This document discusses case control studies and provides examples to illustrate their use. It defines a case control study as an epidemiological approach that starts with identified "cases" who have a disease and compares them to "controls" who do not have the disease. The study then examines past exposure history to identify potential risk factors. Key aspects of case control studies covered include selecting appropriate cases and controls, matching on important variables, measuring past exposure, calculating odds ratios to estimate disease risk associated with exposures, and potential biases like selection bias, recall bias, and survivorship bias. Examples are provided of early case control studies that helped identify links between smoking and lung cancer, and between rubella infection and cataracts.

1. Case Control Studies
Dr Naveen Phuyal
MBBS(KU),MD(MUHS)

2. Introduction
• Imagine you are a clinician
• You have seen few patients with certain type of
cancer
• Almost all of them have been exposed to a
particular chemical
• You hypothesize that their exposure is related to
their risk of developing this type of cancer
• How will you go about confirming or refuting your
hypothesis?

3. Example 1
• In the early 1940s, Alton Ochsner, a surgeon in
New Orleans, observed that virtually all of the
patients on whom he was operating for lung
cancer gave a history of cigarette smoking
• Although this relationship is accepted and well
recognized today, it was relatively new and
controversial at the time that Ochsner made his
observation.
• He hypothesized that cigarette smoking was linked
to lung cancer.
• Based only on his observations in cases of lung
cancer, was this conclusion valid?

4. Example 2
• Again in the 1940s, Sir Norman Gregg, an Australian
ophthalmologist, observed a number of infants and young
children in his ophthalmology practice who presented with
an unusual form of cataract.
• Gregg noted that these children had been in utero during
the time of a rubella (German measles) outbreak. He
suggested that there was an association between prenatal
rubella exposure and the development of the unusual
cataracts.
• Keep in mind that at that time there was no knowledge
that a virus could be teratogenic.
• Thus, he proposed his hypothesis solely on the basis of
observational data, the equivalent of data from ambulatory
or bedside practice today.

5. Classification of research methods
Research
methods
Observational
Descriptive
Case series,
case reports,
CS, cohort
Analytical
Ecological Cross-
sectional
Case control Cohort
Experimental
Controlled
Uncontrolled,
Non-random

6. Position in the evidence hierarchy
6

7. Dogma of case control study
Assemble
cases –
diseased
Time
Direction of enquiry
Assemble
controls –
not having
disease
Measure
exposure
status
Exposed
and non-
exposed
7

8. Design of a case-control study
Hallmark of Case Control Study:
from cases and controls and searches for exposure.

10. Definition
• A case control study is defined as an
epidemiological approach in which the researcher
starts by picking up ‘cases’ who have already
developed particular disease or ‘outcome’ of
interest and a comparison group (controls) who
have not developed the disease but are similar to
cases.
• Than he/she tries to find out the presence of
particular exposure which he/she thinks is a risk
factor and compares the two groups in regards to
presence of history of exposure.

11. • Case : A person in the population or study
group identified as having the particular
disease, health disorder or condition under
investigation. (Dictionary of Epidemiology: 3rd ed; John M Last. 2000)
• Control: Person or persons in a comparison
group that differs, in disease experience (or
other health related outcome) in not having
the outcome being studied. (Dictionary of Epidemiology: 3rd
ed; John M Last. 2000)

12. Features of case controls study
• Both exposure and outcome has happened
before the start of the study.
• The study proceeds backwards from effect to
cause.
• It uses a comparison group to support or
refute an inference.

13. Design of case control study

14. Steps
• Selection of cases and controls
• Matching
• Measurement of exposure
• Analysis and interpretation

15. 1.Selection of cases and controls

16. Selection of cases
• Definition of case
– Diagnostic criteria
• Single hospital
• Network of hospitals
– Eligibility criteria
• Incident cases
• Prevalent cases
• Sources of cases
Hospitals
General population

17. Selection of controls
• Controls must be free from disease under study
• Must be similar to the cases except for the
disease under study
• Selection of controls is the most difficult
• Sources of controls
– Hospitals
– Relatives
– Neighborhood
– General population

18. Source Advantage Disadvantage
Hospital based Easily identified.
Available for interview.
More willing to cooperate.
Tend to give complete and
accurate information
(recall bias).
Not typical of general population.
Possess more risk factors for disease.
Some diseases may share risk factors
with disease under study. (whom to
exclude???)
Berkesonian bias
Population based
(registry cases)
Most representative of the
general population.
Generally healthy.
Time, money, energy.
Opportunity of exposure may not be
same as that of cases. (locn, occu,)
Neighbourhood
controls/ Telephone
exchange random
dialing
Controls and cases similar in
residence.
Easier than sampling the
population.
Non cooperation.
Security issues.
Not representative of general
population.
Best friend control/
Sibling control
Accessible, Cooperative.
Similar to cases in most
aspects.
Overmatching.

