Preparatory lecture

Confounding and Bias

Introduction
Most epidemiological studies measure
disease frequency in two (or more) groups
that differ only on the exposure of interest.
The two measures of disease frequency
are combined into a single measure of
association risk or rate ratio, odds ratio,
risk or rate difference

2 Random Error

Introduction
The next step is to evaluate whether the
result that has been observed in the
data is true, or whether the observed
result is false and there is an alternate
explanation. This is the process of
assessing validity of a study result.

3 Random Error

Accuracy vs. precision

Accuracy: obtaining results close to truth
Survey 1

Survey 2

Survey 3

Real
population
value

Accuracy vs. precision

Precision: obtaining similar results with repeated
measurement (may or may not be accurate)

Accuracy vs. precision

Poor precision (from small sample size) with
:reasonable accuracy (without bias)

Accuracy vs. precision

Good precision (from small sample size) with
:reasonable accuracy (without bias)

Accuracy vs. precision

Good precision (from large sample size), but with
:poor accuracy (with bias)

In sum
Sampling error
Difference between survey result and population value due
to random selection of sample
Greater with smaller sample sizes
Induces lack of precision

Bias
Difference between survey result and population value due
to error in measurement, selection of non-representative
sample or other factors
Due to factors other than sample size
Therefore, a large sample size cannot guarantee absence
of bias
Induces lack of accuracy, even with good precision

Definitions
ERROR:
1. A false or mistaken result obtained in a
study or experiment
2. Random error is the portion of variation
in measurement that has no apparent
connection to any other measurement or
variable, generally regarded as due to
chance
3. Systematic error which often has a
recognizable source, e.g., a faulty
measuring instrument, or pattern, e.g., it is
consistently wrong in a particular direction
(Last)

Bias
Deviation of results or inferences from the
truth, or processes leading to such
deviation. Any trend in the collection,
analysis, interpretation, publication, or
review of data that can lead to conclusions
that are systematically different from the
truth.
(Last)
A process at any stage of inference tending
to produce results that depart
systematically from true values
(Fletcher)

What is meant by bias in

?research
Bias is the term used to describe
differences between the study findings
and truth
Any effect at any stage of investigation
or
inference tending to produce results that
depart
systematically from the true values (to be
distinguished from random error)

Bias
Bias is a systematic error in
an
epidemiologic study that results in an
incorrect estimation of the
association between exposure and
outcome

What can be wrong in the

?study
Random error
Results in low
precision of the
epidemiological
measure measure is
not precise, but true
1 Imprecise measuring
2 Too small groups

Systematic errors
(= bias)
Results in low validity of
the epidemiological
measure measure is
not true
Selection bias 1
Information bias 2
Confounding 3

Random errors

Errors in epidemiological
studies
Error

Random error (chance)

Systematic error (bias)

Study size

Estimation
When we measure OR, we estimate a
point estimate
Will never know the true value

Confidence interval indicates

precision or amount of random error
Wide interval low precision
Narrow interval high precision

OR = 4.5 (2.0 10)

Classification of bias
There are three broad categories of
bias:
selection bias
confounding
measurement bias

Systematic error
Does not decrease with increasing
sample size
Selection bias
Information bias
Confounding

Bias
Systematic deviations in study findings
from the truth
Results from errors in the collection,
analysis, interpretation, publication, or
review of data

Selection
Bias
Error due to systematic
difference between the
characteristics of the
people selected for a
study and those who are
.not

Selection bias
Errors due to systematic differences in
characteristics between those who are
selected for study and those who are not .
(Last; Beaglehole)

When comparisons are made between

groups of patients that differ in ways other
than the main factors under study, that
affect the outcome under study .
(Fletcher)

?What is Selection Bias

Error due to systematic
differences in characteristics
between those who are selected
for study and those who are
not.

