Case control & other study designs-i-dr.wah

1. Case-Control & Other Study Designs
Dr. Win Aye Hlaing
Lecturer
Department of Epidemiology
University of Public Health, Yangon
6/26/2017 1

2. • In the early 1940s, Alton Ochsner, a surgeon
• observed that patients with lung cancer gave a
history of cigarette smoking
• relationship is accepted and well recognized
today
• it was relatively new and controversial at the
time
• He hypothesized that cigarette smoking was
linked to lung cancer
6/26/2017 2

3. • In 1940s, Sir Norman Gregg, an Australian
ophthalmologist
• observed a number of infants and young children
who presented with an unusual form of cataract
• noted that these children had been in utero
during the time of a rubella (German measles)
outbreak
• Association between prenatal rubella exposure
and development of the unusual cataracts
• at that time there was no knowledge that a virus
could be teratogenic
• he proposed his hypothesis solely on the basis of
observational data
6/26/2017 3

4. • 90% of these infants had been in utero during the rubella
outbreak
• concluding that rubella was associated with the cataracts?
• Clearly, the answer is no
• difficult to interpret without data for a comparison group of
children without cataracts
• Study both mothers of children with the cataracts and
without cataracts
• They had been pregnant during the outbreak of rubella
• exposure history-no different for mothers of children with
cataracts than for mothers of controls
• the prevalence of rubella exposure was greater in children
with cataracts than in a group of children without cataracts
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5. • To determine the significance of such
observations
• a comparison or control group is needed
• Without such a comparison, only constitute a
case series
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6. 6/26/2017 6

7. DESIGN OF A CASE-CONTROL STUDY
• A group of people with that disease (cases)
• A group of people without that disease(controls)
• Cases were exposed and were not
• Controls were exposed and were not
• case-control study---if there is an association of
an exposure with a disease,
• the prevalence of history of exposure---higher in
persons who have the disease (cases) than in
those who do not have the disease (controls)
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8. 6/26/2017 8
Case
[Disease (+)]
Control
[Disease (-)]
Exposure (+) a b
Exposure (-) c d
a+c b+d
a/a+c b/b+d

9. • by selecting cases (with the disease) and
controls (without the disease)
• and then measure past exposure by interview
and by review of medical or employee records
or of results of chemical or biologic assays of
blood, urine, or tissues
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10. • If exposure is associated with disease,
a/a + c ˃ b/b + d
• proportion of the cases who were exposed is
greater than proportion of the controls who
were exposed
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12. • data from a case-control study,
• We cannot estimate the prevalence of the
disease
• E.g. we had 200 cases and 400 controls, but
this does not imply that the prevalence is 33%
or 200/200 + 400
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13. • the investigator could have selected
• 200 cases and 200 controls (1 control per case),
or
• 200 cases and 800 controls (4 controls per case)
• Because the proportion of the entire study
population that consists of cases is determined by
the ratio of controls per case, and this proportion
is determined by the investigator, it clearly does
not reflect the true prevalence
6/26/2017 13

14. • erroneous impression that
– cohort studies go forward in time and
– case-control studies go backward in time
• Such a distinction is not correct
• retrospective has been used for case-control
studies
• But retrospective cohort study also uses data
obtained in the past
• Thus, calendar time is not the characteristic that
distinguishes a case-control from a cohort study
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15. • Why the unusual number of controls?
• The investigation planned for two controls per
case (400 controls), and that some of the
controls did not participate
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16. Potential Biases in Case-Control Studies
• Selection Bias
– Selection of case
– Selection of control
• Information Bias
– Limitations in recall
– Recall bias
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17. Selection Bias – Selection of Case
• cases can be selected from a variety of sources,
including hospital patients, patients in physicians’
practices, or clinic patients
• Several problems---selected from a single hospital
• results may not be generalizable to all patients
with the disease
• cases are drawn from a tertiary care facility,
which selectively admits severely ill patients---
risk factors only in persons with severe forms of
the disease
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18. Using Incident or Prevalent Cases
• if we use prevalent cases(already been
diagnosed) :
– a larger number of cases is often available for
study and
– Most people with disease die soon after diagnosis
– Underrepresented in a study
– Highly non-representative group of cases
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19. • If we use incident cases:
– The problem is - wait for new cases to be
diagnosed
– But can exclude that any patients who may have
died before the diagnosis was made
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20. Selection of Controls
• In 1929, Johns Hopkins University
• test the hypothesis that tuberculosis
protected against cancer
• From total 7,500 consecutive autopsies
• Selected 816 cases of cancer and control
group of 816
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21. 6/26/2017 21
Case
[Cancer (+)]
Control
[Cancer(-)]
TB (+) 54 133
TB (-) 762 683
816 816
6.6% 16.3%

