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Module 5: Bias

Bias: systematic error in design or implementation of a study that

results in an incorrect measure of association
The bias may be so strong that it explains the measure of association

Selection Bias

An error due to systematic differences in characteristics between those

selected for study and those not selected
Are participants in study similar in all important factors except for
exposure or disease?
Can occur in case-control and cohort studies

Selection Bias in Case-Control Studies

Exposure can influence the detection, thus selection of cases
If controls are selected by a different mechanism as selecting cases,
selection bias is introduced
E.g. immediate neighbourhood (controls) vs. Southern Ontario
(cases)
Controls more likely to be selected if theyre at home 9-5, more
likely to be unemployed or retired
Bias in introduced when:
Selecting inappropriate control group
Selecting an appropriate control group, but participation related to
exposure status (smokers more likely to enroll in lung cancer study
even if they dont yet have lung cancer)
Selection Bias in Cohort Studies
Retrospective: all cases have already occurred, participants know their
exposure and outcome status, thus more or less likely to participate
depending on their exposure status
Prospective: participants dont know their outcome, and sometimes
dont even know the specific risk factor being measured, so no
selection bias like retrospective
Selection bias can be introduced if there is more available data on
those who were exposed but showed no outcome, and less available
data on those were exposed and showed outcome (company destroys
damning evidence, covering their asses)
Calculated RR would be much smaller than what it should be
Company would be successful in saying that exposure didnt pose
significant risk to developing outcome
Results in biased estimates of RR

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Other Common Selection Biases
Volunteer Bias = volunteers for studies generally healthier and more
interested in health
Non-Response Bias = People invited to participate and ignore invitation
are different from those who respond
Exclusion Bias = exclusion criteria creates group of participants not
representative of population that produces cases
Healthy Worker Effect = those who attend work regularly generally
healthier that those who dont, affects occupational epidemiology
studies

Information Bias (Observation Bias/Measurement

Bias)

Is information about outcome or exposure obtained in same manner?

E.g. same questions asked to all participants
Differential or non-differential information bias

Non-Differential
Measurement of disease not different for exposed and unexposed
subjects
Heart disease tested in same way for those with high or low BMI
(look at troponin levels)
Measurement of exposure is not different diseased and non-diseased
subjects
Those with heart disease have height and weight measured in same
way as those without heart disease
Non-differential misclassification = subjects may be equally
misclassified on exposure regardless of their status as a case or
control, or they may be equally misclassified on disease status
regardless of whether they are exposed or not
Differential
Measurements of disease different for exposed and unexposed
Those who are overweight might not fit into MRI machine, disease
must be measured some other way
Measurement of exposure different for diseased and non-diseased
Those with heart disease more likely to be called into hospital, so
height and weight measured at hospital, vs. healthy patients who
self report height and weight
Differential Misclassification = knowledge of subject exposure status
influences how subjects will be classified on disease status (or vice
versa)

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Other Common Information Biases
Reporting bias = reluctance to report an exposure for social or
psychological reasons
Social desirability bias: under report street drug use
Wish bias: deny exposures to minimize self-blame

Recall Bias

Memory of exposure history distorted by present health state

Occurs in case-control studies
Cases recall previous exposure differently from controls
Lung cancer patients more likely to remember smoking than
controls
Solution = not have people recall, dont rely on participants memory
Look for cases and controls with similar motivation to recall a
certain exposure
Rely on hospital records
Blind participants and study personnel to hypothesis (eliminating
pre-conceived notions on whats causal)
Use objective biomarkers

Interviewer Bias

Systematic difference in obtaining, reporting, interpreting information

from participants
Affects all study designs (case-control: exposure histories, cohort:
reported outcomes)
Ask the right question, and youll get the right answer
Solutions
Cohort: blind exposure status of participants to those measuring
outcome
Case-control: Blind disease status when assessing exposure
Mask hypotheses
Use standardized, closed-form questionnaire

Loss to Follow-Up

Problem in prospective studies (RCTs, cohorts)

Results in systematic difference in following and obtaining outcome
information
Problem if reasons for loss is related to outcome (e.g. outcome causes
patient to not feel well, drops out)
Differential loss to follow-up = exposed who were lost dropped out for
a different reason than unexposed who were lost
This introduces bias, skews measure of association

Solutions
Standard follow-up procedures for all participants
Minimize loss to follow-up (better accommodate participants so they
dont drop out)

Biases in RCTs
Selection Bias

Performance Bias (form of

information bias)
Attrition Bias (loss to follow-up)
Detection Bias = participants figure
out what treatment theyre on

Randomization
Sequence generation
Allocation concealment
Blinding participants,
personnel, outcome assessors
Incomplete outcome data
Losses to follow up
Blinding participants,
personnel, outcome assessors