Examples of Selection bias

Subjects: hospital cases under the care of

a physician
Excluded:
1. Die before admission acute/severe
disease.
2. Not sick enough to require hospital care
3. Do not have access due to cost, distance
etc.
Result: conclusions cannot be generalized
Also known as Ascertainment Bias
)Last(

Ascertainment Bias
Systematic failure to represent
equally all classes of cases or
persons supposed to be represented
in a sample. This bias may arise
because of the nature of the sources
from which the persons come, e.g., a
specialized clinic;

Case ascertainment
Who is your case?
Patient?
Deceased person?

What is the definition of the case?

Cancer (clinically? Pathologically?)
Virus carriers (Asymptomatic patients)
You need to screen the antibody

?Who will be controls

Control

non-case

Controls are also at risk of the disease

in his(her) future.
In a case-control study of gastric
cancer, a person who has received the
gastrectomy cannot be a control.
In a case-control study of car accident,
a person who does not drive a car
cannot be a control.

Selection bias with

volunteers
Also known as response bias
Systematic error due to differences in
characteristics b/w those who choose
or volunteer to take part in a study
and those who do not

Selection bias with Survival

Cohorts
Patients are included in study because they
are available, and currently have the disease
For lethal diseases patients in survival
cohort are the ones who are fortunate to
have survived, and so are available for
observation
For remitting diseases patients are those
who are unfortunate enough to have
persistent disease
Also known as Available patient cohorts

Selection bias due to Loss

to Follow-up
Also known as Migration Bias
In nearly all large studies some members
of the original cohort drop out of the study
If drop-outs occur randomly, such that
characteristics of lost subjects in one
group are on an average similar to those
who remain in the group, no bias is
introduced
But ordinarily the characteristics of the
lost subjects are not the same

Healthy worker effect

A phenomenon observed initially in
studies of occupational diseases:
workers usually exhibit lower overall
death rates than the general
population, because the severely ill
and chronically disabled are ordinarily
excluded from employment. Death
rates in the general population may
be inappropriate for comparison if this
effect is not taken into account.
)Last(

Example. healthy worker

effect
Question: association b/w
formaldehyde exposure and eye
irritation
Subjects: factory workers exposed to
formaldehyde
Bias: those who suffer most from eye
irritation are likely to leave the job at
their own request or on medical advice
Result: remaining workers are less
affected; association effect is diluted

Information Bias
(Observation Bias,
Measurement Bias)

Error due to systematic

differences in the way data
on exposure or outcome are
obtained from various
groups leading to
misclassification of study
subjects

Measurement bias
Systematic error arising from inaccurate
measurements (or classification) of subjects
or study variables.
(Last)

Occurs when individual measurements or

classifications of disease or exposure are
inaccurate (i.e. they do not measure correctly
what they are supposed to measure)
(Beaglehole)

If patients in one group stand a better chance

of having their outcomes detected than those
in another group.
(Fletcher)

Measurement / (Mis)
classification
Exposure misclassification occurs
when exposed subjects are incorrectly
classified as unexposed, or vice versa
Disease misclassification occurs when
diseased subjects are incorrectly
classified as non-diseased, or vice
versa
)Norell(

Causes of misclassification
1. Measurement gap: gap between the
measured and the true value of a
variable
- Observer / interviewer bias
- Recall bias
- Reporting bias
2. Gap b/w the theoretical and
empirical definition of exposure /
disease

Example gap b/w

definitions
Theoretical definition
Exposure: passive
smoking inhalation of
tobacco smoke from
other peoples
smoking
Disease: Myocardial
infarction necrosis of
the heart muscle
tissue

Empirical definition
Exposure: passive
smoking time spent
with smokers (having
smokers as roommates)
Disease: Myocardial
infarction certain
diagnostic criteria
(chest pain, enzyme
levels, signs on ECG)

Exposure misclassification
Non-differential
Misclassification does not differ
between cases and non-cases
Generally leads to dilution of effect,
i.e. bias towards RR=1 (no
association)

