Matching & Confounding Analysis

Confounding, Matching, and
Related Analysis Issues
Kevin Schwartzman MD
Lecture 8a
June 22, 2005
Confounding, Matching & Related Analysis Issues
Readings
Fletcher, chapter 1
Hennekens and Buring, Epidemiology in Medicine, 1987:

Chapter 12, Analysis of Epidemiologic Studies:
Evaluating the Role of Confounding [course pack]
Confounding, Matching & Related Analysis Issues - Slide 1
Objectives
Students will be able to:
1. Define confounding
2. Explain what must be true of a confounding variable
3. Describe design strategies for control of confounding

a. Restriction
b. Randomization, including stratified design
c. Matching, including different matching schemes

Objectives
4. Describe analytic strategies for control of confounding

a. Stratified analyses
b. Standardization
c. Calculation of pooled effect estimates:

the example of the Mantel-Haenszel odds ratio
d. The special case of
matched pair case-control studies
e. Multivariate analyses
5. Identify advantages and disadvantages of matching
6. Define and identify effect modification

Confounding
Refers to
distortion of the true underlying relationship
(or lack thereof)
between an exposure and an outcome of interest,
because of the influence of a third factor
(a confounder or a confounding variable)
At the design phase,

confounding is potential;
its true presence or absence is assessed
through appropriate data analyses
Confounding Variables
A variable is said to be a confounder if:

- it is associated with the exposure of interest
- it is an independent risk factor for
the outcome of interest
- it is not an intermediate along the causal pathway
from exposure to outcome
Exposure
Confounder
Outcome
Case-Control Study
Coffee No Coffee
Lung cancer 260 80
No lung cancer 190 150
Odds ratio = (260 x 150) / (80 x 190) = 2.6

Case-Control Study
Smokers Non-Smokers
No No
Coffee Coffee
Coffee Coffee
Lung Lung
250 50 10 30
Cancer Cancer
No No
Lung 150 30 Lung 40 120
Cancer Cancer
OR = (250 x 30)/(50 x 150) = 1 OR = (10 x 120)/(30 x 40) = 1

Smoking as Confounder
Smoking was associated with coffee drinking

- 400/450 coffee drinkers were smokers,
vs 80/230 non-coffee drinkers
Smoking is an independent risk factor

for lung cancer
- here, OR = (300 x 160)/(40 x 180) = 6.7
By separating the group into

smokers and non-smokers, and
examining the relationship between
coffee and lung cancer within each subgroup,
confounding by smoking was eliminated
Smoking as Confounder
There was no independent association of

coffee drinking with lung cancer
(odds ratio within both smoking subgroups
or strata was 1)
The apparent relationship was due entirely

to confounding by smoking
Confounding can also reduce, eliminate,

exaggerate, or even change the direction
of true underlying associations
The presence of confounding can be assessed

by comparing crude and adjusted effect estimates
(some investigators use 10% rule of thumb)
Design Strategies to Control Confounding
First of all, any potential confounder must be

measured appropriately
Simplest strategy (in terms of design) is restriction,

to eliminate variation in potential confounder
If there is no variation in the potential confounder,

it cannot influence the outcome
Example: restriction of the lung cancer-coffee study

to smokers only
However, in this particular case,

there could still be residual variation in smoking
which could influence outcome
Randomization
Goal is to distribute potential confounders

equally between study groups
Again, if there is no variation

in a potential confounder,
it cannot be responsible for
differences in outcome
Smaller sample sizes may lead to

imbalance between groups with respect
to potential confounders, simply by chance
Randomization
Stratified randomization (often combined with

blocked randomization): promotes equal distribution
of treatment groups across strata of variable(s)
of interest e.g. gender, age, study centre
Number of strata limited by logistical constraints
All reports of randomized studies include a table

for assessing the adequacy of randomization
As soon as analysis is limited to subgroups,

the control of confounding disappears
e.g. compliance bias (healthy behaviours etc.)
Matching
Matching is an element of observational study design,

introduced to help control potential confounders
it involves selection of a comparison group that is

forced to resemble the index group with respect to
the distribution of one or more potential confounders
in case-control studies selection of control group

