EP101 Fundamentals of Epidemiology

Examination paper and marking scheme 2009

Question 1

A study was conducted on 13,668 women aged 60 years and over to investigate the association of calcium
supplement intake with the incidence of hip fracture. Calcium supplement use was assessed using a
questionnaire. Participants also completed a questionnaire about smoking, alcohol intake and physical
exercise. Body mass index was measured. Information on hospital admitted hip fractures was obtained
from general practitioner records. Women were followed for a maximum of 8 years (72,095 person-years
of follow up) during which 237 incident hip fractures occurred. The table below details the age-adjusted
rates according to supplement use.

Incidence rates of hip fracture per 1000 person-years by calcium supplement category

Calcium < once a 1-2 per

Never weekly Daily
supplement intake month month

Age adjusted rate 4.35 3.38 3.35 2.86 2.38

a) What type of study was this? (5 marks)

This was a prospective (2 marks) cohort study (3 marks).

b) Explain the term “person-years” and how it is calculated . (10 marks)

“Person-years” is the time (in years) that women in the study are at risk of a hip fracture and in
the study. It is calculated by adding together the person time at risk for all the women in the
study. For each individual woman the person time in the study is calculated from the date of
entry to the study to the date of the first hip fracture or date of exit from the study (death or loss
to follow-up) or the date of end of follow up of the cohort.

Award 3 marks for any definition that states that it is the time that the women in the study are
at risk. Award an additional 2 marks for stating a start time for each woman and a final or exit
time. Award 1 mark each for stating that the exit could be due to (i) date of having the event,
i.e. hip fracture, or (ii) lost to follow-up/dead, or (iii) end of study follow up for whole cohort (3
marks max). Award a further 2 marks for stating that the total person-years is the addition of
each woman’s follow up time.

c) Calculate the mean follow up time. (5 marks)

5.27 years (72095 pyrs/13668 women) is average follow up time.

Award 5 marks for correct answer. Deduct 1 mark if answer given to less than 1 or more than
3 decimal places. Deduct 2 marks for correct calculation but the omission of the units
(‘years’).

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 d) Calculate the Rate Ratio for each frequency of supplement use relative to the group “Never”.
(10 marks)

Calcium Never < once a 1-2 per weekly Daily

supplement intake month month
Age adjusted rate 4.35 3.38 3.35 2.86 2.38
RR 1.00 0.78 0.77 0.66 0.55

Award 2 marks for each correct RR, including 1.00 in the ‘Never’ group.  Deduct 2 marks from
the total if RRs are given to less than 2 or more than 4 decimal places.

e) Women who reported that they exercised frequently (defined as gym attendance twice a week or
more) had a significantly reduced rate of hip fracture. Does this mean that exercise is a
confounder of the association between supplement intake and hip fracture? (5 marks)

Exercise might be a confounder but this cannot be ascertained from the information given. A
potential confounder must be associated both with the outcome and with the exposure. Exercise
is associated with outcome (hip fracture) but we do not know whether exercise is also associated
with the exposure (supplement use).

Award 3 marks for stating that a confounder must be associated with both the outcome and the
exposure. Award an additional 2 marks for stating that exercise is related to outcome but we
do not know the association with exercise and supplement use.

Although we are not told that exercise is associated with supplement use it is likely that women
who exercise are more health conscious and may therefore be more likely to take calcium
supplements. If full marks are not awarded above then an additional 2 marks may be awarded
for this comment.

f) Based only on the results in the table would you recommend that women should take calcium
supplements to reduce the risk of hip fracture? Justify your answer. (15 marks)

No (3 marks)

Valid justifications (4 marks each up to 12 marks):

• These results are not adjusted for possible confounders that were measured, in particular
physical activity, smoking, alcohol.
• No information on results of statistical tests or 95% confidence intervals.
• There may be unmeasured confounders.
• No information on possible ascertainment bias of hip fracture.
• No information on proportion of drop outs by category of supplement use.
• No information on duration or dose
• No information on the potential harms of calcium supplementation
• Cohort studies don’t provide the strongest type of evidence, a randomized controlled trial
would, however.
• No information on how women were selected for the study/ who agreed to take part
• Calcium intake may not be reported accurately
• Calcium intake may be reported differentially due to known association with fracture
(participants may be aware of hypothesis under study)

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 • Should think about causality – Bradford Hill criteria (need to relate it to specific example
though)
• Any other valid justification.