ExampleNon-differential
Exposure Misclassification

DISEASE
Breast Cancer

EXPOSURE
X-ray exposure

+nt
-nt
Total
+nt 40
80
120
-nt
10000 40000 50000
RR= 40/10000
80/40000
2=

EXPOSURE
X-ray exposure

+nt
-nt
Total
+nt 60
60
120
-nt
20000 30000 50000
RR= 60/20000
60/30000
1.5 =

An example of non-differential
misclassification in an exposure variable
We want to compare mean of blood
pressure levels between cases and
controls.
The blood pressure checker has a
problem and always gives 5mmHghigher than true values.
All subjects were examined by the
same blood pressure checker.
no problem for internal
comparison

Exposure misclassification Differential

Misclassification differs between
cases and non-cases
Introduces a bias towards
RR= 0 (negative / protective
association), or
RR= (infinity)(strong positive
association)

ExampleDifferential
Exposure Misclassification

DISEASE
Breast Cancer

EXPOSURE
X-ray exposure

+nt
-nt
Total
+nt 40
80
120
-nt 9960 39920 49880
10000 40000 50000
RR= 40/10000
80/40000
2=

EXPOSURE
X-ray exposure

+nt
-nt
Total
+nt 40
80
120
-nt 19940 29940 49880
19980 30020 50000
RR= 40/19980
80/30020
0.75 =

Causes of Differential
Exposure Misclassification
Recall Bias:Systematic error due to
differences in accuracy or
completeness of recall to memory
of past events or experience.
For e.g. patients suffering from MI
are more likely to recall and report
lack of exercise in the past than
controls

Causes of Differential
Exposure Misclassification
Measurement bias:
e.g. analysis of Hb by different
methods (cyanmethemoglobin and
Sahli's) in cases and controls.
e.g.biochemical analysis of the two
groups from two different
laboratories, which give consistently
different results

Causes of Differential
Exposure Misclassification
Interviewer / observer bias:
systematic error due to observer
variation (failure of the observer to
measure or identify a phenomenon
correctly)
e.g. in patients of thrombo-embolism,
look for h/o OCP use more
aggressively

Confounding
1. A relationship b/w the effects of
two or more causal factors as
observed in a set of data such that
it is not logically possible to
separate the contribution that any
single causal factor has made to an
effect
(Last)

Confounding
When another exposure exists in the
study population (besides the one
being studied) and is associated both
with disease and the exposure being
studied. If this extraneous factor
itself a determinant of or risk factor
for health outcome is unequally
distributed b/w the exposure
subgroups, it can lead to confounding
)Beaglehole(

Confounding
Confounders are risk
factors for the outcome.
Confounders are related to
exposure of your interest.
Confounders are NOT in
the process of causal
relationship between the
exposure and the outcome
of your interest.

Example of not confounder

-- pineal hormone is not a confounder
EMF: electro-magnetic field
Decrease of pineal hormone
Breast cancer.may be the risk of breast ca

?Causation

Down regulation
of pineal hormone

EMF

EMF exposure induces

down
regulation of pineal
exposure cause breast cancer only through down
regulation of
hormone

.pineal hormone, this is not a confounder

Examples confounding

SMOKING

LUNG CANCER

AGE

As age advances(
chances of lung
)cancer increase

If the average ages of the smoking and(

)non-smoking groups are very different

Examples confounding

COFFEE DRINKING

HEART DISEASE
Smoking increases(
)the risk of heart ds

Coffee drinkers are(

more likely to smoke

SMOKING

Examples confounding

ALCOHOL
INTAKE

MYOCARDIAL
INFARCTION

Men are more likely(

to consume alcohol
)than women

Men are more at risk(

)for MI

SEX

Why do we have to consider

?confounding
We want to know the real
causal association but a
distorted relationship
remains if you do not adjust
for the effects of
.confounding factors

Example multiple biases

Study: ?? Association b/w regular
exercise and risk of CHD
Methodology: employees of a plant
offered an exercise program; some
volunteered, others did not
coronary events detected by regular
voluntary check-ups, including a careful
history, ECG, checking routine heath
records
Result: the group that exercised had
lower CHD rates

