CEE-154/NUTR-204: Fall 2012

Confounding and effect modification

Confounding and Effect Modification

Confounding in an epidemiologic study occurs when an association between an exposure and an outcome is wholly or in part caused by a variable that is both an independent risk factor for the outcome AND is associated with the exposure under study. Note that unless BOTH of these conditions are met, confounding cannot occur.

The confounding triangle in schematic form

Double-headed solid arrow shows a known positive or negative association (NOT necessarily a causal one).

This is the confounding variable

Solid, single-headed arrow shows the confounding variable is an independent risk factor (positive or negative) for the outcome.

This is the exposure of interest

This arrow is dashed because it represents the study question.

This is the outcome of interest

Confounding example
The study question is: Does total cholesterol cause MI? Obesity is a known independent risk factor for MI. Obesity is also associated (positively) with total cholesterol. If not controlled for, obesity may confound any study seeking to answer the above study question.

Is confounding likely, yes or no?

Occupation Lung disease

Smoking

Case A Case B

Smoking

Lung disease

Occupation

Is confounding likely, yes or no?

High-fat dietary pattern Colon cancer Pre-cancerous colon polyps

Case C Case D

Smoking

Lung disease Alcohol consumption pattern

Answers
Case A is likely to be true confounding as smoking is both an independent risk factor for lung disease and is associated with occupational exposure. Case B is also likely to be true confounding as occupation is associated with smoking rates and is also an independent risk factor for lung disease.

continued
High-fat dietary pattern Pre-cancerous colon polyps Colon cancer

This is Case C rearranged. It is most likely that high-fat dietary pattern Pre-cancerous polyps Colon cancer form a causal chain (or causal pathway) in the form of A causes B causes C. In such a situation, you dont want to control for the intermediate variable (or variables) because then the effect of A on C will be lost (or at least attenuated). Case D is not confounding because alcohol consumption pattern is not causally related to lung disease. Note that if we reversed the smoking and alcohol boxes (a different research question), we would have a strong confounding example.

Certain variables are frequently important confounders. Below are some major ones:
Age. This is a powerful potential confounder. There is almost no disease that does not dramatically increase in incidence as age increases. Even diseases that do not are usually associated with a particular age group. For example, testicular cancer (18-34) or multiple sclerosis (20-40). Additionally, as is required to be a confounder, age is associated with many exposures (in intensity and/or duration if not absolutely). Thus, age must always be taken into account, either in the design or analysis phase of any study.

Sex
The biologic differences between males and females are great enough that some control must be used to prevent confounding in any study that includes both sexes. Most researchers have decided that it is not just the known, but the unknown differences that make controlling for confounding by sex so difficult. Therefore, the majority of epidemiologic studies are now either all male or all female or have enough of both to examine each separately.

Race
After decades of studies, scientists now know that some disease processes differ between the worlds races. Some perceived differences have been convincingly shown to be due to causes other than race per se, but many true variations have also been demonstrated. Therefore, in studies that include more than one race, possible confounding must be taken into account.

Smoking
No real issue here. Smoking is a proven cause of several diseases and, often for unknown reasons, it is also strongly associated with certain important exposures (eg., the heavy alcohol use example above). Finally, for many of the diseases that it is causally related to, smoking has a large relative risk, so studies that include smokers must carefully control for this in the analysis phase to avoid potentially severe confounding.

Socioeconomic status (SES)

People with little income or political power are often more vulnerable to exposures (e.g., traffic congestion, hazardous waste sites, smoking, and less access to medical care) and more likely to get a disease. Thus, SES is often a confounder in studies that do nothing to control for differing levels of wealth. As a recent head of the National Cancer Institute said bluntly: Poverty is a carcinogen.

Be careful.
It must be emphasized that while the previous five examples tend to be strong confounding variables in most studies (if not controlled for), anything can be a strong confounding variable in a given study.

Effect Modification
Effect modification, also called interaction, is a finding, often confused with confounding, that can be very informative. It occurs when individuals with a certain characteristic exhibit a differential response to an exposure.