Full marks should not awarded if one or more invalid answer is given even if 3 valid answers
are given. In this situation, 4 marks should be dropped for each invalid answer, but not more
than half of the awarded marks in total, i.e.:

1 valid answer only = 4 marks

2 valid answers only = 8 marks
3 or more valid answers only = 12 marks
1 valid and any invalid = 2 marks
2 valid and any invalid = 4 marks
3 valid and 1 invalid = 8 marks
3 valid and 2 or more invalid = 6 marks

Subsequently a large randomised double blind placebo controlled trial was undertaken to test the effect of
daily calcium supplements on the incidence of hospital admitted hip fracture in women aged 60 and over.
The trial lasted for 3 years. Twenty per cent of the women dropped out of the trial but continued to be
followed for hip fracture information via their general practitioners. The proportions that dropped out
were similar in both the active (intervention) and placebo (control) groups.

g) What is meant by “double blind randomised placebo controlled trial”? (15 marks)

“Double blind” - neither the subject nor investigator know whether the subject is on placebo or
active treatment (up to 5 marks).

“Placebo controlled” - a placebo is an inert tablet that has the same appearance and taste as the
active tablet. The placebo group provide a measure of the hip fracture rate in women not given
the supplement and therefore are the control group (up to 5 marks)

“Randomised” - random allocation to active or placebo group (up to 5 marks)

h) Why do you think the investigators choose a double blind design? (10 marks)

Award up to 5 marks for each of following points:

• Women might change their behaviour if they knew whether they were taking active or
placebo treatment, for example the placebo group might take calcium supplements.
• Investigators might be more likely to report hip fractures in women on placebo if they
thought the association might be true. [If the direction is not stated, 3 marks may be
awarded for the more general point that reporting of fracture might vary according to
placebo/intervention status].

Award 3 marks for a simple statement such as “To reduce bias from knowledge of treatment
allocation” with no additional details.

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The trial results are shown below.

Rate ratios of hip fracture comparing calcium supplement to placebo

Rate Ratio for supplements

95% CI
compared to placebo

Intention to treat 0.92 0.81-1.05

On randomised treatment 0.81 0.62-0.99

i) What is meant by the terms “Intention to treat” and “On randomised treatment”? (5 marks)

“Intention to treat” – includes all women in the analysis, irrespective of whether they took the
treatment or dropped out of the trial (2.5 marks).

“On randomised treatment” – includes only those who remained in the trial and stayed on
randomised treatment (2.5 marks).

j) Describe the results of the trial. What do you conclude? (20 marks)

Summary of results

In the “intention to treat” analyses there was no significant effect of randomised treatment on the
rate of hip fracture (or a non-significant decrease on the rate of hip fracture) (2 marks).
Although there was an observed reduction of 8%, the 95% confidence interval crosses unity (1
mark). In the “on randomised treatment analysis” there is a significant benefit from calcium
supplements (2 marks) with a 19% reduction in the hip fracture rate (1 mark). We know it is
significant because the 95% confidence interval does not include 1 (1 mark) although the upper
CI is very close to 1.00 (0.99) and therefore to non-significance (1 mark).

Interpretation

“Intention to treat” is not biased by loss to follow up because it compares the groups as
originally randomised (2 marks). However the effect may be underestimated because it includes
women who dropped out or did not take the treatment (3 marks). As the drop out rate was
similar in both arms of the trial it is unlikely that bias has been introduced (2 marks).