Biases operating
Selection: volunteers might have had
initial lower risk (e.g. lower lipids etc.)
Measurement: exercise group had a
better chance of having a coronary
event detected since more likely to be
examined more frequently
Confounding: if exercise group
smoked cigarettes less, a known risk
factor for CHD

Methods for controlling

Selection Bias
During Study Design
1. Randomization
2. Restriction
3. Matching
During analysis
1. Stratification
2. Adjustment
a) Simple / standardization
b) Multiple / multivariate adjustment

Randomization
The only way to equalize all
extraneous factors, or everything
else is to assign patients to groups
randomly so that each has an equal
chance of falling into the exposed or
unexposed group
Equalizes even those factors which
we might not know about!
But it is not possible always

Restriction
Subjects chosen for study are
restricted to only those possessing
a narrow range of characteristics,
to equalize important extraneous
factors

Example restriction
Study: effect of age on prognosis of MI
Restriction: Male / White /
Uncomplicated anterior wall MI
Important extraneous factors controlled
for: sex / race / severity of disease
Limitation: results not generalizable to
females, people of non-white
community, those with complicated MI

 For example:

Babies who are breast-fed have less illness

than babies who are bottle-fed.
Which illnesses? How is feeding type defined?
How large a difference in risk?
A better example:
Babies who are exclusively breast-fed for
three months or more will have a reduction in
the incidence of hospital admissions for
gastroenteritis of at least 30% over the first
year of life.

Matching - definition
The process of making a study group
and a comparison group comparable
with respect to extraneous factors
(Last)

For each patient in one group there are

one or more patients in the
comparison group with same
characteristics, except for the factor of
interest
(Fletcher)

Types of Matching
Caliper matching: process of matching
comparison group to study group within a
specific distance for a continuous variable
(e.g., matching age to within 2 years)
Frequency matching: frequency
distributions of the matched variable(s)
be similar in study and comparison
groups
Category matching: matching the groups
in broad classes such as relatively wide
age ranges or occupational groups

Matching is often done for age, sex, race,

place of residence, severity of disease,
rate of progression of disease, previous
.treatment received etc

:Limitations
controls for bias for only those factors involved in the match
Usually not possible to match for more than a few factors because of the
practical difficulties of finding patients
that meet all matching criteria
If categories for matching are relatively crude, there may be room for substantial
differences b/w matched groups

Stratification
The process of or the result of separating
a sample into several sub-samples
according to specified criteria such as age
groups, socio-economic status etc.
(Last)

The effect of confounding variables may

be controlled by stratifying the analysis of
results
After data are collected, they can be
analyzed and results presented according
to subgroups of patients, or strata, of
similar characteristics
(Fletcher)

Examples confounding
Disease
MI

Exposure-alcohol

+nt
-nt

+nt
140

-nt
100

RR = 140/30000
100/30000
1.4 =

Total 30000 30000

Disease
MI

Exposure-alcohol

RR = 120/20000
+nt
-nt
60/10000 (M)
male female male female
1=
+nt 120
20
60
40
RR = 20/10000
-nt
40/20000 (F)
1=
Total 20000 10000 10000 20000

Standardization
A set of techniques used to remove as far
as possible the effects of differences in
age or other confounding variables when
comparing two or more populations
The method uses weighted averaging of
rates specific for age, sex, or some other
potentially confounding variable(s),
according to some specified distribution
of these variables
)Last(

Example direct
standardization
HOSPITAL A
Preop

Pts Deaths %
High
500
30
6
Medium 400
16
4
Low
300
2
.67
Total 1200
48
4

HOSPITAL Std

Preop

Pts Rate Exp.deaths

High
400 6
24
Medium 400
4
16
Low
400 .67
2.68
Total 1200
42.68
(3.6%)

Multivariate adjustment
Simultaneously controlling the effects of
many variables to determine the
independent effects of one
Can select from a large no. of variables
a smaller subset that independently
and significantly contributes to the
overall variation in outcome, and can
arrange variables in order of the
strength of their contribution
Only feasible way to deal with many
variables at one time during the
analysis phase

Examples Multivariate
adjustment
CHD is the joint result of lipid
abnormalities, HT, smoking, family
history, DM, exercise, personality type.
Start with 2x2 tables using one
variable at a time
Contingency tables, i.e. stratified
analyses, examining the effect of one
variable changed in the
presence/absence of one or more
variables

Dealing with measurement

bias
1.
2.