Example of examining data for confounding and effect modification

An investigation of moderate aerobic exercise done five times per week and the occurrence of coronary heart disease over five years in a cohort study of 5,333 participants who were between 45 and 56 at the studys start revealed the following data:

Table 1: Crude (or unadjusted) table:

CHD Exercise Yes No Total RR Exercisers

Yes

25

2960

2985

0.71

No
Total

28
53

2320
5280

2348
5333 56%

A potential problem
Since both males and females were in the study, confounding by a persons sex had to be considered. The data in table 1 were stratified and the following 2x2 tables were presented:

Table 2: MALES
CHD Exercise Yes No Total Yes 17 18 35 No 1810 1150 2960 Total 1827 1168 61% RR 0.60 Exercisers

Table 3: FEMALES CHD Exercise Yes No Yes 8 10 No 1150 1170 Total 1158 1180 RR 0.81 Exercisers

Total

18

2320

2338

49.5%

So
These data show the crude 2x2 table was confounded by sex. In the unadjusted table, women make up a larger percentage of the non-exercisers since tables 2 and 3 show an 11.5% difference in exercising individuals (males > females). Thus, in this study, the first criterion for confounding is present: a persons sex is related to exposure since fewer women are exercisers. Table 3 shows that in a baseline comparison of non-exercising women versus non-exercising men, the women get far less of the outcome (notice, in fact, that non-exercising women have a rate of CHD that is less than exercising men). Thus, the second criterion for confounding is met, since sex is an independent risk factor for the outcome, that is, women simply get less of the outcome independent of their exercise status.

After stratifying by sex:

We see the true situation for males and females, without the confounding in table 1, however, something else becomes evident. For males, the protective effect of aerobic exercise done several times per week is about 40%; for females it is 20%. The effect on females is considerably weaker, and it suggests interaction is occurring. That is, while exercise is beneficial for both sexes, it is more protective against CHD for men than for women.

Note:
While an effect modifier can be a confounding variable, as in the above example, this need not be the case. A study examining liver cancer and exposure to a chemical encountered in the rubber industry found a strong positive odds ratio. Alcohol consumption (which, for the purposes of this lecture, can be defined as drinker or non-drinker), was distributed exactly the same between exposed and unexposed. Confounding by alcohol intake was impossible since there was no association between alcohol intake and the exposure (the double-headed arrow is missing). However, when the data were stratified on drinking status, a stronger odds ratio was observed for drinkers than for non-drinkers. These findings suggest alcohol is an effect modifier in these data.

Your turn: Diarrheal disease in infants

A study was done examining exposure to X and the prevalence of significant diarrheal illness in infants 1-4 months of age. A total of 1074 infants were assessed and the following table summarizes the data:
Diarrheal disease Yes No 160 303 136 475 296 778
Totals 463 611 1074

Exposed to X Unexposed to X Totals

Stratifying on breastfeeding status

Diarrheal disease Yes No 60 240 25 175 85 415 Diarrheal disease Yes No 100 63 111 300 211 363 Totals 300 200 500

Exposed to X Unexposed to X Totals

Exposed to X Unexposed to X Totals

Totals 163 411 574

Main question from examination

Colleagues show you these three tables in a hallway at CDC. They need you to quickly assess the role of breastfeeding in the relationship between X and diarrheal disease. Theyve heard you dont even need a calculator to do this for them. Impress them by determining, just by looking at the tables, whether breastfeeding is a confounding variable, an effect modifying variable, neither, or both in these data. Explain your reasoning in roughly a (short) paragraph.

Indentifying effect modification in the presence of two or more exposures

Suppose an individual is exposed to A (RR = 2.0) and B (RR = 3.0). What would we expect the joint effect of this dual exposure? Since RRs (or IRs and ORs) work on a multiplicative scale, the usual result of exposure to RR = 2.0 and RR = 3.0 is RR = 2.0 x 3.0 = 6.0.

Example
There is evidence that individuals exposed to moderate smoking (RR 2.5) and moderate high blood pressure (RR 2.5) incur an increased risk of CHD of about RR = 6.25. This is about what we would expect given the RR of each individual exposure.

Example
Individuals exposed to moderate smoking incur a risk ratio for lung cancer of about 10.0. Individuals exposed to moderate on-the-job asbestos incur an increased risk ratio for lung cancer of about 4.0. Individuals exposed to both moderate smoking and moderate asbestos incur a risk ratio for lung cancer of about 110.0 Inferences?