Академический Документы
Профессиональный Документы
Культура Документы
(EC07)
Module: EPM301 Epidemiology of Communicable Diseases
Course: PG Diploma/ MSc Epidemiology
This document contains a copy of the study material located within the
computer assisted learning (CAL) session. The first three columns designate
which page, card and screen position the text refers to.
If you have any questions regarding this document or your course, please
contact DLsupport via DLsupport@lshtm.ac.uk.
Important note: this document does not replace the CAL material found on
your module CDROM. When studying this session, please ensure you work
through the CDROM material first. This document can then be used for
revision purposes to refer back to specific sessions.
These study materials have been prepared by the London School of Hygiene & Tropical Medicine as
part of the PG Diploma/MSc Epidemiology distance learning course. This material is not licensed either
for resale or further copying.
London School of Hygiene & Tropical Medicine September 2013 v1.0
Objectives
By the end of this session you should be able to:
This session should take you between 2.5 and 4 hours to complete.
Iu Iv x 100
Iu Iu
Refers to the presence of parasites (i.e. infection), and also to the amount of
parasites present (i.e. density).
Unadjusted VE =
You can read the full paper later in this session to see how these results were
interpreted.
Interaction: Calculation: Unadjusted VE =
Using the attack rates (AR) as a measure of disease incidence, calculate the
efficacy of the measles vaccine in this setting.
Enter your answer as a percentage to one decimal place in the box below.
Vaccine efficacy =
If the infection has a short and discrete incubation period, the incidence rates
should be calculated as household secondary attack rates (Review this from
session EC03). It may also be possible to extend this approach to include
neighbourhood contacts.
One of the advantages of contact studies is that all the contacts should be equally
exposed to the infection, independent of their vaccination status. However, there
could be a bias in the selection of households, as families with a large number of
cases may be more likely to be recruited and could be more likely to include
vaccination failures.
Sorry, in fact the vaccine efficacy for DTaP is 55%. You should have used the
formula:
VE = 100 x (SARu SARv) / SARu,
where SAR has been substituted as the appropriate measure of incidence in a
contact study. Then the answer can be calculated as:
VE = 100 x (47.1 21.3) / 47.1 = 55%.
This is different from sensitivity, which is the proportion of true positives that are
correctly identified as such.
Also known as predictive value positive.
Interaction: Hyperlink: negative predictive value (pop up box appears):
Negative Predictive Value
The proportion of individuals with a negative test result who genuinely are
negative.
This is different from the specificity, which is the proportion of true negatives that
are correctly identified as such.
Also known as predictive value negative.
Interaction: Tabs Exercise:
Using this adjustment, how many of the children that were vaccinated
seroconverted as a result of vaccination?
Number of seroconversions =
The implications of case misclassification will be further discussed later in this
session.
(You will be given an opportunity to read the remainder of the paper later in this
session. Use that reading to consider the benefits and deficits of this
methodology.)
Interaction: Calculation: Number of seroconversions =___:
Correct Response 161 (pop up box appears):
Correct
The authors estimated that 12 seropositives with a history of measles were true
positives, 48 seropositives with no history of measles were also true positives.
Out of the 221 seropositives in the vaccinated group, that leaves only 161
children (66%) in whom seropositivity was induced by vaccination (see Results
section).
Incorrect Response (pop up box appears):
The authors estimated that 12 seropositives with a history of measles were true
positives, 48 seropositives with no history of measles were also true positives.
Out of the 221 seropositives in the vaccinated group, that leaves only 161
children (66%) in whom seropositivity was induced by vaccination (see Results
section).
Hint: Find-out the incubation period for meningococcal disease (MD) from
http://www.cdc.gov/meningitis/index.html .
Interaction: Hyperlink: meningococcal disease (pop up box appears):
Meningococcal disease
For more information on this disease see
http://www.cdc.gov/meningitis/index.html
Interaction: Button: clouds picture (pop up box appears and text appears on
upper RHS):
The incubation period of Neisseria meningiditis varies between 2-10 days. By
starting recruitment of new cases of MD 4 weeks after the administration of the
second dose of the campaign (see Study Design in the paper), individuals
infected prior to vaccination were excluded from the case definition.
Were cases and controls likely to be comparable? (Consider how the controls
were selected and defined.)
Yes
No
As the symptoms for both cases and controls would be similar, it is likely that
they would be comparable with regard to their use of health facilities when sick.
It is also likely that they would come from the same hospital catchment areas.
Although the study was not matched by hospital, the analyses were stratified by
place of residence.
The vaccine had been tested in Cuba in a double-blind randomised control trial
(see Introduction in the paper). This provides an estimate of how well the
vaccine might work under controlled natural conditions. A case-control study
assesses VE under normal programmatic conditions, which are likely to vary
between countries. In addition, the study in Cuba had shown a high protective
efficacy in all age groups (see p1056, paragraph 1), while a previous casecontrol study in Sao Paulo, Brazil had demonstrated a variable protection by
age (see Introduction).
Read the remainder of this paper after the session, noting the important issues
involved in case-control studies.
(PPV PCV)
x 100
(PPV x [1-PCV])
Click below to see the graph generated from this formula, which shows the
theoretical proportion of cases that will have been vaccinated in a given setting
for different levels of vaccine efficacy.
Interaction: Button: Graph (pop up box appears):
You can see from the graph that, as vaccine coverage increases, a larger
proportion of cases will occur among the vaccinated individuals.
Source
Orenstein WA, Bernier RH, Dondero TJ, Hinman AR, Marks JS, Bart KJ, Sirotkin B.