Blinding
Subject
Observer / interviewer
Analyser
Strict definition / standard definition
for exposure / disease / outcome
3. Equal efforts to discover events
equally in all the groups

Controlling confounding
Similar to controlling for selection
bias
Use randomization, restriction,
matching, stratification,
standardization, multivariate analysis
.etc

How can we solve the problem of

?confounding
Prevention at study design
Limitation
Randomization in an
intervention study
Matching in a cohort
study But not in a casecontrol study

How can we solve the problem of

?confounding
Treatment at statistical analysis
Stratification by a confounder
Multivariate analysis

Error & Bias

Error: random error
Bias systematic error
differential misclassification
!This is a problem

non-differential misclassification

EXAMPLES OF RANDOM ERROR,

BIAS, MISCLASSIFICATION AND
CONFOUNDING IN THE SAME
:STUDY
STUDY: In a cohort study, babies of
women who bottle feed and women who
breast feed are compared, and it is found
that the incidence of gastroenteritis, as
recorded in medical records, is lower in
.the babies who are breast-fed

EXAMPLE OF RANDOM
ERROR
By chance, there are more episodes of
gastroenteritis in the bottle-fed group in
, the study sample
Or, also by chance, no difference in risk
, was found

EXAMPLE OF RANDOM
MISCLASSIFICATION
Lack of good information on feeding
history results in some breastfeeding mothers being randomly
classified as bottle-feeding, and vice.. versa

EXAMPLE OF BIAS
The medical records of bottle-fed babies
only are less complete (perhaps bottle
fed babies go to the doctor less) than
those of breast fed babies, and thus
record fewer episodes of gastro-enteritis
in them only.
This is called bias because the
observation itself is in error.

EXAMPLE OF CONFOUNDING
The mothers of breast-fed babies are of higher
social class, and the babies thus have better
hygiene, less crowding and perhaps other factors
that protect against gastroenteritis. Crowding and
hygiene are truly protective against
gastroenteritis, but we mistakenly attribute their
effects to breast feeding. This is called
confounding. because the observation is correct,
but its explanation is wrong.

Prevention of Bias
Sampling
Sample Size
Study design

Sources of data
collection
Methods of data

Selection bias
Error because the association
exposure disease
is different for participants and nonparticipants in the study
Errors in the
procedures to select participants
factors that influence participation

Examples of selection bias

Self-selection bias
Non-response
Loss to follow-up

Self selection bias

Selection bias is the distortion of
statistics by the way in which a
sample is selected.
Self-selection bias is the distortion
caused when the sample chooses
itself certain characteristics are
over-represented because they
correlatewith willingness to be
included.

Non response
non-response occurs when certain
questions in a survey are not
answered by a respondent.
non-response takes place also when
a randomly sampled individual
cannot be contacted or refuses to
participate in a survey.

Sources of selection bias

Inappropriate selection of study subjects from the
study population
non-random selection of subjects from the
same population
selection of subjects from different or ill-defined
study populations
failure to locate or unwillingness of people to
participate
loss of persons from the study population
because of the health outcome eg selective
survival

example selection bias

suppose we would like to conduct a casecontrol study of the
association between liver cancer and smoking.
Cases (those identified as having liver cancer) could be all
available individuals in all the hospitals in town during the
year of the study.
Controls (individuals without history of liver cancer) would be
recruited by local mass media advertisementshence they
would be volunteers. The study results would most probably
show a strong association between smoking and liver cancer,
not necessarily because smoking and liver cancer are
related, but because the selection process was different for
cases and controls. Although the cases were arguably
sampled from the population at large, the controls were
sampled from a population of volunteers!