(matched to cases with respect to potential
confounders)
in cohort studies selection of unexposed group

(matched to exposed with respect to potential
confounders)
Subjects can be matched

for continuous covariates (e.g. age) or
categorical covariates (e.g. sex, HIV serology, etc.)
Matching may be done at the level of the individual

or of the group
In a case-control study, individual matching means

that each case is separately matched to
one or more control(s) according to
the matching factor(s)
Matching or variable ratio may be fixed

(e.g. 1 case:1 control, 1:2, etc.)
We will primarily discuss matching

in case-control studies
For categorical covariates,

individual matching means that for each case,
the control subject(s) is/are drawn from the
same category, e.g. male controls for male subjects
Continuous covariates may also be categorized,

e.g. age divided into categorical ranges:
20-39, 40-59, 60-79, etc.
Continuous variables may be matched by
a) Caliper matching:
a rule by which
values are considered sufficiently close
Matching done on sex plus age within 3 years

Potential controls:
men aged 28, 35, 39, 49, 57
women aged 31, 34, 43
Case 1: 31 y.o. male matched to 28 y.o. male

Case 2: 38 y.o. female no match found
case discarded
or additional controls identified
Continuous variables may be matched by
b) Nearest available matching

- controls are selected based on
the closest value of the matching factor
In above example,
the match for the 38 y.o. female case
would be a 34 y.o. female control
Advantage:
less restrictive, more efficient
Disadvantage:
Subjects may be less well matched if
the distribution of the matching variable is
quite different between cases and controls
Example:
cases of a disease which affects primarily elderly persons
Controls drawn from the general population with

matching based on nearest age may be
considerably younger, on average, depending on
the number of potential controls identified.
- the same may occur when continuous variables

are categorized into wide ranges
- the impact of the study will depend on the

nature of the relationship between the matching factor,
the exposure, and the outcome of interest
Group level matching
Cases are stratified according to the

matching factor, and then
controls are selected to match
the grouping of cases
a) Stratified sampling:
The levels of the covariate in which
sampling occurs are defined.
Then preset numbers of cases and controls
are drawn from each stratum, with
a consistent matching ratio
Example of stratified sampling:

Case-control study examining coffee intake and lung cancer
Coffee
Stratum Yes No Total
Current smokers Lung cancer 100

No cancer 200
Former smokers Lung cancer 100 preset
No cancer 200
Never smokers Lung cancer 200
No cancer 400
Note that within each stratum,

There are 2 controls fo every lung cancer case
b) Frequency matching
There is also a constant proportion of

controls to cases,
but the distribution of cases is not fixed
according to the matching factor.
However, controls are forced to have the

same distribution of the matching factor
as do the cases.
The distribution of the matching factors is

therefore representative of that among
the population that gave rise to cases.
Example of frequency matching: Coffee intake and lung cancer
Coffee
Stratum Yes No Total
Current smokers Lung cancer 140

No cancer 280 not
Former smokers Lung cancer 220 preset
No cancer 440
Never smokers Lung cancer 40
No cancer 80
- here the number of cases in each smoking stratum

reflects the distribution of smoking behaviour
among lung cancer cases
- the matching ratio is 2 controls per case throughout
Analysis of case-control studies with matching:
- Always requires stratification by

the matching factor (or the multivariate equivalent
- conditional logistic regression).
- The crude odds ratio will be biased toward

the null value.
- This is because matching forces the cases

and controls to be more alike
with respect to the exposure of interest
than would ordinarily be the case.
Hypothetical example:
Obesity
Yes No Total
Smokers Heart disease 480 20 | 500
No heart disease 420 80 | 500
_________________________________
Total 900 100 | 1000
_________________________________
OR = 4.6
Obesity
Yes No Total
Non-smokers Heart disease 8 42 | 50
_________________________________
Totals 10 90 | 100
_________________________________
OR = 4.6
Crude analysis of same data