19. How many controls are needed?
• 1:1 for larger studies
• 1:2
• 1:3
• 1:4
• Multiple control
• Failure to select appropriate control group
results in bias.

20. • Multiple controls of different types are valuable for
exploring alternate hypothesis & for taking into account
possible potential recall bias.
• (From Gold EB, Gordis L, Tonascia J, Szklo M; Risk factors for brain tumors in
children. Am J Epidemiol 1979)
Children with
brain tumours
Children with
other cancers
Children without
cancer
Radiation
causes
cancers
Radiation
causes brain
cancers only

21. 2.Matching

22. Matching
• Matching is a process in which we select
controls in such a way that they are similar to
cases with regard to certain pertinent
variables (eg. age) which are known to
influence the outcome of disease and which if
not adequately matched for comparability
could distort or confound the results.

23. What is a confounding factor?
Esophageal cancerAlcohol
Smoking

24. Matching types
• Group matching (Frequency matching)
• Pair matching ( Individual matching)

25. 3.Measurement of exposure

26. Measurement of exposure
• Interviews
• Questionnaires
• Past records
– Hospital records
– Employment records

27. 4. Analysis

28. Analysis
• Find out
– Exposure rates among cases and controls to
suspected factor
– Estimation of disease risk associated with
exposure ( Odds Ratio)

29. Exposure rates
Cases
(with Ca Lung)
Controls ( without
Ca lung)
Total
Smokers
( <5/day)
33
(a)
55
(b)
88
(a+b)
Non-smokers 2
(c)
27
(d)
29
(c+d)
Total 35
(a+c)
82
(b+d)
117
(a+b+c+d)
A case control study between smoking and lung cancer

30. Exposure rates
Cases
(with Ca Lung)
Controls ( without
Ca lung)
Total
Smokers
( <5/day)
33
(a)
55
(b)
88
(a+b)
Non-smokers 2
(c)
27
(d)
29
(c+d)
Total 35
(a+c)
82
(b+d)
117
(a+b+c+d)
A case control study between smoking and lung cancer

31. Exposure rates
• Cases= a/(a=+c)= 33/35= 94.2 %
• Controls= b/(b+d)= 55/82= 67 %
• So frequency of smoking was definitely higher
among lung cancer patients than those
without cancer

32. • Odds Ratio / Relative odds
– Odds: Odds of an event is defined as the ratio of the
number of ways an event can occur to the number of
ways an event cannot occur. (Epidemiology; Leon Gordis. 2004)
• If the probability of event X occurring is P, then odds of it
occurring is = P/ 1-P.
– Odds ratio: Ratio of the odds that the cases were
exposed to the odds that the controls were exposed.

33. • Odds ratio:
Odds that case was exposed
Odds ratio =
Odds that control was exposed
= (a/c)/ (b/d) = ad / bc
Outcomes of Case Control Study
Diseased/ Cases Not diseased/
Controls
Exposed a b
Not exposed c d

34. Estimation of risk
• Odds Ratio (Cross-product ratio)
• Odds that cases were exposed= a/c
• Odds that controls were exposed=
b/d
• Odds ratio= (a/c)/(b/d)= ad/bc= 8.1

35. Interpretation
• The odds of smoking more than 5 cigarettes
per day was 8.1 times more in the lung cancer
patient than those without lung cancer.
OR
• Smoking (>5/day) was found be associated
8.1 times more in patients with lung cancer
than those without lung cancer.

