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Bias: A systematic error in the design, recruitment, data collection or analysis that
results in a mistaken estimation of the true effect of the exposure and the outcome.
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If the method used to select subjects or collect data results in an incorrect association, .
If an effect is real but the magnitude of the effect is different for different groups of
individuals (e.g., males vs females or blacks vs whites).
Bias limits validity (the ability to measure the truth within the study design) and
generalizability (the ability to confidently apply the results to a larger population) of study
results. Bias is rarely eliminated during analysis. There are two major types of bias:
Suppose you are selecting cases of rotator cuff tears (a shoulder injury). Many older
people have experienced this injury to some degree, but have never been treated for
it. Persons who are treated by a physician are far more likely to be diagnosed (and
identified as cases) than persons who are not treated by a physician. If a study only
recruits cases among patients receiving medical care, there will be selection bias.
Some investigators may identify cases predicated upon previous exposure. Suppose
a new outbreak is related to a particular exposure, for example, a particular pain
reliever. If a press release encourages people taking this pain reliever to report to a
clinic to be checked to determine if they are a case and these people then become
the cases for the study, a bias has been created in sample selection. Only those
taking the medication were assessed for the problem. Ascertaining a case based
upon previous exposure creates a bias that cannot be removed once the sample is
selected.
Exposure may affect the selection of controls e.g, hospitalized patients are more
likely to have been smokers than the general population. If controls are selected
among hospitalized patients, the relationship between an outcome and smoking may
be underestimated because of the increased prevalence of smoking in the control
population.
In a cohort study, people who share a similar characteristic may be lost to follow-up.
For example, people who are mobile are more likely to change their residence and
be lost to follow-up. If length of residence is related to the exposure, than our
sample is biased toward subjects with less exposure.
In a cross-sectional study, the sample may have been non-representative of the
general population. This leads to bias. For example, suppose the study population
includes multiple racial groups but members of one race participate less frequently in
the type of study. A bias results.
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Are we more likely to misclassify cases than controls? For example, if you interview cases
in-person for a long period of time, extracting exact information while the controls are
interviewed over the phone for a shorter period of time using standard questions, this can
lead to a differential misclassification of exposure status between controls amd cases.
Confounder: an extraneous variable that wholly or partially accounts for the observed
effect of a risk factor on disease status.. The presence of a confounder can lead to
inaccurate results.
Confounding masks the true effect of a risk factor on a disease or outcome due to the
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1. Knowledge
2. Prior experience with data
3. Three criteria for confounders
Example of Confounding
We survey patients as a part of the cross-sectional study asking whether they have
coronary heart disease and if they are diabetic. We generate a 2 2 table (below):
'0' indicates those who do not have coronary heart disease, '1' is for those with coronary
heart disease; similarly for diabetes, '0' is the absence and '1' the presence of diabetes.
The prevalence of coronary heart disease among people without diabetes is 91 divided by
2340, or 3.9% of all people with diabetes have coronary heart disease. Similarly the
prevalence among those with diabetes is 12.04%. Our prevalence ratio, considering
whether diabetes is a risk factor for coronary heart disease is 12.04 / 3.9 = 3.1. The
prevalence of coronary heart disease in people with diabetes is 3.1 times as great as it is
in people without diabetes.
We can also use the 2 x 2 table to calculate an odds ratio as shown above:
The odds of having diabetes among those with coronary heart disease is 3.38 times as
high as the odds of having diabetes among those who do not have coronary heart
disease.
Which of these do you use? They come up with slightly different estimates.
It depends upon your primary purpose. Is your purpose to compare prevalences? Or, do
you wish to address the odds of dibetes as related to coronary health status?
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First of all, prior knowledge tells us that hypertension is related to many heart related
diseases. Prior knowledge is an important first step but let's test this with data.
These data show that there is a positive relationship between hypertension and CHD in
non-diabetics. (note the small p-values)
2) This leads us to our next question, "Is diabetes (exposure) associated with
hypertension?"
Again, the results are highly significant! Therefore, our first two criteria have been met for
hypertension as a confounder in the relationship between diabetes and coronary heart
disease.
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Now we will use an extended Maentel Hanzel method to adjust for hypertension and
produce an adjusted odds ratio When we do so, the adjusted OR = 2.84.
The Mantel-Haenszel method takes into account the effect of the strata, presence or
absence of hypertension.
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Both estimates of the odds ratio are lower than the odds ratio based on the entire sample.
If you stratify a sample, without losing any data, wouldn't you expect to find the crude odds
ratio to be a weighted average of the stratified odds ratios?
