Bias Confonder PG Lecture Series

Bias and Confounders
J Kishore
MBBS, MD, PGCHFWM, PGDEE, MSc,
MNAMS, FIPHA
Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

What is Research?
• Research is a quest for knowledge through
diligent search or investigation or
experimentation aimed at the discovery and
interpretation of new knowledge.
• Lets take one example

Exposure to Effect of cholera
Genetic Factors
contaminated toxins on bowel
Poverty water wall cells
Increased Ingestion of
Susceptibility Cholera Cholera
vibrio
Malnutrition
Crowded housing
Risk factors for cholera Mechanisms for cholera

Exposure to Effect of cholera toxins on
Genetic Factors contaminated water bowel wall cells
Poverty
Healthy
Agent Disease Complications
Person
Malnutrition
Crowded
housing
What are the causes of What are Mechanisms What Complications?

Why?
Susceptibility of healthy
How can be prevented?
“An event, condition or characteristic that
preceded the disease event and without
which the disease event either would not
have occurred at all or would not have
occurred until some later time.”
Rothman, 1998
Necessary, sufficient and component causes

Observed association,
could it be:
Selection or
measurement bias
No
Assessing the Confounding

relationship No
between a possible Chance
cause and an
Probably Not
outcome
Causal

Fact = Truth + Error
(Systematic) (Random)
Bias Chance
Research Method Statistics

•Type of study • p value
•Randomization • confidence interval
•Stratification • Sample size
•Blinding
Validity of Research
• It is the degree to which a research /test /
survey measures what it is intended to
measure.
• It is the ability of research to detect the truth
(disease/health event/finding).

THREATS TO VALIDITY
A study’s internal validity, or how close its

findings are to the TRUTH, can be
compromised by three things….
• BIAS
• 3rd VARIABLES (CONFOUNDING or
INTERACTION)
• CHANCE

Relationship between bias and chance
Faulty
Instrument/
True Blood Blood Pressure Observation
Pressure (Sphygmomanometer)
No. of (Intraarterial)
Observ
ations
Chance Non Differential

Misclassification
Bias
80 90
Diastolic Blood Pressure (mm Hg)
Internal Validity and Generalizability (External Validity)
All patients with the Study on Sampled Patients

conditions of interest
Sample Sample
In Selection
te
rn
alV
al
id
ity Measurement
Ext
ern Confounding
al V
alid Chance
ity
General Population Having CONCLUSION
Normal &
Diseased persons
External Validity/
Generalizability
Cross Sectional Studies
Case Control Studies
Cohort Studies
Non-Randomized Studies
Randomized Controlled Trial

Internal
Dr. J KishoreValidity
Professor MAMC, New Delhi; drjugalkishore@gmail.com
What is bias?
• Prejudice; deviation from truth; the concept
of bias is the lack of internal validity or
incorrect assessment of the association
between an exposure and an effect in the
target population. Result of such studies can
not be extrapolate to general population.
There is no external validity without
internal validity.
Types of biases
• There may be more than 100 biases,
however, for the understanding they are
simply divided in to:
• Selection Bias
• Information Bias
References: J Kishore. A Dictionary of Public Health 2007

Systematic Errors
Selection Bias
• Ascertainment Bias is systematic error resulting
from failure to identify equally all categories of
individuals who are supposed to be represented in a
group, e.g., study based on specialty hospital.
• Non-Random Sampling bias, e.g. non-
representative sample.
• Healthy worker effect is another selection bias
which may take place when employed are
compared with unemployed.
Selection Bias
Selection Bias
A faulty assumption that occurs because there

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

Information Bias
• occurs during data collection. The main types
of information bias are:
• 1. Misclassification Bias
• 2. Observer/interviewer Bias
• 3. Recall Bias
• 4. Reporting Bias
• 5. Other information biases: Hawthorne
effect, loss to Dr.
follow up,
J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com
MISCLASSIFICATION BIAS
Misclassification Bias: the erroneous
classification of an individual, a value, or an
attribute into a category other than that to
which it should be assigned
• often results from an improper “cutoff point”

in disease diagnosis or exposure
classification;
• Originated when sensitivity and or specificity
of the test is low.
• 2 types of misclassification bias
– differential (systematic)
Differential misclassification
• Misclassification is different in groups to be
compared
• e.g. recall of exposure in disease patients
and control. Disease patients will try to
recall the exposure more than control group.
This will result in greater association in
disease and exposure, i.e., moving away
from null hypothesis.
Differential Misclassification
"True Situation"
CasesControls Total
Exp. 85 40 125
Not Exp. 15 60 75
Total 100 100 200
85X60/15X40 OR= 8.5
30% unexposed misclassified as exposed in cases,

