Bias

Jason Ryan, MD,

MPH
Bia
s• Systematic error in a
study
• Group selection
• Measurement
• Outcome assessment
• Exposure assessment
• Confounding

Wikimedia Commons
Selection
Bias
• Errors in selection or retention of study
groups
• Usually used as a general term
• Many subtypes
Recruiting
participants
Selection Bias
Sampling
Bias
• Subtype of selection bias
• Patients not representative of actual practice, patients in
your study dont match the general population

• Results not generalizable to clinical practice

• Example: average age many heart failure trials = 65
• Average age actual heart failure patients = 80+
• Study results may not apply, because there is a
disproportionately younger population in the trial

Picmpedia/org
 Attrition
Bias
• Subtype of selection bias
• Occurs in prospective studies
• Patients lost to follow-up unequally between
groups
• Suppose 100 smokers lost to follow-up due to death
• Study may show smoking not harmful
participants lost to follow up have a
different prognosis than those who
complete the study

Attrition bias does not occur when the losses

happen randomly between the exposed and
unexposed groups, as this simply leads to a Pixabay/Public

smaller study population. Domain

Berkson’s
Bias
• Subtype of selection bias
• Hospitalized patients chosen as treatment or control
arm
• This patients tend to have more severe symptoms
• May have better access to care
• Alters results of study

• Example:
• Study of hospitalized pneumonia patients
• Shows many patients have history of stroke
• Pneumonia associated with stroke
• Similar study in community: there is no association
Wikipedia/Public Domain
Nonresponse
Participation Bias
Bias
• Subtype of selection bias
• Occurs with survey and questionnaire studies
• Non-responders not included
• Patients who respond may represent a selected
group

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Prevalence
Neyman Bias
Bias
• Subtype of selection bias
• This occurs in studies trying to associate exposure with disease where exposure occurs
long before disease assessment
• When there is a big time difference between exposure and assessment
patients exposed who die quickly are not going to be included
• So the prevalence of disease is based on select group of survivors

Exposure Assessment
 Interpreting results
Confounding bias Length-time bias

Lead-time bias
 Confounding occurs when the exposure-disease

Confounding relationship is muddled by the effect of a

confounding variable, an extraneous factor
associated with both exposure and disease. 
Bias
• Unmeasured factor confounds study results
• Example:
• Alcohol users more like to develop lung cancer than non-
users
• Smoking much more prevalent among alcohol users
• Smoking is true cause of more cancer
• Smoking is a confounder of results
Initial crude analysis suggested that alcohol use was associated with bladder carcinoma
(similar to shoe size being associated with intelligence), with a relative risk (RR) of 1.81
and a p-value <0.05.  However, smoking is associated with both bladder carcinoma and
alcohol use.  Therefore, smoking is a potential confounder that may explain the
association observed between alcohol use and bladder cancer.  Stratified analysis by
smoking status shows that both smokers and non-smokers have an RR ~1 with large p-
values (>0.05).  The RR of 1.81 found on crude analysis disappears and there is no true
association between alcohol consumption and bladder cancer.
 Screening test detects diseases with long
Length-time latency period, while those with shorter latency
period become symptomatic earlier
Bias
• Patients with severe disease do not get studied because
they die
• Example: analysis of HIV+ patients shows the disease
is asymptomatic
• May overestimate survival because severe cases missed,
because they die
• Example: screening program identifies only slow-
growing
tumors
• Screening programs may appear more effective because it
finds this tumors but tumors that grow more quickly lead to
death more quickly and therefore those patients don't end up in
the screening
OpenClipArt
Lead-Time Early detection interpreted as ↑ survival, but
the disease course has not changed

Bias
• Screening test identifies disease earlier
• Survival appears longer when it is not→ It appears to
exaggerate survival time because patients are known to have the cancer
for longer

• Example:
• Average time from detection of breast lump to death = 5
years
• Screening test identifies cancer earlier
• Time from detection to death = 7 years
• Avoided by controlling for disease severity
• Expected survival based on stage at detection

Public Domain
 Observer-expectancy bias

Performing study
Recall bias Procedure bias

Measurement bias
Measurement
Bias Information is gathered in
•Sloppy research technique a systemically distorted
manner

• Blood pressure measured incorrectly in one

arm
• Protocol not followed

• Avoided by standardized data collection

• Objective, previously-tested methods
• Carefully planned ahead of time

Wikipedia/Public Domain
 Hawthorne
• Type of measurement bias
•Effect
Study patients improve because they are being
studied Participants change behavior upon awareness
of being observed

• Common in studies of behavioral patterns

• Example:
• Physicians know patientsare being surveyed about
vaccination status
• Physicians vaccinate more often, it Will look like physicians
are being more careful to vaccinate everyone than they are in
reality if you werent studying them
• Example:
• Patients being studied for exercise capacitystandardized, and previously tested
Use objective,
• Patients exercise more often methods of data collection that are planned ahead of
time
Use placebo group
Observer
Bias
• Form of measurement bias
• Investigators know exposure status of patient
• Examples:
• Cardiologist interprets EKGs knowing patients have CAD
• Pathologist reviews specimens knowing patients have
cancer
• Avoided by blinding

PxHere
Recall
Bias
• Inaccurate recall of past events by study subjects
• Common in survey studies common in retrospective studies
• Example:
• Parents of disabled children asked about lifestyle during
pregnancy
• Pregnancy occurred many years ago
• Poor recall leads to inaccurate findings
• Avoided
Decreaseby
timeminimizing
from exposure recall timeframe
to follow-up; use
medical records as sources

Patients with disease recall exposure after

learning of similar cases

Shutterstock
Misclassification bias is an incorrect categorization of subjects regarding their exposure,
outcome status, or both.  In case-control studies, recall bias usually leads to
misclassification of the exposure status.