The “on randomised treatment” analysis may be a better assessment of the biological effect of
the supplement because it is considers the person time and events only for people who took the
randomised treatment (3 marks). However a 20% drop out over 3 years is quite high and people
who discontinue treatment may be different from those who stay on treatment (2 marks).

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Question 2

It has previously been shown that people who are exposed to large amounts of ultraviolet (UV) radiation
from sunlight are more likely to develop malignant melanoma (skin cancer) than people who are not. A
study was carried out to examine whether a similar relationship exists between ocular melanoma (skin
cancer in the eye) and UV radiation.

The age, sex, and year of diagnosis of the 6,673 patients diagnosed with ocular melanoma during 1983-
1994 in Europe were obtained from 33 separate cancer registries. The age-specific populations covered
by each cancer registry were also acquired. Crude incidence rates of ocular melanoma for each cancer
registry were calculated.

The investigators plotted the incidence rates according to the latitude of the cancer registry. Their results
are shown below.
Incidence of ocular melanoma 1983-1994 by latitude for 33 cancer
registries in Europe
9.0
8.0
Incidence of ocular melanoma

7.0
(per million population)

6.0
5.0
4.0
3.0
2.0
1.0
0.0
35 40 45 50 55 60 65 70 75
Latitude of cancer registry (°N)
South North
(Higher UV exposure) (Lower UV exposure)

a) What type of study was this? (5 marks)

This was an ecological study (5 marks)

b) List TWO advantages and TWO disadvantages of this type of study. (12 marks)

Valid advantages:
• Quick
• Cheap
• Useful for generating hypotheses
• Useful when it is difficult to obtain individual-level data (such as here, individual UV
exposure)

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 Valid disadvantages:
• Cannot conclude causality at the individual level (ecological fallacy)
• Cannot easily control for confounding
• Susceptible to information bias e.g. different ascertainment in different countries

Award 3 marks for each valid advantage/disadvantage up to a maximum of 6 marks for

advantages and 6 marks for disadvantages.

Full marks should not awarded if one or more invalid answer is given even if 2 valid answers
are given. In this situation, 3 marks should be dropped for each invalid answer, but not more
than half of the awarded marks in total, i.e.:

1 valid answer only = 3 marks

2 valid answers only = 6 marks
1 valid and any invalid = 1.5 marks
2 valid and any invalid = 3 marks

c) The investigators used latitude to measure exposure to UV radiation. What is this type of
measure called? (5 marks)

Latitude is being used as a proxy measure for UV exposure (5 marks).

d) Why do you think the investigators chose to measure UV radiation in this way?
(8 marks)

The investigators probably chose to use a proxy because individual UV exposure would not have
been recorded by the cancer registry (3 marks). Obtaining this information for each individual
would have been expensive, and prone to information bias, particularly as many of the
participants are likely to have died (3 marks). Using latitude enables a measure of UV radiation
to be attributed to all the patients in the study in a cheap and easy way (2 marks).

e) The investigators did not age-standardize their results because “there were small numbers of
cancers in some age groups for some registries”. Do you think that the investigators were right
to do this? Explain your answer. (15 marks)

No, it would have been better to present age-standardized results (3 marks). Cancer incidence is
likely to be associated with age (3 marks) and the age structure of populations varies across
Europe (2 marks) in a way which may be associated with latitude (2 marks). Since the age
structure of populations of Northern European countries may be different to the populations of
Southern Europe, comparing non-standardized rates might be misleading (5 marks).

[NOTE: Cancer is highly age-dependent (risk increases exponentially with age), and Northern
European populations tend to be older than Southern European ones, but students would not be
expected to know this level of detail to gain full marks].

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 f) If you were asked to age-standardize these data, which method of standardization would you use?
Explain your answer. (15 marks)

Indirect standardization (5 marks). This would be better than direct standardization in this
situation where there were small numbers of cancer diagnoses in some registry-age sub-groups
(5 marks). If we performed direct standardization the rates would be subject to substantial
sampling error (5 marks).