Obesity
Yes No Total
Heart disease 488 62 | 550
____________________
Totals 910 190 | 1100
OR crude = 2.4
Despite matching, the underlying association between

smoking (confounder) and obesity (exposure) remains:
smokers were much more likely than non-smokers
to be obese.
However, matching on smoking behaviour made cases

and controls more similar with respect to obesity, thereby
leading to underestimation of the odds ratio.
Stratified analysis corrects this problem.

Matching in cohort studies -

does not lead to inappropriate crude risk/rate ratio estimates
e.g. cohort study of obesity and heart disease
Obesity
Yes No Total
Smokers Heart disease 460 100
No heart disease 540 900
_______________________________________
Total 1000 1000 2000
_______________________________________
RR = 4.6
Obesity
Yes No Total
Non-smokers Heart disease 46 10
No heart disease 954 990
_______________________________________
Total 1000 1000 2000
_______________________________________
RR = 4.6
Crude analysis
Coffee
Yes No Totals
Smokers Lung cancer 506 110 | 616
No cancer 1494 1890 | 3384
___________________________________
Totals 2000 2000 | 4000
RR = 4.6
Here the crude RR is the same as within the individual strata.
This is because matching eliminates

the association between smoking (confounder)
and coffee drinking (the exposure studied).
Stratified Analysis
If effect estimates are identical across strata,

then it is easy to report a single summary estimate
(e.g. odds ratio)
More often, they are not precisely identical, which

may reflect random error/imprecision
(e.g. small strata), residual confounding, or
truly different effects (effect modification)
Effect modification will be described separately

Combining Effects from Strata
Can take some type of weighted average
One approach is to use weights which reflect the distribution

of the stratification variable in the population of interest
For example, age-specific risk ratios could be combined

using a weighted average that accounts for
the age distribution of the general population
This is an example of standardization: the effect

is adjusted to reflect a standard age distribution
This does not assume that the effects are homogeneous
The most heavily weighted strata may not have

much information
Mantel-Haenszel Odds Ratio
An odds ratio that reflects pooling of effects across strata,

to summarize the overall association between
exposure and outcome, while adjusting for the
effect of the confounder of concern
Pooling assumes that the effect is homogeneous, and

variation reflects random error
Is a weighted average of odds ratio estimates across strata
Weights reflect quantity of information in each stratum,

expressed as bc/T where b and c are exposed controls and
unexposed cases within the stratum, and T is total subjects
within the stratum
Note this differs from standardization using external weights

Mantel-Haenszel Odds Ratio
OR MH = [(bc/T) x ad/bc] = (ad/T)

__________________ _________
(bc/T) (bc/T)
For the case-control study of obesity and heart disease,

this would be:
(480 x 80)/1000 + (8 x 48)/100

__________________________
(20 x 420)/1000 + (42 x 2)/100
= (38.4 + 3.84)/(8.4 + 0.84) = 4.6

Analysis of matched pair data in case control studies
can be thought of as a
special case of stratified analysis
each matched pair constitutes a single stratum

with 2 subjects
only informative strata are those where

exposure status of case and control are discordant
Recall Mantel-Haenszel OR estimates
OR MH = ( ad/T)
_______
( bc/T)
Concordant strata: E + E-
D+ 1 0
D- 1 0
or E + E-
D+ 0 1
D- 0 1
ad = 0, bc = 0
The pairs can be grouped as follows:
Case
Control Exposed Unexposed
Exposed r s
Unexposed t u
Then OR MH = t/s
i.e. N(case exposed, control unexposed)

_____________________________
N(case unexposed, control exposed)
where N refers to number of pairs

Example:
Marrie et al conducted a study evaluating the

relationship between certain infections (the exposure)
and the subsequent development of multiple sclerosis
(the outcome). Data was taken from a general practice
database.
Cases and controls were matched on age ( 2 years),

sex, physician practice, and date seen.
Imagine a 1:1 design (in fact it was 1:4, on average).