Preventing selection bias

Same selection criteria
High response-rate
High rate of follow-up

Information bias
Error because the measurement of
exposure or disease
is different between the comparison
groups.
Errors in the
procedures to measure exposure
procedures to diagnose disease

Examples of information
bias
Diagnostic bias
Recall bias
Researcher influence

Measurement bias
Inaccurate measurement of study variables
can lead to bias
Sources of inaccurate measurement:
subject error error within the individual for
any reason, eg imperfect recall of past
exposures
Instrument error eg equipment not
properly calibrated, wording of question
Observer error error in use of instrument
or recording

Types of measurement error

Non-differential error
the inaccuracies of measurement are the
same among subgroups of subject
Non-differential measurement error in
exposure and outcome will always lead to
bias towards finding no effect
Differential error
the inaccuracies of measurement are
different among subgroups of subject can
lead to bias towards or away from no effect

Misclassification
True

TBE-cases
Controls
Differential

Nondifferential

TBE-cases
Controls
TBE-cases
Controls

Dog
20
20
Dog
24
20
Dog
24
28

Nodog
20
60
Nodog
16
60
Nodog
16
52

O
R=ad/bc=3,0
O
R=ad/bc=4,5
O
R=ad/bc=2,8

Non-differential
misclassification
Same degree of misclassification in
both cases and controls
OR will be underestimated
True value is higher

If no causal effect found, ask:

Could it be due to non-differential
misclassification?

Preventing information bias

Clear definitions
Good measuring methods
Blinding
Standardised procedures
Quality control

Minimising measurement
bias
1. use valid reliable tools to measure all study
subjects
2. train staff and monitor their use of research
tools
3. regular quality checks of research tools
4. blinding of study subjects and assessors
5. subjects in C-C study unaware of study
hypothesis
6. consider sub-study to determine validity and
reliability of measurements

Confounding
It occurs when there is a confounder,
which is associated with both exposure
. and disease independently
Exposure

Disease
Confounder

97 SLIDE

Confounding
defined as: a situation in which the
measure of effect of exposure on
disease is distorted because of the
association of the study factor with
other factors that influence the
outcome.
These other factors are called
confounders

A variable can be a confounder if all

:the following conditions are met
It is associated with the exposure of
interest (causally or not).
It is causally related to the outcome.
AND ... It is not part of the
outcome causal pathway

exposure

Confounding: Example

Alcohol

Lung cancer

Smoking

Confounding: example

Lung cancer

No lung
cancer

Drinker

50

50

Non-drinker

50

150

100

200

of cases are drinkers, but only 25% 50%

.of controls are drinkers
Therefore, it appears that drinking is
.strongly associated with lung cancer

Confounding: example

Smoker Lung cancer

Drinker

45

Non-drinker

30
75

No lung
cancer

15
10

Among smokers,
45/75=60% of lung
cancer cases drink and
of controls 60%=15/25
.drink

25

Non-smoker
Lung cancer
Drinker

No lung
cancer

Among non-smokers
5/25=20% of lung
140 cancer cases drink and

Non-drinker

35

20
25

175

of 20%=35/175
.controls drink

Stratification: Series of 2x2

tables
Idea: Take a 2x2 table and break it into
a series of smaller 2x2 tables (one
table at each of J levels of the
.confounder yields J tables)
Example: in testing for an association
between lung cancer and alcohol
drinking (yes/no), separate smokers
.and non-smokers

