Chapter 6

Wednesday, March 4, 2020 1:24 PM

Latency period: Period of time between exposure to a risk factor and the expression of its
pathologic effects

In the mid 2000s, clinicians began reporting cases of an unusual form of femoral fracture in
women. Bisphosphonates, drugs taken to prevent osteoporosis, were suspected because they
had been introduced in the decades before and act by reducing bone remodeling. Case series
reported an association between bisphosphonates and atypical fractures, but the women in
these studies took other drugs and had other diseases that could also have been related to the
risk of fractures. To provide a more definitive answer to whether bisphosphonates were
independently associated with atypical fractures, investigators in Sweden did a case-control
study (1). From the National Swedish Patient Register, they identified all 59 women age 55 yea
eir

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had been introduced in the decades before and act by reducing bone remodeling. Case series
reported an association between bisphosphonates and atypical fractures, but the women in
these studies took other drugs and had other diseases that could also have been related to the
risk of fractures. To provide a more definitive answer to whether bisphosphonates were
independently associated with atypical fractures, investigators in Sweden did a case-control
study (1). From the National Swedish Patient Register, they identified all 59 women age 55 yea
or older with atypical femoral fractures in 2008. They also identified 263 controls, women in th
same registry who had had ordinary femoral fractures (to match for underlying vulnerability to
fractures). Other variables that might be related to both bisphosphonate use and atypical
fractures were recorded, including age, use of bone-modifying drugs such as corticosteroids or
estrogens, and diseases such as osteoporosis and previous fractures. After taking these other
factors into account, women taking bisphosphonates were 33 times more likely to develop
atypical fractures.

Head injuries are relatively common among alpine skiers and snowboarders. It seems plausible
that helmets would prevent these injuries, but critics point out that helmets might also increas
head injuries by reducing field of vision, impairing hearing, and giving athletes a false sense of
security. To obtain more definitive evidence of helmets’ actual effects, investigators in Norway
did a case-control study (Fig. 6.2) (2). Cases and controls were chosen from visitors to eight
major Norwegian alpine ski resorts during the 2002 winter season. Cases were all 578 people
with head injuries reported by the ski patrol. Controls were a sample of people waiting in line a
the bottom of the main ski lift at each of the eight resorts. For both cases and controls,
investigators recorded other factors that might confound the relationship between helmet use
and head injury, including age, sex, nationality, type of equipment, previous ski school
attendance, rented or owned equipment, and skiing ability. After taking confounders into
account, helmet use was associated with a 60% reduction in risk of head injury.

Design of case-control studies

How to select for cases
• New (incident) cases

How to select controls

• Population approach (population-based case-control studies)
○ Random sample of a defined population
• Cohort approach (nested case-control study)
○ Drawing cases and controls from the same cohort
• Hospital and community controls
○ Selecting controls in a way that selection seems to produce controls that
are comparable to cases
• Multiple control groups
○ Adding several control groups with apparently complementary scientific
strengths and weaknesses

In the helmets and head injury example (2), the main control group was uninjured
people skiing or snowboarding on the same hills on the same days, but one could
imagine disadvantages to these controls, such as their not having similar risk-taking
behavior to cases. To examine the effect of choice of control group on results, the
investigators repeated the analyses with a different control group—skiers with other
injuries. The estimated relative risk was similar—a reduction in risk of 55% rather
than 60% with the original control group—suggesting that choice of control group
did not substantially affect results.

• Multiple controls per case

○ Often done with rare diseases to provide more information
• Matching
○ If study includes one or more controls that possess the same
characteristics
○ Done so if there are other factors strongly associated with exposure or
outcome
○ Umbrella matching: Matching on a variable such as hospital or
community that is a proxy for many other variables that could confound
 ○ If study includes one or more controls that possess the same
characteristics
○ Done so if there are other factors strongly associated with exposure or
outcome
○ Umbrella matching: Matching on a variable such as hospital or
community that is a proxy for many other variables that could confound
the exposure-disease relationship and would be difficult to measure one
at a time
○ Overmatching: Can occur if investigators match on variables related to
exposure that exposure rates become similar in both cases and controls

Measuring exposure
• Safest approach is to depend on complete, accurate records, like pharmacy
records.
• Concern is misclassification bias and recall bias (likeliness to remember
exposure event)

What are the risk factors for suicide in China? Investigators studied 519 people who
had committed suicide and 536 people who had died from other injuries (4). Both
groups came from 23 geographically representative sites in China. Exposure was
measured by interviews with family members and close associates. The authors noted
that as with other studies that depended on a “psychological autopsy” for
measurement of exposure, “interviewers were aware of the cause of death of the
deceased (suicide or other injury) so we could not completely eliminate potential
interviewer bias.” They went on to explain that they “tried to keep this bias to a
minimum by using the same interview schedule for cases and controls, employing
objective measures of potential risk factors, independently obtaining evidence from
two sources (family members and close associates), and giving extensive training to
interviewers.” They also chose controls who died from injuries to match for one
important characteristic that might affect responses in the interview, the recent death
of a family member or associate. The study identified eight predictors of suicide: high
depression symptom score, previous suicide attempt, acute stress just prior to death,
low quality of life, high chronic stress, severe interpersonal conflict in the 2 days
before death, a blood relative with previous suicidal behavior, and a friend or
associate with previous suicidal behavior.

