Risk: From Disease to

Exposure
• Cohort studies are a wonderfully logical and direct way of studying risk,
but they have practical limitations. Most chronic diseases take a long time
to develop. The latency period, the period of time between exposure to a
risk factor and the expression of its pathologic effects, is measured in
decades for most chronic diseases. For example, smoking precedes
coronary disease, lung cancer, and chronic bronchitis by 20 years or more,
and osteoporosis with fractures occurs in the elderly because of diet and
exercise patterns throughout life. Also, relatively few people in a cohort
develop the outcome of interest, even though it is necessary to measure
exposure in, and to follow-up, all members of the cohort. The result is
that cohort studies of risk require a lot of time and effort, not to mention
money, to get an answer. The inefficiency is especially limiting for very
rare diseases
• This chapter describes another way of studying the relationship between a
potential risk (or protective) factor and disease more efficiently: case
control studies. This approach has two main advantages over cohort
studies. First, it bypasses the need to collect data on a large number of
people, most of whom do not get the disease and so contribute little to the
results. Second, it is faster because it is not necessary to wait from
measurement of exposure until effects occur.
• But efficiency and timeliness come at a cost: Managing bias is a more
difficult and sometimes uncertain task in case-control studies. In addition,
these studies produce only an estimate of relative risk and no direct
information on other measures of effect such as absolute risk, attributable
risk, and population risks.
• A case-control study is designed to help determine if an exposure is
associated with an outcome (i.e., disease or condition of interest). In
theory, the case-control study can be described simply.
• First, identify the cases (a group known to have the outcome) and the
controls (a group known to be free of the outcome). Then, look back
in time to learn which subjects in each group had the exposure(s),
comparing the frequency of the exposure in the case group to the
control group.
The validity of case-control studies depends on the care with which
cases and controls are selected, how well exposure is measured, and
how completely potentially confounding variables are controlled.
Selecting Cases

• The cases in case-control research should be new (incident) cases, not

existing (prevalent) ones.
• At best, a case-control study should include all the cases or a representative
sample of all cases that arise in a defined population.
• Some case-control studies, especially older ones, have identified cases in
hospitals and referral centers where uncommon diseases are most likely to
be found. This way of choosing cases is convenient, but it raises validity
problems.
• However the cases might be identified, it should be possible for both them
and controls to be exposed to the risk factor and to experience the outcome.
For example, in a case-control study of exercise and sudden death, cases and
control would have to be equally able to exercise (if they chose to) to be
eligible.
• Selecting Controls

• Above all, the validity of case-control studies depends on the

comparability of cases and controls. To be comparable, cases and
controls should be members of the same base population and have an
equal opportunity of being exposed.
• The best approach to meeting these requirements is to ensure that
controls are a random sample of all non-cases in the same population or
cohort that produced the cases.
The Population Approach
• Studies in which cases and controls are a complete or random sample
of a defined population are called population-based case-control
studies. In practice, most of these populations are dynamic—that is,
continually changing, with people moving in and out of the
population.
•The Cohort Approach
• Another way of ensuring that cases and controls are comparable is to
draw them from the same cohort. In this situation, the study is said to
be a nested case control study (it is “nested” in the cohort).
• With nested case-control studies, there is an opportunity to obtain
both a crude measures of incidence from a cohort analysis and a
strong estimate of relative risk, that takes into account a rich set of
direct interest, from a case-control analysis
Measuring Exposure
• The validity of case-control studies also depends on avoiding
misclassification when measuring exposure. The safest approach is to
depend on complete, accurate records that were collected before disease
developed.
• Examples include pharmacy records for studies of prescription drug risks,
surgical records for studies of surgical complications, and stored blood
specimens for studies of risk related to biomolecular abnormalities. With
such records, knowledge of disease status cannot bias reporting of
exposure.
• However, many important exposures can only be measured by asking cases
and controls or their proxies about them. Among these are exercise, diet,
and overthe-counter and recreational drug use.
• When cases and controls are asked to recall their previous exposures, bias
can occur for several reasons. Cases, knowing they have the disease under
study, may be more likely to remember whether they were exposed, a
problem called recall bias.
THE ODDS RATIO: AN ESTIMATE
OF RELATIVE RISK

It shows the dichotomous classification of exposure and disease typical

of both cohort and casecontrol studies and compares how risk is
calculated differently for the two. These concepts are illustrated with
the different studies, which have or had both a cohort and a case-
control component.
The odds ratio is defined as
the odds that a case is exposed divided by the odds
that a control is exposed
Case-Control Study
• Cases (people with illness) and controls (people with no illness)
• Compare foods eaten by cases and controls
• Foods more commonly eaten by cases than controls might be
associated with illness