22. • Of the 816 autopsies of patients with cancer
• 54 had tuberculosis (6.6%)
• whereas of the 816 controls with no cancer
• 133 had tuberculosis (16.3%)
• the prevalence of tuberculosis was higher in
the control group than in the case group
• concluded that tuberculosis had an
antagonistic or protective effect against
cancer
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23. • At the time of the study, tuberculosis was one of
the major reasons for hospitalization at Johns
Hopkins Hospital
• Inadvertently done in choosing the cancer-free
control group was diagnosed with and
hospitalized for tuberculosis
• selected the controls, they came from a pool that
was heavily weighted with tuberculosis patients,
which did not represent the general population
• Clearly, this conclusion was not justified on the
basis of these data
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24. • A fundamental conceptual issue relating to
selection of controls is:
• the controls should be similar to the cases in
all respects other than having the disease or
• they should be representative of all persons
without the disease in the population from
which the cases are selected
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25. • Controls may be selected
• from non-hospitalized persons living in the
community or
• from hospitalized patients admitted for
diseases other than that for which the cases
were admitted
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27. Use of Hospitalized Patients as Controls
• more economical
• ill-defined reference population that generally
cannot be characterized
• a conceptual attractiveness to comparing
hospitalized cases to hospitalized controls
from the same institution who come from the
same reference population
6/26/2017 27

28. Use of Non-Hospitalized People as Controls
• Other sources include school rosters, selective service
lists, and insurance company lists
• neighborhood in which the case lives--- neighborhood
controls
• identify the home of a case as a starting point
• and from there walk past a specified number of houses
in a specified direction and seek the first household
that contains an eligible control
• Because of increasing problems of security in US, many
people will no longer open their doors to interviewers
• in developing countries, the door-to door approach to
obtaining controls may be ideal
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29. • Alternate method for selecting such controls is
to use random digit dialing
• a case’s seven-digit telephone number,
• the first three digits are the constant,
• the terminal four digits of the phone number
are randomly selected
6/26/2017 29

30. • Another approach to control selection is to use a best
friend control
• A case is asked for the name of a best friend who
participate in the study
• there are also disadvantages:
• A control is similar to the case in age and in many other
demographic and social characteristics
• A resulting problem may be that the controls may be
too similar to the cases in regard to many variables,
including the variables that are being investigated in
the study
• it may be useful to select a spouse or sibling control
• a sibling may provide some control over genetic things
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31. Information Bias – Limitations in Recall
• collecting data from subjects by interviews
• Because all human beings are limited to varying
degrees in their ability to recall information
• Some of the cases or controls who were exposed
will be erroneously classified as unexposed
• and some who were not exposed will be
erroneously classified as exposed
• leads to an underestimate of the true risk of the
disease associated with the exposure
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32. Recall Bias
• possible relationship of congenital malformations to
prenatal infections
• Interview mothers of children with congenital
malformations (cases) and mothers of children without
malformations (controls)
• Each mother is questioned about infections during the
pregnancy
• A mother who has had a child with a birth defect tries to
identify some unusual event that occurred during her
pregnancy
• She wants to know whether the abnormality was caused
• a mother of a child without a birth defect may not even
notice or may have forgotten entirely
• This type of bias is known as recall bias
6/26/2017 32

33. Matching
• the process of selecting the controls so that
they are similar to the cases in certain
characteristics, such as age, race, sex,
socioeconomic status, and occupation
• Matching may be of two types:
(1) group matching
(2) individual matching
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34. Group Matching
• Group matching (or frequency matching)
• selecting the controls with the same
characteristic
• If cases are married, controls will be also
married
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35. Individual Matching
• Individual matching (or matched pairs)
• a control is selected who is similar to the case
• E.g.
• if the first case enrolled in our study is a 45-year-
old white woman,
• we will seek a 45-year-old white female control
• the second case is a 24-year-old black man,
• we will select a control who is also a 24-year-old
black man
6/26/2017 35

36. Practical Problems with Matching
• to match according to too many characteristics,
• difficult or impossible to identify an appropriate
control
• E.g.
• If the case is a 48-year-old black woman who is
married, has four children, lives in zip code
21209, and works in a photo-processing plant,
• it may prove difficult or impossible to find a
control
6/26/2017 36

37. Conceptual Problems with Matching
• More important problem
• If we match the cases (breast cancer) and the controls (no
breast cancer) for marital status,
• we can no longer study whether or not marital status is a
risk factor for breast cancer
• Why not? Because in matching according to marital status
• We have artificially established an identical proportion in
cases and controls
• if 35% of the cases are married,
• we create a control group in which 35% are also married
6/26/2017 37