Hypothetical data
MS (cases)
No MS (controls) Infection No infection
Infection 30 5
No infection 20 170
OR = 20/5 = 4
Suppose the key confounder is physician practice
- the physicians most likely to see and diagnose infections

may also be those most likely to pursue and establish
the diagnosis of multiple sclerosis
Unmatched analysis
MS No MS
Infection 50 35
No infection 175 190
Crude OR = (190x50) / (175x35) = 1.6
As before, the unstratified analysis yields an OR estimate

biased toward the null.
As before, this is because the matching forces the controls

to resemble the cases with respect to the
distribution of exposure in the crude analysis.
Multivariate Analysis
Has become the standard approach for identifying

and accounting for confounding
Complex process: computer essentially solves

multiple equations to identify best guess effect estimate
while holding other covariates constant, e.g. effect of obesity
while holding smoking behaviour, sex, diabetes constant
Mathematically breaks the data down into numerous strata
Examples:
logistic regression for binary outcome data (very frequent),
Cox proportional hazards modelling for incidence data,
Poisson model for count data
Rationale for Matching
Matching can be considered a form of partial restriction:

the controls are restricted so as to resemble the cases
with respect to some factor(s).
The main purpose of matching is to improve statistical efficiency

(precision).
In principle, stratified analysis alone (including multivariate

techniques) should be sufficient to deal with the confounder
in question.
However, matching may be needed to ensure that

all strata are sufficiently informative.
Example:
An investigator wishes to investigate a possible

association between use of calcium channel blockers
(drugs used for blood pressure and heart disease)
and Alzheimers disease.
Age is obviously a key confounder:

increasing age is associated with use of the drugs
in question and with the onset of Alzheimers disease
Unmatched controls drawn from the general population

will be younger and hence
less likely to be using calcium channel blockers,
leading the crude analysis to overestimate any
potential association
This can be handled through stratified analysis by age

(e.g. various age categories)
If unmatched general population controls are used,

there may be few controls in the oldest age strata,
leading to imprecise OR estimates in those strata
(wide confidence intervals)
Matching ensures sufficient numbers of subjects for

each level of the matching variable(s) - in this case, age
Matched cohort studies are also more efficiently analyzed

using stratification by the matching factor(s)
Advantages of matching
1. Promotes efficiency, as discussed above.

Studies are most efficient when the
the ratio of index to referent subjects
(e.g. cases:controls) is constant
across the different strata of a confounder.
2. Very useful in situations where

the confounder is difficult to quantify or control,
making stratification impossible.
Classic example: using sibling controls.

Disadvantages of matching
1. Practical - may be cumbersome, expensive,

time consuming.
Depending on the circumstances,
index subjects may be dropped if no matching referent
subjects are found loss of data.
Also very onerous when many matching factors are used.
2. The effect of the matching factor on

the outcome of interest cannot be evaluated.
3. Potential for overmatching.

Overmatching
Refers in general to situations where matching

interferes with the logistics, statistical efficiency, or
scientific validity of a study.
1. Overmatching as a cause of logistical inefficiency
matching on many factors, or on factors

that are difficult to match, adds to
the expense and difficulty of study conduct
difficulty with matching may lead to

loss of cases as well as of potential controls
(in case-control studies)
2. Overmatching as a cause of reduced statistical efficiency
occurs when matching factor is not a true confounder,

e.g. associated with exposure but not with outcome
simplest example is with matched pair

case-control design
if cases and controls made more similar with

respect to exposure frequency, then there will be
many uninformative pairs
these do not contribute to the odds ratio estimate

and are essentially wasted
conversely with fewer discordant pairs, the

precision of the odds ratio estimate is reduced
the same holds true for other matching ratios

