odds ratio
• If adjusted OR differs (> 10-20%) from crude OR, then
confounding is present and adjusted OR should be
reported
 Procedure for analysis

• When two (or more) exposures seem to be associated

with disease
1. Choose one exposure which will be of interest
2. Stratify by the other variable
– Meaning. Making one two by two table for those with and one
for those without the other variable (for example, one table
for men and one for women)
• Repeat the procedure, but change the variables
 Example

Crude Data from a Hypothetical Case-Control Study of DDE

Exposure and Breast Cancer
DDE Level Cases Controls
High 500 600
Low 1500 3400
Total 2000 4000

Odds ratio= 1.9

 Confounding
Is age a confounder for the DDE  Breast cancer
association?
Stratify: Make one 2x2 table for age less than 50
and one for age 50 or older

DDE Breast Cancer

Age
 Example
Age-stratified DATA form a Hypothetical Case-Control Study of DDE Exposure
and Breast Cancer
Age less than 50 years Age 50 years and older
DDE Level Cases Control DDE Level Cases Contro
l
High 50 300 High 450 300
Low 450 2700 Low 1050 700
Total 500 3000 Total 1500 1000
Stratum-specific Odds ratio =1.0 Stratum-specific Odds ration +
1.0

Each stratum specific odds ratio is 1.0. Thus, the magnitude of the odds ratio(1.0) are
different form the crude odds ratio( 1.9)
The difference between the crude and stratum-specific odds ratio indicates that
confounding by age is present..
 Multivariable regression
• Analyse the data in a statistical model that includes both
the presumed cause and possible confounders
• Measure the odds ratio OR for each of the exposures,
independent from the others
• Logistic regression is the most common model in
epidemiology
• But explore the data first with stratification!
Summary

Questions ?