38. • Unplanned matching may inadvertently occur
in case-control studies
• E.g.
• if we use neighborhood controls--matching for
socioeconomic status as well as for cultural
and other characteristics of a neighborhood
• If we use bestfriend controls--share many
lifestyle characteristics
• Planned or an inadvertent manner--
Overmatching
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39. Use of Multiple Controls
(1) Controls of Same Type
(1) Controls of Different Types
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40. Control of the Same Type
• two controls or three controls for each case
• used to increase the power of the study
• 1 case to 4 controls
• Why use multiple controls for each case?
• there may be a limit to the number of potential
cases available for study
• the number of cases cannot be increased without
either extending the study in time to enroll more
cases or developing a collaborative multicentered
study
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41. Multiple Controls of Different Types
• exposure of the hospital controls- not represent the rate of
exposure- in a population of nondiseased persons
• the controls may be a highly selected-non-diseased
individuals and have a different exposure experience
• hospitalized patients smoke more than people living in the
community
• we do not know what the prevalence level of smoking in
hospitalized controls represents or how to interpret a
comparison of these rates with those of the cases
• To address this problem, we may choose to use an
additional control group, such as neighborhood controls
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43. • Case-control studies are also valuable when
the disease being investigated is rare
• Possible to identify cases for study from
disease registries, hospital records, or other
sources
• cohort study for a rare disease, an extremely
large study population may be needed in
order to observe a sufficient number of
individuals to develop the disease
• cohort design may involve many years of
follow-up and logistical difficulty and expense
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47. Case-Control Studies based in a Defined Cohort
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48. Two Types
• Nested Case Control Study
• Case Cohort Study
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49. Nested Case-Control Studies
• A nested case-control study is conducted
within a defined cohort in which exposure
data and population characteristics are
available to some extent, often from the time
of enrollment into the cohort
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50. • Both cases and controls are from a known,
defined population at risk of disease
• Exposure data are collected prior to the diagnosis
of the disease
• Information collected has not been influenced by
the knowledge of disease status (no
interviewer/information bias)
• Is less costly than a cohort study because fewer
subjects and fewer tests and/or specimens are
required
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51. • In a study to determine whether the
helicobecter pylori infection was associated
with the development of gastric cancer, 189
patients with gastric cancer and 189 cancer-
free individuals were identified from 130,000
people from a cohort followed since the 1960s
• Helicobacter pylori infection status was
determined using stored serum collected
during the 1960s
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52. Example
• Figure - A shows the starting point as a
defined cohort of individuals
• Some of them develop the disease in question
but most do not
• In this hypothetical example, the cohort is
observed over a 5-year period
• During this time, 5 cases develop—1 case
after 1 year, 1 after 2 years, 2 after 4 years,
and 1 after 5 years
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54. • Figures - B–I show the time sequence in which
the cases develop after the start of observations
• At the time each case or cases develop, the same
number of controls is selected
• The solid arrows on the left side of the figure
denote the appearance of cases of the disease
• and the dotted arrows on the right side denote
the selection of controls who aredisease-free but
who are at risk of developing the disease
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55. • Figure - B shows case #1 developing after 1 year
and Figure - C shows control #1 being selected at
that time
• Figure - D shows case #2 developing after 2 years
and Figure - E shows control #2 being selected at
that time
• Figure – F shows cases #3 and #4 developing after
4 years and Figure - G shows controls #3 and #4
being selected at that time
• Finally, Figure - H shows the final case (#5)
developing after 5 years and
• Figure - I shows control #5 being selected at this
point
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61. • Figure - I is also a summary of the design and the
final study populations used in the nested case-
control study
• At the end of 5 years, 5 cases have appeared and
at the times the cases appeared a total of 5
controls were selected for study
• In this way, the cases and controls are matched
on calendar time and length of follow-up
• Because a control is selected each time a case
develops
• a control who is selected early in the study could
later develop the disease and become a case in
the same study
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62. Advantages of Nested Case-Control Studies
• Possibility of recall bias is eliminated, since data
on exposure are obtained before disease
develops
• Exposure data are likely to represent the pre-
illness state since they are obtained years before
clinical illness is diagnosed
• Costs are reduced compared to those of a
prospective study, since laboratory tests need to
be done only on specimens from subjects who
are later chosen as cases or as controls
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63. Case-Cohort Studies
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64. • The second type of cohort-based case-control
study is the case-cohort design
• Cases develop at the same times that were
seen in the nested case-control design,
• but the controls are randomly chosen from
the defined cohort with which the study
began
• This subset of the full cohort is called the
subcohort
6/26/2017 64

65. • An advantage of this design is that because
controls are not individually matched to each
case, it is possible to study different diseases
(different sets of cases) in the same case-cohort
study using the same cohort for controls
• In this design, in contrast to the nested case-
control design, cases and controls are not
matched on calendar time and length of follow-
up;
• instead, exposure is characterized for the
subcohort
• This difference in study design needs to be taken
into account in analyzing the study results
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66. Ecologic Studies
• The first approach in determining whether an
association exists might be to conduct studies of
group characteristics, called ecologic studies
• the relationship between breast cancer incidence
and average dietary fat consumption in each
country
• The higher the average dietary fat consumption,
the higher breast cancer incidence
• conclude that dietary fat may be a causal factor
for breast cancer
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68. • The problem is that we do not know whether
the individuals who developed breast cancer
actually had high dietary fat intake
• All we have are average values
• it is conceivable that those who developed
breast cancer ate very little dietary fat
• That does not reveal whether this might be
true
• individuals in each country are characterized
by the average figure
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69. • This problem is called the ecologic fallacy
• we may be ascribing to members of a group
that they in fact do not possess as individuals
• We only have data for groups
• we do not have exposure and outcome data
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70. Comparison of Cohort and Case-Control
Studies
• Table 13-1
• Page - 241
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72. THANK YOU!!
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