The existence of disease can also lead to exposure, especially when the exposure
under study is a medical treatment.
• Does early manifestation of disease lead to treatment, or does treatment cause
disease?

Do beta-blocker drugs prevent first myocardial infarctions in patients being treated

for hypertension? A case-control study addressed this question (5). Because angina is
a major indication for use of beta-blockers, and also a symptom of coronary disease,
 • Does early manifestation of disease lead to treatment, or does treatment cause
disease?

Do beta-blocker drugs prevent first myocardial infarctions in patients being treated

for hypertension? A case-control study addressed this question (5). Because angina is
a major indication for use of beta-blockers, and also a symptom of coronary disease,
the investigators carefully excluded any subjects with a history that suggested angina
or other manifestation of coronary heart disease. They found that patients with
hypertension treated with beta-blockers had a reduced risk of non-fatal myocardial
infarctions, even after those with angina or other evidence of coronary disease were
carefully excluded.

Multiple exposures

Ovarian cancer is notoriously difficult to diagnose early in its course when treatment
might be more effective. Investigators in England did a case-control study of
symptoms of ovarian cancer in primary care (6). Cases were 212 women over 40 years
of age diagnosed with primary ovarian cancer in 39 general practices in Devon,
England, 2000–2007; 1,060 controls without ovarian cancer were matched to cases by
age and practice. Symptoms were abstracted from medical records for the year before
diagnosis. Seven symptoms were independently associated with ovarian cancer:
abdominal distension, postmenopausal bleeding, loss of appetite, increased urinary
frequency, abdominal pain, rectal bleeding, and abdominal bloating. After excluding
symptoms reported in the 180 days before diagnosis (to get a better estimate of
“early” symptoms), three remained independently associated with ovarian cancer:
abdominal distension, urinary frequency, and abdominal pain.

Odds ratio
The meaning of odds ratio is analogous to relative risk
• If frequency of exposure is higher in CASES, OR > 1

Crude OR: OR calculated from 2x2 table; has not taken into account varaibles other
than exposure and disease
Adjusted OR: Adjused for effects of other variables

Investigation of a disease outbreak

A large outbreak of gastroenteritis, with many cases complicated by hemolytic-uremic

syndrome (a potentially fatal condition with acute renal failure, hemolytic anemia,
and thrombocytopenia) occurred in Germany in May 2011 (8). During the epidemic,
there were 3,816 reported cases, 845 with hemolytic-uremic syndrome. Figure 6.4
shows the epidemic curve, the number of cases over time. The immediate cause,
infection with a toxin-producing strain of the bacterium Escherichia coli was quickly
identified, but the source of the infection was not. Investigators did a case-control
study comparing 26 cases of hemolytic-uremic syndrome with 81 controls, matched
for age and neighborhood (9). They found that 6/24 cases (25%) and 7/80 controls
(9%) were exposed to sprouts, for an odds ratio of 5.8, suggesting that the infection
was transmitted by eating contaminated sprouts. (Note that the odds ratio is not
exactly the cross-products in this case because the calculation of odds ratio took into
account the matching.) However, cucumbers and other produce were also implicated,
although less strongly. To take this further, investigators did a small cohort study of
people dining in groups at a single restaurant during the epidemic period. Cases were
empirically defined as diners who developed bloody diarrhea or hemolytic-uremic
syndrome or were found by culture to have the offending organism. Twenty percent
of the cohort met these criteria, 26% of whom had hemolytic-uremic syndrome. The
account the matching.) However, cucumbers and other produce were also implicated,
although less strongly. To take this further, investigators did a small cohort study of
people dining in groups at a single restaurant during the epidemic period. Cases were
empirically defined as diners who developed bloody diarrhea or hemolytic-uremic
syndrome or were found by culture to have the offending organism. Twenty percent
of the cohort met these criteria, 26% of whom had hemolytic-uremic syndrome. The
relative risk for sprout consumption was 14.2, and no other food was strongly
associated with the disease. Sprout consumption accounted for 100% of cases.
Investigators traced back the source of sprouts from the distributor that supplied the
restaurant to a single producer. However, they could not culture the causal
Escherichia coli from seeds in the implicated lot. Following the investigation, and after
attention to the producer, the epidemic subsided (Fig. 6.4) and incidence returned to
the low levels seen before the epidemic.