This is an example of confounding - the stratified results are both on the same side of the
crude odds ratio.This is positive confounding because the unstratified estimate is biased
away from the null hypothesis. The null is 1.0. The true odds ratio, accounting for the
effect of hypertension, is 2.8 from the Maentel Hanzel test. The crude odds ratio of 3.38
was biased away from the null of 1.0. (In some studies you are looking for a positive
association; in others, a negative association, a protective effect; either way, differing from
the null of 1.0)
This is one way to demonstrate the presence of confounding. You may have a priori
knowledge of confounded effects, or you may examine the data and determine whether
confounding exists. Either way, when confounding is present, as in this example, the
adjusted odds ratio should be reported. In this example, we report the odds-ratio for the
association of diabetes with CHD = 2.84, adjusted for hypertension.
If you are analyzing data using multivariable logistic regression, a rule of thumb is if the
odds ratio changes by 10% or more, include the potential confounder in the multi-variable
model. The question is not so much the statistical significance, but the amount the
confounding variable changes the effect. If a variable changes the effect by 10% or more,
then we consider it a confounder and leave it in the model.
We will talk more about this later, but briefly here are some methods to control for a
confounding variable (known a priori):
Controlling potential confounding starts with good study design including anticipating
potential confounders.
Effect modification: occurs when the effect of a factor is different for different groups.
We see evidence of this when the crude estimate of the association (odds ratio, rate ratio,
risk ratio) is very close to a weighted average of group-specific estimates of the
association. Effect modification is similar to statistical interaction, but in epidemiology,
effect modification is related to the biology of disease, not just a data observation.
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In the previous example we saw both stratum-specific estimates of the odds ratio went to
one side of the crude odds ratio. With effect modification, we expect the crude odds ratio
to be between the estimates of the odds ratio for the stratum-specific estimates.
Effect modifier: variable that differentially (positively and negatively) modifies the
observed effect of a risk factor on disease status.
2) Breast Cancer occurs in both men and women. Breast cancer occurs in men at
approximately a rate of 1.5/100,000 men. Breast cancer occurs in women at
approximately a rate of 122.1/100,000 women. This is about an 800 fold difference. We
can build a statistical model that shows that gender interacts with other risk factors for
breast cancer, but why is this the case? Obviously, there are many biological reasons why
this interaction should be present. This is the part that we want to look at from an
epidemiological perspective. Consider whether the biology supports a statistical interaction
that you might observe.
If you do not identify and handle properly an effect modifier, you will get an incorrect crude
estimate.The (incorrect) crude estimator (e.g., RR, OR) is a weighted average of the
(correct) stratum-specific estimators. If you do not sort out the stratum-specific results, you
miss an opportunity to understand the biologic or psychosocial nature of the relationship
between risk factor and outcome.
so,
3. Present stratum-specific estimates. Use Breslow-Day Test for Homogeneity of the
odds ratios, from Extended Mantel-Haenszel method, or -2 log likelihood test from
logistic regression to test the statistical significance of potential effect modifiers and
to calculate the estimators of exposure-disease association according to the levels of
significant effect modifiers. Alternatively, if assumptions are met, use proportional
hazards regression to produce an adjusted hazards ratio.
When you combine men and women the crude odds ratio = 4.30.
Stratifying by gender, we can calculate different measures. Look at the odds ratios above.
The odds ratio for women is 6.66, compared to the crude odds ratio of 4.30. Therefore,
women are at much greater risk of diabetes leading to the incident coronary heart disease.
For men, the odds ratio is 2.23.
Is diabetes a risk for incident heart disease in men and in women? Yes. Is it the same
level of risk? No. For men the OR is 2.23, for women it is 6.66. The overall estimate is
closer to a weighted average of the two stratum specific estimates. Gender modifies the
effect of diabetes on incident heart disease. We can see that numerically because the
crude odds ratio is more representative of a weighted average of the two groups.
What is the most informative estimate of the risk of diabetes for heart disease? 4.30 is not
very informative of the true relationship. What is much more informative is to present the
stratum specific analysis.
During data analysis, major confounders and effect modifiers can be identified by
comparing stratified results to overall results.
With a Confounder:
the crude estimator (e.g. RR, OR) is outside the range of the two stratum-
specific estimators ( in the hypertension example - the crude odds ratio was
higher than both of the stratum specific ratios);
If the adjusted estimator is importantly (not necessarily statistically) different
(often 10%) from the crude estimator, the adjusted variable is a confounder.
In other words, if including the potential confounder changes the estimate of
the risk by 10% or more, we consider it important and leave it in the model.
Statistical methods (Extended Mantel-Haenszel method, multiple regression,
multiple logistic regression, proportional hazards) are available to calculate the
adjusted estimator, accounting for confounders.
With Effect modifiers:
the crude estimator (e.g. RR, OR) is closer to a weighted average of the
stratum-specific estimators;
the two stratum-specific estimators differ from each other
Report separate stratified models or report an interaction term.
To review, confounders mask a true effect and effect modifiers means that there is a
different effect for different groups.
You have reached the end of the reading material for Week 3!!! Go to the Week 3
activities in ANGEL.
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