An Example

Maternal coffee
consumption during
pregnancy

Delivery of low birth

weight infant

Example
Low Birth
Weight

Normal Birth
Weight

Coffee

170

96

No Coffee

90

88

Crude OR = (170)(88) / (96)(90) = 1.73

Smokers
Low Birth
Weight

Normal Birth
Weight

Coffee

160

16

No Coffee

80

Stratum-specific OR = (160)(8) / (16)(80) = 1.00

Non-smokers
Low Birth
Weight

Normal Birth
Weight

Coffee

10

80

No Coffee

10

80

Stratum-specific OR = (10)(80) / (80)(10) = 1.00

Evidence of Confounding
ORcrude = 1.73
ORsmokers = 1.00
ORnon-smokers = 1.00
The association between coffee consumption
and having a low birth weight baby is
confounded by smoking. This is demonstrated
.by the lack of effect in each stratum

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
Females

88
62
150

68
82
150

OR= [88 x 82] [68 x 62]

= 1.71

: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

?
Outdoor
occupation

Male
gender

Malaria

?First criterion: Is the putative confounder associated with exposure

Outdoor
Indoor

Males
N
(%)
68 (43.5)
88
156 (100)

Females
N
(%)
13
(9.0)
131
144 (100)

OR=7.8

: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

Outdoor
Indoor

Malaria
Cases
N
(%)
63
(42.0)
87
150 (100)

.
Controls
N
(%)
18
(12.0)
132
150 (100)

OR=5.3

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
?
Outdoor
occupation

Male
gender

Yes, it could be
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

Controlling confounding
In the design
Restriction of the
study
Matching

In the analysis
Restriction of the
analysis
Stratification
Multivariable
regression

Strategy

Control confounding at the

stage
Advantages designing
Disadvantages

Specification
Include only
non-smokers.

Easily understood

Limits generalizability
May limit sample size

Matching
Match
smoking status
of cases and
controls

Useful for eliminating

influence of strong
constitutional
confounders like age
and sex

Decision to match must be

made when designing and can
have irreversible adverse
effects on analysis
Time consuming
Can not analyze associations
of matched variables with the
outcome

119 SLIDE

Control confounding at the analysis

stage
Strategy
Advantages
Disadvantages
Stratification
Conduct analysis
separately for
smokers and nonsmokers.

Easily understood
Reversible

Statistical
Multiple confounders
adjustment
can be controlled.
Conduct
Reversible
multivariate
analysis controlling
(adjusting) for
smoking status.

May be limited by
sample size for each
stratum
Difficult to control for
multiple confounders
Need advanced
statistical techniques
Results may be difficult
to understand

120 SLIDE

Restriction
We study only mothers of a certain age

Many children

Downs

year old 35
mothers

Matching
Selection of controls to be identical to the
cases with respect to distribution of one or
.more potential confounders

Many children

Downs

Maternal
age

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

Example
miners exposure and lung
cancer

one group of miners exposed to the

underground environment and the
other group not exposed
Hence any differences in lung cancer
rate would be due to exposure to
working underground

Example
Selection bias and
confounding

Bias occurs when the exposed and non

exposed groups have different risks of
developing the outcome of interest for
reasons other than being exposed.
This can be due to selection bias or
confounding
eg. more underground workers smoke

Confounding variables
In our study of miners:
1. .smoking is an independent risk factor
(cause) of the disease (lung cancer)
2. .more underground miners smoke ie
smoking is unevenly distributed among
the exposed and non-exposed
3. .smoking is not on the causal pathway
between exposure and disease

When examining the relationship between

an explanatory factor and an outcome,
we are interested in identifying factors
that may modify the factor's effect on the
outcome (effect modifiers). We must also
be aware of potential bias or confounding
in a study because these can cause a
reported association (or lack thereof) to
be misleading. Bias and confounding are
related to the measurement and study
:design. Let 's define these terms

If the method used to select subjects or collect

, .data results in an incorrect association
! THINK >> Bias
If an observed association is not correct because
a different (lurking) variable is associated with
both the potential risk factor and the outcome,
, but it is not a causal factor itself
! THINK >> Confounding
If an effect is real but the magnitude of the effect
is different for different groups of individuals
.(e.g., males vs females or blacks vs whites)
!THINK >> Effect modification

A confounding factors
is one that affects both the
exposure and the disease-that is
(has an association with both the
disease and the risk factor under
study) that may distort relationships
between the two and confound
(confuse) the study results.