UV radiation may also be a risk factor for non-Hodgkin lymphoma (NHL, a cancer of white blood cells).
A study was conducted to examine this hypothesis.

All adults living in Australia and diagnosed with NHL between January 2000 and August 2001 were
included in the study. A comparison group of adults without NHL were randomly selected from the
electoral roll and matched to those with NHL on age, sex, and state of residence. A self-administered
questionnaire and telephone interview measured total hours of sun exposure at 10, 20, 30, 40, 50 and 60
years of age.

Some of the results of the study are shown in the table below.

Odds ratios of Non-Hodgkin Lymphoma (NHL) by category of sun exposure

Quartiles of total sun 95% Confidence

Odds Ratio
exposure hours interval
1 (Lowest sun exposure) 1.00 -
2 0.72 0.53-0.98
3 0.66 0.48-0.91
4 (Highest sun exposure) 0.65 0.46-0.91

g) What type of study was this? (5 marks)

Case-control study (5 marks)

h) List TWO advantages of this study compared to the study of ocular melanoma described above.
(10 marks)

• Sun exposure was measured at the individual level (much better than latitude)
• Sun exposure was measured using 2 methods (self administered questionnaire and
telephone interview) which would improve the reliability of the measure
• Confounding by age, sex, and state of residence reduced by matched design
• As we are likely to know much more about each individual cancer patient from the
questionnaire, controlling for other confounders is much more straightforward
• Able to assess sun exposure before the development of the disease (enables us to assess
temporality). [NOTE: this information is collected retrospectively, so may be biased.
However it would provide a reported level of sun exposure at ages prior to the cancer
diagnosis, which is an improvement on the ecological study design described above].

Award 5 marks for each valid advantage.

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 Full marks should not awarded if one or more invalid answer is given even if 2 valid
answers are given. In this situation, 5 marks should be dropped for each invalid answer,
but not more than half of the awarded marks in total, i.e.:

1 valid answer only = 5 marks

2 or more valid answers only = 10 marks
1 valid and any invalid = 2.5 marks
2 valid and any invalid = 5 marks

i) What do you conclude about the relationship between ocular melanoma and UV radiation, and
NHL and UV radiation? Explain your answer. (25 marks)

In both of these studies it appears that UV radiation is protective against cancer (5 marks).

• Ocular Melanoma:
There is a strong inverse association between latitude and ocular melanoma (up to 5 marks).
The incidence rate in Southern Europe (higher UV areas) is lower than in Northern Europe
(lower UV areas) (up to 3 marks). However, we need to interpret these results with caution,
as they originate from an ecological study so we cannot conclude causality at an individual
level (up to 3 marks), nor have the rates been age-standardized (up to 3 marks). The results
may also be subject to bias (up to 3 marks).

Award up to a maximum 10 marks even all of the above is mentioned.

• NHL
There is also a strong inverse relationship between NHL and UV radiation (up to 5 marks).
The odds ratios show that those exposed to higher levels of sun exposure are less likely to
have NHL suggesting that sunlight has a protective effect (up to 3 marks). The relationship
is significant because in all three categories, the confidence intervals do not cross 1 (up to 3
marks). There also appears to be a dose-response relationship (up to 3 marks). However,
the results may also be subject to reporting bias (up to 3 marks).

Award up to a maximum 10 marks even all of the above is mentioned.

Neither of these study’s findings are consistent with what is known about on malignant melanoma
(skin cancer), where UV radiation increases the risk of developing the disease (3 additional
marks may be awarded for this comment if full marks are not awarded above).

[NOTE: It is likely that the association between ocular melanoma and UV radiation is related to
the protective role of ocular pigmentation, and the protective effect for NHL is related to
increased levels of vitamin D. Students would not be expected to know or guess this, however].

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