So what happens is that

in the case study people
with the disease already
have thought a lot about
what should have been
the reasons for the
disease ( in contrast to
people that doesnt have
the diseas-controls ). So
we have a recall bias in
the cases. We are more
like to misclassify the
exposure in the controls
than in the cases
Procedure
Bias
• One group receives procedure (e.g., surgery) and
another does not →Subjects in different groups are not treated the
same

• More care and attention given to procedure patients

Patients in treatment group spend more time in highly

specialized hospital units

• Avoided by blinding (masking)

• Care team unaware which patients had procedure
• Also avoided by using placebo Public Domain

• Sometimes sham surgery performed

Pygmalion Effect or Observer-expectancy
effect
• Researcher believes in efficacy of treatment
Blinding (masking) and
use of placebo reduce
influence of
• Influences outcome of study participants and
• Example: researchers on
procedures and
• Creator of a new surgical device overseeing interpretation of
study outcomes
as neither are aware of
• Creator assesses outcomes positively group assignments

An observer expecting
treatment group to show
signs of recovery is more
likely to document positive
outcomes

Shutterstock
Procedure
Bias
• One group receives procedure (e.g., surgery) and
another does not
• More care and attention given to procedure patients
• Avoided by blinding (masking)
• Care team unaware which patients had procedure
• Also avoided by using placebo
• Sometimes sham surgery performed

Public Domain
Stratified
Analysis
Eliminates Confounding Bias
Lung Cancer
-
Alcohol Use
+
+ 50 50

10 90
-

RR = 5

Smokers Non-Smokers
Lung Cancer Lung Cancer
- -
Alcohol Use

Alcohol Use
+ +
+ 15 35 + 15 35

15 35 15 35
- -

RR = 1 RR = 1
Controlling for
Confounders
• Randomization
• Ensures equal variables in both arms
• Matching
• Case-control studies
• Careful selection of control subjects
• Goal is to match case subjects as closely as
possible
• Choose patients with same age, gender, etc.
Ways to Reduce
Bias
• Randomization - limits confounding and selection
bias
• Matching of groups
• Blinding
• Crossover studies

Public Domain
Crossover
• Subjects randomly assigned to a sequence of treatments
Study
• Group A: placebo 8 weeks –> drug 8 weeks
• Group B: drug 8 weeks –> placebo 8 weeks
• Subjects serve as their own control
• Avoids confounding (same subject!)
• Drawback is that effect can “carry over”, so for exalmpl3 alfter you stop
the drug the effects can carry over into the placebo period so to avoid
studies have a “wash out” period
Crossover
Study
Placebo Drug
Washout
Period
Group 1

Group 2
Washout
Period
Drug Placebo
 Effect
• Not a type of bias (point of confusion)
• Occurs when thirdModification
factor alters the effect
of clinical study
• Consider:
• Drug A is shown to increase risk of DVT
• To cause DVT, Drug A requires Gene X to be
present
• Gene X is an effect modifier

Effect modification results when an external variable positively or negatively impacts the

observed effect of a risk factor on disease status.  When analysis is performed based on
stratification by this external variable, there will be a significant difference in risk between
the stratified groups.  For instance, aspirin use is associated with Reye syndrome in children
but not adults; therefore, age modifies the effect of aspirin on Reye syndrome development. 
Effect modification can easily be confused with confounding; but stratified analysis can help
distinguish between them.  With confounding, there is usually no significant difference
between the strata (as in this case with the smoker and non-smoker strata).
 Effect
Modification
Stratified Analysis DVT
+ -

Drug A
+ 50 50

10 90
-
RR = 5

Gene X (+) Gene X (-)

DVT DVT
+ - + -
Drug A

Drug A
+ 25 25 + 15 35

5 45 15 35
- -

RR = 5 RR = 1

So in contrast to cofounding where the relative risk was the same in both groups in a
stratified análisis, in a effect modification scenario the relative risk will persis but only in one
group and that tells you that that subgroup contains an effect modifier for the drug you are
studying
Confounding vs. Effect
Modification
• Confounding:
• A 3rd variable distorts the effect on outcome
• Smoking and alcohol
• Alcohol appears associated with cancer (positive)
• Real effect of exposure on outcome distorted by
confounder- of smoking
• Effect modification:
• A 3rd variable maintains effect but only in one group
• There is a real effect of exposure on outcome
• But that effect requires presence of 3rd variable-that third
variable is called an effect modifier
Confounding vs. Effect
Example
Modification
• Patients taking drug A have increased rates of lung
cancer
• Drug A is taken mostly by smokers
• Breakdown data into smokers and non-smokers:
• NO relationship between Drug A and cancer
• Smoking is the real cause
• Drug A has no effect
• This is confounding
Confounding vs. Effect
Example
Modification
• Patients taking drug A have increased rates of lung
cancer
• Drug A activates gene X to cause cancer
• Breakdown data into gene X (+) and (-)
• Relationship exists between Drug A and cancer but only in gene X
(+)
• Drug A does have effect (different from confounding)
• But drug A requires another factor (gene X)
• This is effect modification (not a form of bias)
Pygmalion vs.
Hawthorne
• Pygmalion effect
• Provider believes in treatment
• Influences results to be positive
• Pygmalion unique to investigator driving positive
benefit
• Hawthorne Effect
• Subjects/investigators behave differently because of study