Confounding

ExposureOutcome

Third variable

Confounding

Coffee

CHD

Smoking
Smoking is correlated with coffee drinking and
a risk factor even for those who do not drink
coffee

: Confounding factor
Drinking coffee causes CHD
Drinking coffee may not be the cause of
CHD, but rather the fact that smokers
are also coffee drinkers.

Confounding
Risk Factor
Independent
Variable
Coffee

Disease
Dependent
Variable
CHD
Covariable
Confounder
Smoking

133

:Example
In a study of the association between
tobacco smoking and lung cancer,
age would be a confounding factor if
the average ages of the non-smoking
and smoking groups in the study
population were very different, since
lung cancer incidence increases with
age.

:Another example
the possible association between
meat consumption and cancer
colon may be due to other
accompanying factors such as
decreased intake of vegetables
or increased intake of fat rather
than the meat consumption itself.

problem
The annual report of POF Hospital for the year
2006 shows 200 cases of Myocardial Infarction, 35
cases of Cholecystitis, 105 cases of Pneumonia
and 350 cases of Acute Gastroenteritis. The result
of this report cannot be generalized on the total
population of Faisalabad on account of:
a. Confounding bias
b. Memory bias
c. Selection bias
d. Berkesonian bias
e. Interviewers bias
Key: True: d

Mothers education is therefore a potential confounding variable.

In order to give a true picture of the relationship between bottlefeeding and diarrhea of under-twos, the influence of mothers education
should be controlled.
This could either be addressed in the research design, e.g., by selecting
only mothers with a specific level of education, or it could be taken into
account during the analysis of the findings by analyzing the relation
between bottle-feeding and diarrhea separately for mothers with
different levels of education.

A study was done to compare the lung capacity of coal miners to the
lung capacity of farm workers. The researcher studied 200 workers
of each type. Other factors that might affect lung capacity are
smoking habits and exercise habits. The smoking habits of the two
worker types are similar, but the coal miners generally exercise
less than the farm workers
?Which of the following is the explanatory variable in this study . 1
a. Exercise
b. Lung capacity
c. Smoking or not
d. Occupation
?Which of the following is a confounding variable in this study . 2
a. Exercise
b. Lung capacity
c. Smoking or not
d. Occupation

 Essential principles (features) of properly

designed clinical trials:
Control of variables surrounding the
experimental subjects
The investigator has control of the subjects, the
intervention, outcome measurements, and sets
the conditions under which the experiment is
conducted. In particular, the investigator
determines who will be exposed to the
intervention and who will not. This selection is
done in such a way that the comparison of
outcome measure between the exposed and
unexposed groups is as free of bias as possible.

 Randomization refers to the practice of

assigning subjects to experimental or
treatment groups in a completely random
manner. Thus each subject has an equal
chance of being placed in the experimental
group. This avoids the potential bias of the
researcher choosing subjects s/he feels
would be most likely to benefit from the
intervention for the intervention group, and
a similar possible bias if the choice were left
up to the subjects.

 Blindness refers to the practice in which

the researcher remains uninformed and
unaware of the identities of experimental
and control groups throughout the period
of experimentation and data gathering.
Thus, the researcher can remain
unbiased in judging the responses of any
particular subject or group.

When studies involve human subjects, it

is important that the subjects also
remain uninformed as to whether they
have been placed in the experimental
group (receiving the treatment) or
control group (receiving the placebo).
Such procedure is referred to as doubleblind (neither researcher nor subjects
. know who is receiving the treatment)

 ). This is important because some

people begin to feel better if they
believe they have received a
treatment. Only at the end of the
study would the code (known by the
statistician) be broken and the
results analyzed according to who
had been taking the drug and who
had not.

So, the gold standard design for

clinical trials, i.e., the least prone to
bias, is the randomized double.blind controlled trial