Confounding

Could results be accounted for by a factor associated with both

exposure and outcome but not directly in the causal pathway?
E.g. association between yellow teeth and lung cancer, confounding
variable would be smoking

Types of Errors

Random Error = Reduces

precision of the estimates
(OR, RR)
Systematic Error = reduces
validity or accuracy of
estimates

Bias Involves Validity

Internal Validity
Degree to which study
provides unbiased
estimates of what it claims to measure
Absence of systematic or random error

Module 6: Confounding and Effect

Modification

Confounding refers to the mixing of the effect of the exposure with

the effect of another factor (confounder) on the outcome
This distorts the estimated measure of association
Confounding is a potential problem with all observational studies
Without randomization, theres no way to insure that confounders
are distributed evenly between study groups
This uneven distribution of confounders leads to biases on OR or RR

A confounder is a variable that is

A risk factor for the disease of
interest independent of the exposure
of interest
A variable that is not on the causal
pathway; i.e. variable not a
consequence of exposure that lead to
disease
Confounder must cause the outcome
even in the absence of the exposure
of interest

An example of confounding: E = yellow

fingernails, D = lung cancer, is smoking
a confounding variable?

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Smoking is a risk factor for lung cancer, independent of yellow
fingernails
Smoking is not a consequence of yellow fingernails, not on causal
pathway
Smoking is a confounder
Yellow fingernails not a confounder, as it is a consequence of
smoking, and yellow fingernails independent of smoking does not
cause lung cancer

Another example: E = smoking, D = stress urinary incontinence, is

coughing a confounder?
Coughing is not a confounder, as it is a consequence of smoking

If E = coughing, D = stress urinary incontinence, is smoking a

confounder?
Smoking is part of the causal pathway: Smoking Coughing Stress
Urinary Incontinence
Smoking is therefore not a confounder, as it does not cause urinary
incontinence independent of coughing (exposure of interest)
Smoking only causes urinary incontinence through coughing

Another example: E = obesity, D = mastitis (breast inflammation), is

age a confounder?
Age is a risk factor for mastitis
Age is not in causal pathway; obesity does not influence age of
cows
Age is a confounder

Stratified analysis = test association between exposure and

outcome separately within each level of confounder

Stratification by age (confounder) shows that there is no association

between obesity and mastitis
Age (confounder) has created an association between obesity and
mastitis when really none exists

Handling Confounding
Design Stage
Randomization balances known
and unknown confounders
(obviously cant be done for
observational study)
Restriction: limit subjects to
those who only fall in one
category of confounder (e.g
include young cows only)
Reduces number of study
subjects
Residual confounding if
category not narrow enough
(young cows vs. very young
cows)
Cannot study influence of
other categories of the
confounder
Matching: only pick controls
with comparable characteristics
to cases
Time consuming and costly
Cannot evaluate effects of
matched variables

Analysis Stage
Multivariable regression
analysis = add confounding
variables into simple regression
models
Must ensure youve
measured the confounder in
the sample
Stratification (same shit as
above)
Computationally difficult
with multiple confounders
(many strata thus many
tables)
Impossible when confounder
is a continuous variable that
cannot be categorized

Identifying Confounders

Conduct literature search to suggest potential confounders for which

data should be collected
Consider biologic plausibility

Effects of Confounding

Effect Modification (EM)

Exposure-disease association differs at different levels of a third

variable (the effect modifier)
Effect modification vs. confounding
Effect modification = biological phenomenon where exposure has
different impact in different circumstances
Confounding = form of bias
E.g. Case-control study: E = physical activity, D = myocardial
infarction, is alcohol consumption an effect modifier?
Is the association between physical activity and myocardial
infarction modified by alcohol consumption?
Stratify based on categories of alcohol consumption (drink, dont
drink)

If
measure of
association differs for each category, then the third variable is an
effect modifier

Parallel lines indicate confounding; effect of exposure on disease is the

same at different levels of confounder
Non-parallel lines indicate effect modification; exposure-disease
association different at different levels of effect modifier

Mantel-Haenszel Estimator

Crude OR/RR falls outside range of stratum-specific OR/RR

Thus crude OR/RR is not a good estimate of association
Mantel-Haenszel estimator measures the average effect of exposure
across all strata, accounting for confounding and EM
Estimate lies between OR/RR of stratum 1, and OR/RR of stratum 2
Variable would be a confounder if the stratum-specific and MantelHaenszel relative risks were equivalent to one another, but the crude
relative risk was higher or lower than the other estimate
Variable is an effect modifier if stratum-specific relative risks are
different, but the crude and Mantel-Haenszel relative risks are virtually
the same
Variable would be an effect modifier and confounder if the stratumspecific relative risks are different, AND the crude relative risk is
outside of the bound established by the stratum-specific relative risks