Ate food
Cases
Did not eat food
Population
at risk
Ate food
Controls
Did not eat food

> Case-control studies

• In a case-control study, subjects are enrolled based on whether they
have (or had) the disease associated with the outbreak or not. (In
these studies, persons with the disease of interest are called “cases”
or “case-patients” and persons without the disease are called
“controls”).
• Prior exposures, such as eating a particular food item, are compared
between cases and controls to see if there is a relationship between
the disease and the exposure.
• (Notice how this differs from cohort studies. In a cohort study we
look at people who ate a food or did not eat a food and determine if
they became ill or not. With a case-control study, we look at people
who were ill or not and look back to see if they ate the food or not.)
• Two sisters and their mother from Vancouver, British Columbia,
developed signs and symptoms suggestive of botulism. After
these cases were publicized, 34 additional cases of botulism
were identified in the area. All case-patients had eaten at a
single, family-styled restaurant.
• A case-control study was undertaken to determine the source of
the outbreak at the restaurant. Cases were persons who had
eaten at the Vancouver restaurant who had neurologic signs and
symptoms suggestive of botulism. Controls were persons who
ate at the restaurant with case-patients but developed no
gastrointestinal or neurologic symptoms in the following 2 weeks.
Twenty-two case-patients and 22 controls were interviewed. It
was determined that 20 (91%) of 22 case-patients but only 3
(14%) of 22 controls ate a beef dip sandwich at the restaurant.
Outbreak of Botulism in Vancouver, B.C.
• 36 cases of botulism among patrons of Restaurant X
• Case-control study undertaken
• 20 (91%) of 22 cases ate beef dip sandwich
• 3 (14%) of 22 controls ate beef dip sandwich

> Case-control studies

Odds Ratio (OR)
• Measure of association for a case-control study
• Compares odds of cases having eaten a certain
food to odds of controls having eaten the food

odds of eating food among cases

odds ratio =
odds of eating food among controls

• Answers the question “How much higher is the

odds of eating the food among cases than
controls?”

> Case-control studies

Odds Ratio (Optional) 
Case Control
Ate food a b (two-by-two
Did not eat food c d table)
TOTAL a+c b+d

a/c
odds ratio = odds of eating food (cases) =
odds of eating food (controls) b/d

axd
odds ratio = (cross product)
bxc

> Case-control studies

Odds Ratio
• Close to 1.0 = odds of eating food is similar among
cases and controls  no association between food
and illness
• Greater than 1.0 = odds of eating food among cases is
higher than among controls  food could be risk
factor
• Less than 1.0 = odds of eating food among cases is
lower than among controls  food could be
“protective factor”
• Magnitude reflects strength of association between
illness and eating the food.

> Case-control studies

What is our Odds Ratio
for our Outbreak of
Botulism in Vancouver?
Outbreak of Botulism in Vancouver
Returning to the outbreak of botulism:
• 20 of 22 cases ate beef dip sandwich (2 didn’t)
• 3 of 22 controls ate beef dip sandwich (19 didn’t)

odds of eating food (cases) 20/2

odds ratio = =
odds of eating food (controls) 3/19
odds ratio = 63

> Case-control studies

• An odds ratio of 63 means that the odds that cases ate the
beef dip sandwich was 63 times higher than the odds
among controls. Eating the beef dip sandwich might be a
risk factor for botulism in this outbreak.
• Cyclosporiasis is a parasitic disease caused by the microorganism
Cyclospora cayetanensis. Cyclospora infects the small bowel and
usually causes watery diarrhea, bloating, increased gas, stomach
cramps, nausea, loss of appetite, and profound weight loss.
Cyclosporiasis is transmitted in food or water.
• In 1996, a number of outbreaks of cyclosporiasis were occurring
across the United States. In late June, the New Jersey Department
of Health and Senior Services (NJDHSS) undertook a case-control
study to examine an association between cyclosporiasis and eating
raspberries. The cases did not come from one particular setting or
event but were spread across the state. (Sporadic is the term often
used to describe cases that do not appear to be related to a
particular event or exposure.)
• In the case-control study, 21 (70%) of 30 cases reported eating
raspberries in the week before onset of illness whereas 4 (7%) of 60
controls ate raspberries.
•What is the odds ratio for the outbreak
•What does this odds ratio mean?
 
Class Question
• Outbreak of cyclosporiasis in New Jersey not
associated with particular event/establishment
• Case-control study undertaken
– 21 (70%) of 30 cases ate raspberries
– 4 (7%) of 60 controls ate raspberries

> Case-control studies