50% of exposed misclassified as unexposed in
controls
Cases Controls
Exp. 85 + 5 20
Not Exp. 10 60 + 20
Total 100 100
90X80/10X20 OR=36.0
Bias away from the null (1.0)
• Non-differential Misclassification
Bias
rate of misclassification does NOT differ between
study groups (Cases and Control)
– all study groups and control equally
susceptible to inaccuracy in classification,
e.g., faulty instrument applied to all disease
and control group
– dilutes the true association
– RR or OR shifts towards null (1.0)

Non-Differential Misclassification
"True Situation"
CasesControls Total
Exp. 85 40 125
Not Exp. 15 60 75
Total 100 100 200
85X60/15X40 OR= 8.5
50% of exposed misclassified as unexposed
Cases Controls
Exp. 43 20
Not Exp. 15 + 42 60 + 20
Total 100 100
43X80/57X20 OR=3.0
Bias towards the null (1.0)
• Non differential (random)

misclassification is somewhat less serious
a problem for validation of study findings
since the bias introduced is towards the
null (more conservative)
• Differential bias (non-random,

systematic) can be quite serious because
the direction of the bias is UNKNOWN.

CONTROLLING FOR MISCLASSIFICATION
BIAS
• improving sensitivity and specificity

of diagnostic tests
– raises or lowers the “cutoff point” for
diagnosis
• increasing the completeness of

medical records
• multiple questions that ask same
information
– acts as a built in double-check
• multiple checks in medical records

Confounding
Now Lets take one situation
Research Question
Is down syndrome associated with
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
• Could there be another factor
(confounding) responsible for Down
syndromes?

What is “Confounding”?
• From the Latin confundere, to mix
together
• “The distortion of the apparent effect of

an exposure (e.g. Birth Order) on risk
(e.g. Down Syndrome) brought about
by the association with other factor[s]
(e.g. age of mother) that can influence
the outcome”
• A Dictionary of Epidemiology by John Last, 1995.
28
Cases of Down Syndrom by age groups
Cases per 1000

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

What is “Confounding”?, continued...
• Confounding Principles:
– Indirect (spurious or weaker than we think)
association (A1) between exposure (E) and disease
(D) that depends on A2 [and is weaker than direct association (A3)
between confounder and disease]
– Confounder (C) must associate with both E & D
A1 Down syndrome
Birth Order
(D)
(E)
A2 A3
Age of mother
(C)
30
Cases of Down syndrom
by birth order and mother's age
Cases per 100000
1000
900
800
700
600
500
400 40
+
300 35
30 -39
200 -34
100 25
20 -29
0 -24 s
<2 oup
1 2 3 4 5 0 r
geg
A
Birth order

EXPOSURE DISEASE
(coffee drinking) (heart disease)
CONFOUNDING
VARIABLE
(cigarette smoking)
Does night light increase the risk of
Myopia?
Quinn et al 1999
Nightligh
t Myopia children
exposure
before
age 2 yrs
Myopic Parents
Zadnik et al 2000,
Gwiazda et al 2000

Common feature of Confounder
Exposure
Confounder ?
Disease
Outcome
EXAMPLE:
Is maternal smoking a risk factor of perinatal death?
Is the association confounded by low birth weight?
Maternal
smoking
Low birth
?
weight
Perinatal
mortality

OR RATHER:
Is low birth weight the reason why maternal smoking is
associated to higher risk of perinatal death?
Maternal
smoking
Low birth
weight
Perinatal
mortality

BUT THERE COULD BE AN ADDITIONAL QUESTION:
Does maternal smoking cause perinatal death by
mechanisms other than low birth weight?
Maternal
smoking
Direct
Low birth
Block by toxic
weight
adjustment effect?
Perinatal
mortality

Confounding
Criteria for a Confounding Factor ( Rothman and Greenland,
1998):
1. A confounding factor must be a risk factor for the disease.

