INTRODUCTION TO EPIDEMIOLOGY FOR GLOBAL HEALTH

Controlling for Confounding

Lecturer: Dr. Brandon Guthrie

We’re now going to talk a little about how we deal with confounding in epidemiology.

Remember that confounding occurs when we have another factor, or third variable, that may
be causing us to see an association between our exposure and our outcome that isn’t due to a
causal effect of the exposure on the outcome. Before we assess confounding, we need to be
sure that effect modification isn’t present. Effect modification is when the exposure-disease
relationship is different when looking within categories, or strata, of that third variable.

To determine whether effect modification is present, you can take a similar approach to what
we discussed in the confounding lecture to evaluate whether confounding is present. First, look
at the exposure-disease relationship within strata of that third factor. If effect modification is
present, the relationship between the exposure and disease will look different within categories
of that variable. If confounding is present, then the relationship between the exposure and
disease will be the same within categories of that variable.

Let’s consider an example of the risk of diarrheal disease among those in households with an
unimproved water source. When we look at the overall association between having an
unimproved water source and risk of diarrheal disease, we see that the relative risk is 3.6,
indicating those with an unimproved water source have 3.6-times the risk of diarrhea disease as
those with an improved water source. We are concerned that the observed overall association
may be confounded by whether or not the household is in an area that receives extreme levels
of rainfall versus less extreme rainfall.

First, let’s look at what we might expect to see if rainfall level is a confounder, but not an effect
modifier. In this hypothetical example, we see that when we stratify by the confounder, we
have the same relative risk within strata of our potential confounder, rainfall levels. These
stratified relative risks are meaningfully different from the overall relative risk, which indicates
that rainfall level is a confounder of the relationship between unimproved water source and the
risk of diarrheal disease.

Now let’s look at what we might see if rainfall level was an effect modifier of the relationship
between unimproved water source and risk of diarrheal disease. Now that when we stratify by
rainfall level, we see a that in areas with extreme rainfall, an unimproved water supply is
associated with a 6.8-fold higher risk of diarrheal disease. In contrast, in areas with less extreme

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rainfall, an unimproved water supply is associated with a much more modest 1.4-fold higher
risk of diarrheal disease. From this, we see that the association between an unimproved water
supply and diarrheal disease risk depends on the level of rainfall in the area. Therefore, rainfall
is an effect modifier of the association and it is inappropriate to calculate a single adjusted
relative risk.

When effect modification is present, report results stratified by that third factor, since this is a
true difference in the relationship between exposure and outcome, not a form of bias to be
controlled.

The first type of confounding control can be conducted at the design phase. One of the best
strategies here is to conduct a randomized trial. In the process of randomization, we remove
associations between exposure and potential confounders. This controls for both known and
unknown or unmeasurable confounders, which is why the strongest level of evidence for causal
inference comes from randomized trials. If randomization occurs correctly, then we can be
confident that all confounders, known and unknown, should be controlled through the process
of randomization.

However, confounding may still occur due to accidents of randomization. Particularly in

relatively small trials, it may be possible that important risk factors for the outcome may be
imbalanced between the randomization groups. This didn't happen due to any systematic bias
but it happened just by chance.

The best approach to reduce this risk is to have a sufficiently large sample size for the study and
potentially to use stratified randomization methods in which you randomize within the relevant
categories of known risk factors for disease. Finally, you can deal with imbalances in factors
following randomization in the same way that we would handle such imbalances in an
observational study. We'll cover that when we talk about confounding control at the analysis
step.

Another way to control confounding at the design stage is what's called restriction. When we
use restriction, we require all members of the study population to have the same status of
potential confounders. This is most useful when potential subjects have the same status for
these potential confounders. For example, if we're looking at breast cancer, we would probably
limit the study subjects to females. While males can develop breast cancer, the overwhelming
number of breast cancer cases are among females. And so the inclusion of males would actually
make it more difficult to investigate factors that we're interested in in terms of their relation to
breast cancer risk.

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Another example would be studies focused on birth outcomes or newborn health. If we are
looking at factors associated with birth outcomes, we might restrict our analysis to singleton
births, excluding the twin births which may have different relationships between the exposure
and disease and can result in confounding that's going to be difficult to control for at the
analysis step.

The advantages of restriction are that it enhances our ability to make statistical inferences free
of bias. However, it can reduce our generalizability. If we restrict a population in a way that it
does not apply to the larger population to which we would want to generalize a result, we're
going to have difficulty interpreting our study. It also eliminates our ability to assess effect
modification—that would be where we would have a different exposure disease relationship
based on some other factor that we’ve now restricted on. For example, if we had a different
relationship between our exposure of interest and breast cancer among males and females, we
would be unable to assess this effect modification if we restrict it only to females. Finally, it may
be difficult or expensive to find a sufficient number of subjects if we restrict it in a way that we
limit the number of people who would qualify for our study.

A third strategy to control confounding at the design stage is what's called matching. In a cohort
study, we could match each exposed subject to one or more non-exposed subjects based on
the potential confounders that we're concerned about. Similarly, in a case-control study, we
might match each case to one or more controls who have the same level of the potential
confounder. So, if we had a case who is a male and we believe that sex assigned at birth is a
confounding factor, we might match that case to one or more controls who are also male.
Another category for which matching is commonly used is to control for confounding by age. If
we're concerned that age is an important confounder, we may want to make sure that our
cases and controls are matched based on age.

Matching allows good control for a few well-known strong risk factors. It increases the
efficiency particularly of case-control studies. However, it precludes examining the matching
factors as risk factors for the outcome. Because here, we've determined ahead of time what the
relationship is between our matching factor and the case or control status in a case-control
study. We may also be concerned if there's differential loss to follow-up that results in
imbalance in the matching factors. In this case, the benefit of the matching will be lost if we
have differential follow-up. Matching can also create bias in case-control studies if your
matching factors are actually not related to the outcome that you're studying.

Confounding can also be controlled at the analysis phase. We've already discussed conducting
stratified analysis in which we conduct separate analysis based on categories of the
confounder. But we can also conduct what's called rate adjustment or standardization. I’ll
discuss this more in the next lecture.
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So, to summarize, I talked about two phases where we can control for confounding. In the
design phase, we can control for confounding through randomization if we are able to conduct
a randomized trial. The process of randomization can remove associations between exposure
and potential confounders. Or we could use restriction, in which all members of the study
population have the same status of potential confounders. Lastly, we could do matching, where
we match exposed and unexposed or cases and controls such that they have the same level of a
relevant potential confounder.

We can control confounders through the analysis phase as well, such as through stratified
analysis or rate adjustment.

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