36. Bias in case control studies
• Bias due to confounding
• Selection bias
• Survivorship bias
• Healthy worker effect
• Memory or recall bias
• Berkesonian bias
• Interviewers bias

37. Bias due to confounding
Esophageal cancerAlcohol
Smoking

38. Bias in case control studies
• Bias due to confounding
• Selection bias
• Survivorship bias
• Healthy worker effect
• Memory or recall bias
• Berkesonian bias
• Interviewers bias

39. Selection bias
• Selection of inappropriate control group
• Basic dictum is controls should be derived
from the same source population from which
the cases have come and that the controls
should be equally at risk.

40. None use of condoms(exp) and
development of STD(outcome)
• Cases: STD clinic
• Controls: same clinic who did not have STD
• But many of the controls may not have developed
STD because their partner may not have STD
weather they use condom or not.
• What was the right way to select cases and
controls?
Cases: Has STD and partners also have STD
Controls: Does not have STD but partner has STD

41. Bias in case control studies
• Bias due to confounding
• Selection bias
• Survivorship bias
• Healthy worker effect
• Memory or recall bias
• Berkesonian bias
• Interviewers bias

42. Survivorship bias
• A case control study taken to evaluate protective
effect of physical exercise on MI
• Case: Patients with MI
• Control : Healthy
• Exposure : Exercise
• But Both cases and control gave a Hx of physical
exercise
• Conclusion: Exercise does not protect MI
In reality 25% to 30% of the MI cases die in first
3 hrs and do not survive.
So only those who survived are available as
cases
.Maybe exercise prevents acute manifestations
of MI
Out of MI those who exercised survived but
those who did not may have died so we have a
biased conclusion.

43. Bias in case control studies
• Bias due to confounding
• Selection bias
• Survivorship bias
• Healthy worker effect
• Memory or recall bias
• Berkesonian bias
• Interviewers bias

44. Healthy worker effect

45. Bias in case control studies
• Bias due to confounding
• Selection bias
• Survivorship bias
• Healthy worker effect
• Memory or recall bias
• Berkesonian bias
• Interviewers bias

46. Memory/ Recall Bias
• The person who is diseased is more likely to
remember about the exposure than the non –
diseased.
• X-ray exposure and congenital malformation
• Unprotected sexual intercourse and HIV

47. Bias in case control studies
• Bias due to confounding
• Selection bias
• Survivorship bias
• Healthy worker effect
• Memory or recall bias
• Berkesonian bias
• Interviewers bias

48. Berkesonian bias
• Hospital selective admissions
• Eg. Cigarette smoking causes peptic ulcer????
• Eg. High fever and febrile seizures.

49. Bias in case control studies
• Bias due to confounding
• Selection bias
• Survivorship bias
• Healthy worker effect
• Memory or recall bias
• Berkesonian bias
• Interviewers bias

50. Advantage of case-control study
• Easy to carry out
• Rapid and inexpensive
• Rare disease investigation
• No risk to subjects
• Allows study of several etiological factors
• Rational prevention and control measures
• No attrition
• Minimal ethical problems

51. Disadvantages
• Bias
• Control selection is difficult
• Incidence cannot be measured
• Cannot differentiate between causes and
associated factors
• Not suitable for evaluation of Rx.
• Representiveness of cases and controls

52. Examples of case control studies
• Adenocarcinoma of vagina
• Oral contraceptives and thromboembolic
disease
• Thalidomide tragedy

53. Adenocarcinoma of vagina in young
women
• 7 young women (15-22 yrs) born in Boston
hospital
• 7 cases (time clustering) in 4 years at same
hospital led to case control investigation
• As the disease was rare , 4 matched controls
for each case
• Controls: taken from birth records, same
hospital as cases

54. Adenocarcinoma of vagina in young
women
• Information collected by personnel interview
on:
1. Maternal age
2. Maternal smoking
3. Antenatal radiology
4. DES (diethyl-stilbestrol) exposure in foetal life

55. 7 cases were exposed to DES in foetal life
Their mother were given this drug to prevent miscarriage in pregnancy
While none of the mothers in control group were given this drug.

56. Thalidomide tragedy
• Thalidomide was used as a safe hypnotic in 1960s
• 1961: Birth of babies with congenital
malformation in UK, prev rare
• Case control study of 46 mothers who delivered
deformed babies showed that 41 were found to
have thalidomide in their ealry pregnancy.
• This was compared to 300 mothers who
delivered normal babies bit their was no
thalidomide exposure.
• Later laboratory experiments confirmed that
thalidomide was teratogenic.

57. THANK YOU