2. A confounding factor must be associated with the exposure
under study in the source population (the population at risk
from which the cases are derived). Typically, (for a rare
disease) check this condition by looking for an association in
the control group.
3. A confounding factor must not be affected by the exposure or
the disease. In particular, it cannot be an intermediate step in
the causal path between the exposure and the disease.
Control of Confounding
Approaches
1. Design Aspects of a Study
Randomization – used in experimental design to allocate individuals
into experimental groups.
Restriction – selecting subjects with equal values for variables
which might be confounders (can use complete restriction or
partial restriction known as matching).
2. Analytic Methods
Stratification – using homogeneous categories; using
Direct, Indirect stratification, Mantel Haenszel tests,
Model Fitting – such as regression models-Linear
regression, Logistic Regression, etc.
Coping with confounders
Matching (mostly in case control studies)
 Selection of cases and controls with matching
values of the confounding variable
Pair wise matching
e.g in coffee drinking study as a predictor of MI, each case (a
patient with MI) could be matched with one or more controls
that smoked roughly the same amount as the case (10-20
cigarettes/day)

Matching
Advantages:
 Can eliminate influence of strong confounders
 Can increase precision (power) by balancing the number
of cases and controls in each stratum
 May be sampling convenience making it easier to select
controls

Matching
Disadvantages
 Time consuming
 Requires early decision as to which variables are
predictors and which are confounders
 Requires matched analysis
 Creates the danger of over matching( matching on a
factor which is not a founder, thereby reducing power)

Comparing control of bias in RCT & NRS
Source of bias RCTs Cohort/other NR Comments
studies
Selection bias Randomi- Control for Many other
zation confounders study-specific
threats
Performance Double- Exposure Misclassifica-

bias blinding measurement tion/ non-
(Exposure) comparability
Attrition bias Complete Complete F/U What amount is

F/U critical?
Detection bias Masked Masked Misclassifica-

(Outcome) assessmt assessment tion
Hill criteria - used to evaluate possibility of causation;
(from Rothman, Modern Epidemiology, 2nd ed., 1998)
1. Strength of association (magnitude of effect): Measured as

relative risk or Odds ratio?
• Consistency - more an argument against associations
due to chance. Has effect been seen by others?
3. Specificity - idea that a cause should lead to a single effect -
not tenable.
4. Temporality: Did exposure precede outcomes?
5. Biologic gradient (dose-response)
6. Biologic plausibility: Is the association make sense?
7. Coherence (also biologic)—with natural history of
disease/condition. Is the association consistent with available
evidence?
8. Experimental evidence: Has a randomized controlled trials
been done?
9. Analogy — parallels exposure-outcome relationship for similar
exposure and/or disease. IsProfessor
Dr. J Kishore an association similar
MAMC, New Delhi; to others?
drjugalkishore@gmail.com
It’s the beginning !
We have a
long way to go
Thanks- Dr. J Kishore

Bias Confonder PG Lecture Series

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Bias and Confounders

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

• Lets take one example

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Risk factors for cholera Mechanisms for cholera

What are the causes of What are Mechanisms What Complications?

Necessary, sufficient and component causes

Assessing the Confounding

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Research Method Statistics

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

A study’s internal validity, or how close its

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Chance Non Differential

All patients with the Study on Sampled Patients

Case Control Studies

Randomized Controlled Trial

References: J Kishore. A Dictionary of Public Health 2007

A faulty assumption that occurs because there

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

• often results from an improper “cutoff point”

30% unexposed misclassified as exposed in cases,

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

50% of exposed misclassified as unexposed

• Non differential (random)

• Differential bias (non-random,

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

• improving sensitivity and specificity

• increasing the completeness of

• multiple checks in medical records

Now Lets take one situation

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

• “The distortion of the apparent effect of

Cases per 1000

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

– Confounder (C) must associate with both E & D

Cases per 100000

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

1. A confounding factor must be a risk factor for the disease.

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Dr. J Kishore Professor MAMC, New Delhi; drjugalkishore@gmail.com

Performance Double- Exposure Misclassifica-

Attrition bias Complete Complete F/U What amount is

Detection bias Masked Masked Misclassifica-

1. Strength of association (magnitude of effect): Measured as

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