With weak confounders (e.g. limited effect on outcome)

the loss of statistical efficiency may
outweigh any apparent benefits of matching
Recall that stratified analysis and multivariate techniques

will still account for potential confounders in
the absence of matching
3. Overmatching as a cause of biased effect estimates
Occurs when matching factor is:
a) produced by exposure and related to disease

(e.g. an intermediate in pathway)
or
b) produced by disease and related to exposure

Effect Modification
Effect modification refers to the situation

where the biologic effect of exposure on outcome
differs according to some additional factor,
e.g. different influence of smoking on development
of COPD in men and women
Also known as interaction
In stratified analysis, will see different

exposure-outcome relationships within different strata,
e.g. different odds ratios, rate ratios, etc.
In the absence of confounding, the overall effect estimate

will simply be an average of the stratum-specific estimates,
weighted by the size of the strata e.g. males and females
Effect modification is NOT the same as confounding

- It refers to biologic variation in an effect,
not artefactual distortion of results because of
inadequate design or analysis
Effect modification should be noted and reported,

rather than controlled through design and
analysis strategies
Effect modification is relevant to randomized trials

as well as observational studies
Effect modification is only evident from stratified analysis,

with stratification by the factor(s) of interest
Analyses/effect estimates restricted to specific strata

(e.g. women, young adults) have less precision
and statistical power than the study as a whole
If investigators wish to detect and document effect

modification, they need to ensure the necessary
sample sizes

Matching & Confounding Analysis

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Matching & Confounding Analysis

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Confounding, Matching, and

Related Analysis Issues

Hennekens and Buring, Epidemiology in Medicine, 1987:

Students will be able to:

2. Explain what must be true of a confounding variable

3. Describe design strategies for control of confounding

b. Randomization, including stratified design

c. Matching, including different matching schemes

4. Describe analytic strategies for control of confounding

c. Calculation of pooled effect estimates:

5. Identify advantages and disadvantages of matching

6. Define and identify effect modification

At the design phase,

A variable is said to be a confounder if:

Lung cancer 260 80

No lung cancer 190 150

Odds ratio = (260 x 150) / (80 x 190) = 2.6

OR = (250 x 30)/(50 x 150) = 1 OR = (10 x 120)/(30 x 40) = 1

Smoking was associated with coffee drinking

Smoking is an independent risk factor

By separating the group into

There was no independent association of

The apparent relationship was due entirely

Confounding can also reduce, eliminate,

The presence of confounding can be assessed

Design Strategies to Control Confounding

First of all, any potential confounder must be

Simplest strategy (in terms of design) is restriction,

If there is no variation in the potential confounder,

Example: restriction of the lung cancer-coffee study

However, in this particular case,

Goal is to distribute potential confounders

Again, if there is no variation

Smaller sample sizes may lead to

Stratified randomization (often combined with

Number of strata limited by logistical constraints

All reports of randomized studies include a table

As soon as analysis is limited to subgroups,

Matching is an element of observational study design,

it involves selection of a comparison group that is

in case-control studies selection of control group

in cohort studies selection of unexposed group

Subjects can be matched

Matching may be done at the level of the individual

In a case-control study, individual matching means

Matching or variable ratio may be fixed

We will primarily discuss matching

For categorical covariates,

Continuous covariates may also be categorized,

Continuous variables may be matched by

Matching done on sex plus age within 3 years

Case 1: 31 y.o. male matched to 28 y.o. male

Continuous variables may be matched by

b) Nearest available matching

Controls drawn from the general population with

- the same may occur when continuous variables

- the impact of the study will depend on the

Group level matching

Cases are stratified according to the

Example of stratified sampling:

Current smokers Lung cancer 100

Note that within each stratum,

There is also a constant proportion of