Confounding and effect modification

Preben Aavitsland
 Can we believe the result?

Rice Salmonellosis

OR = 3.9
 Systematic error
Does not decrease with increasing sample
size

Selection bias
Information bias
Confounding
 Confunding - 1
Mixing of the effect of the exposure on
disease with the effect of another factor that is
associated with the exposure.

Exposure Disease

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

Surgeon Post op inf.

Op theatre I
 Criteria for a confounder
1 A confounder must be a cause of the disease (or a marker
for a cause)
2 A confounder must be associated with the exposure in the
source population
3 A confounder must not be affected by the exposure or the
disease

Umbrella Less tub.

2 1
3 Class
Downs syndrome by birth order
 Find confounders
Second, third and fourth child are more often
affected by Downs syndrome.

Many children Downs

Maternal
age
Downs syndrome by maternal age
Downs syndrome by birth order and
maternal 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 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
 Controlling confounding
In the design In the analysis
Restriction of the Restriction of the
study analysis
Matching Stratification
Multivariable
regression

Before data collection! After data collection!

 Restriction
Restriction of the study or the analysis to a
subgroup that is homogenous for the possible
confounder.
Always possible, but reduces the size of the study.

Umbrella Less tub.

Lower
Class
class
 Restriction
We study only mothers of a certain age

Many children Downs

35 year old
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
 Disadvantages of matching
Breaks the rule: Control group should be
representative of source population
Therefore: Special matched analysis needed
More complicated analysis
Cannot study whether matched factor has
a causal effect
More difficult to find controls
 Why match?
Random sample from source population
may not be possible
Quick and easy way to get controls
Matched on social factors: Friend controls,
family controls, neighbourhood controls
Matched on time: Density case-control studies
Can improve efficiency of study
Can control for confounding due to factors
that are difficult to measure
 Should we match?
Probably not, but may:

If there are many possible confounders

that you need to stratify for in 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 (ORmh) 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
Salmonella after wedding dinner
Disease seems to be associated with both chicken and rice
But many had both chicken and rice

Exposure Cases Controls Odds ratio 95% ci

Rice 37 / 50 21 / 50 3,9 (1,7 - 9,2)
Chicken 40 / 50 20 / 50 6,0 (2,8 - 12,7)
Cake 32 / 50 27 / 50 1,5 (0,7 - 3,4)
Juice 16 / 50 20 / 50 0,7 (0,3 - 1,6
 Confounding
Is rice a confounder for the chicken
salmonellosis association?
Stratify: Make one 2x2 table for rice-eaters
and one for non-rice-eaters (e.g. in Episheet)

Chicken Salmonellosis

Rice
 No confounding
Because:
OR for chicken alone = ORmh for
chicken controlled for rice
Exposure Cases Controls Odds ratio 95% ci
Rice-eaters: Chicken 36 / 37 18 / 21 6,0 (0,6 - 62)
Non-rice-eaters: Chicken 4 / 13 2 / 29 6,0 (0,9 - 38)
Chicken "controlled for rice" 40 / 50 20 / 50 6,0 (1,4 - 26)
 Confounding
Is chicken a confounder for the rice
salmonellosis association?
Stratify: Make one 2x2 table for chicken-eaters
and one for non-chicken-eaters (e.g. in
Episheet)
Rice Salmonellosis

Chicken
 Confounding
Because:
OR for rice alone = ORmh for rice
controlled for chicken

Exposure Cases Controls Odds ratio 95% ci

Chicken-eaters: rice 36 / 40 18 / 20 1,0 (0,17 - 1,0)
Non-chicken-eaters: rice 1 / 10 3 / 20 1,0 (0,09 - 11)
Rice "controlled for chicken" 37 / 50 21 / 50 1,0 (0,24 - 4,2)

Not 3,9
 Conclusion
Chicken is associated with salmonellosis
Rice is not associated with salmonellosis
confounding by chicken because many
chicken-eaters also had rice
rice only appeared to be associated with
salmonellosis
Stratification was needed to find
confounding
Compare crude OR to adjusted OR (OR mh)
If > 10-20% difference confounding!
 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!
 Controlling confounding
In the design In the analysis
Restriction of the Restriction of the
study analysis
Matching Stratification
Multivariable methods
 Effect modification
Definition: The association between
exposure and disease differ in strata of the
population
Example: Tetracycline discolours teeth in
children, but not in adults
Example: Measles vaccine protects in children
> 15 months, but not in children < 15 months
Rare occurence