Field evaluation of vaccine efficacy. Bulletin of the World Health Organisation
1985; 63(6): 1055-1068.
11.1: Meta-analysis
Look through the paper by Rodrigues et al. (1993) in your workbook. It
describes a meta-analysis of BCG vaccine in relation to protection against
tuberculosis.
What was the hypothesis being tested? Choose the answer from the options given
opposite.
Interaction: Hyperlink: tuberculosis:
Tuberculosis
See http://www.cdc.gov/tb/ for more information about this disease.
Protective effect of BCG may vary
according to the study design used.
11.2: Meta-analysis
Now look at the VE estimates in Table 1 and Table 2 of the paper.
What is the overall effect of BCG against meningeal and miliary tuberculosis?
Write down your answer and then check the feedback below.
Interaction: Button: clouds picture (pop up box appears):
There were few randomised control trials (RCTs) that distinguished these forms of
disease as an outcome of interest. The RCTs available showed a highly protective
effect but the confidence intervals were very wide in all cases. The results from
the case-control studies varied between 58-100%, but the confidence intervals
were narrower. The summary protective effect was 75% with 95% confidence
intervals between 61% and 84% (see footnote to Table 2).
11.3: Meta-analysis
This meta-analysis allowed the authors to test their hypothesis from existing
data, rather than needing to conduct a new trial. The summary estimates take
into account the sample size of each study, and the results can be stratified by
study design, geographical area, etc.
However, there are a number of limitations to this method.
Limitations
Interaction: Tabs: Variation:
Study designs usually vary quite a lot. While it may be possible to conduct
different analyses for different types of studies, as in this case, sometimes there
will not be so many studies conducted.
In addition, other factors will vary between the studies, such as age groups
included, dosages given, geographical areas chosen.
Interaction: Tabs: Publication bias:
Another limitation is that meta-analyses are often conducted on published
studies. However, there is a well-known publication bias, with studies with clear
and positive results being more likely to be published.
This would bias the overall effect, so it is important to include as many studies,
both published and unpublished, in this type of analysis.
The type of ascertainment will determine the type and severity of disease. For
example, individuals only attend health facilities when they feel quite sick, and
cases admitted to hospital will be particularly severe.
Interaction: Hyperlink: ascertainment:
Ascertainment
The method by which something is found out. In epidemiology this usually refers
to the method of detecting cases.
It is also important that equal effort is made to detect cases among vaccinated
and unvaccinated populations. Which of the following is more likely to give a
biased estimate of the protective effect of the vaccine in preventing disease?
Some individuals are more likely to be vaccinated and also less likely to be
infected. A prime example is BCG vaccination which has been conducted through
schools, leaving-out the less fortunate individuals who do not attend school. In
such circumstances it is important to collect data to control for confounding.
Read the papers from this session in full, looking closely at the methodological
issues that have just been discussed.
Think about whether each of these studies took these methodological issues
into consideration, and how. Think about the benefits and deficits of each
paper.
Use this reading to help consolidate what you have just learned.
After your break, you can continue with the remainder of the session and a few
exercises.
The total population impact of a vaccination programme will include both these
direct and indirect effects of vaccination.
Complete the diagram by dragging the correct effects into the boxes on the
right.
Interaction: Drag and Drop: Indirect effects:
Correct Response middle box on RHS(pop up box appears):
Thats correct. Transmission will have been reduced in A communities because
of herd immunity effects. Therefore, a comparison of unvaccinated individuals
in the vaccinated communities with unvaccinated individuals in the
unvaccinated communities will measure the indirect effects of vaccination.
Incorrect Response:
This graph shows the changes observed in the age distribution of percentages of
cases for three infections following the introduction of a mass vaccination
programme in Bangkok (Nokes & Anderson 1988).
Source
Nokes DJ and Anderson RM. The use of mathematical models in the
epidemiological study of infectious diseases and in the design of mass
immunization programmes. Epidemiology and Infection 1988; 101(1): 1-20.
(e.g. less than 20% of vaccinated individuals could get infected), risks and rates
will be very similar.
For more common diseases, the two measures of incidence will be different, and
their usage will vary according to the mechanism of immune protection (Smith et
al. 1984).
VE = (PPV PCV) / (PPV[1 PCV]) x 100, you can see that the decision was
correct.
If PCV = PPV, then the numerator will be 0 and VE will be equal to 0. This
situation occurred in Sweden in 1980, and led to Sweden being the only country
in the world not to give pertussis vaccine routinely to children.
(b) 80% of children are vaccinated
against measles in your region. You
are getting many calls from the
primary health care workers, worried
about the efficacy of measles vaccine
as half the cases are vaccinated.
15.1: Exercises
Remember, when you compare vaccine coverage in cases and in the population
in this simple way, there is no control for confounding factors. You don't know
whether the cases are really representative of the whole population.
The case-population method is a 'quick and dirty' method for initial evaluation,
and helps to determine whether there is likely to be a cause for concern.
However, the result could be misleading, so it needs to be considered critically by
someone with a sense of the population concerned.
15.2: Exercises
Exercise 2
A double-blind RCT of a Hepatitis B virus (HBV) vaccine was carried-out among
homosexual men attending sexually transmitted disease clinics.
Three doses of vaccine were given: at entry, after one month and after six
months. Serological testing was done at 2, 4 and 8 months after entry into the
study. The main outcome of interest was the presence of HBV surface (HBs)
antigen in blood, which is a marker of HBV infection. The incubation period for
HBV ranges from 6 weeks to 6 months.
Calculate the vaccine efficacy in each case, and then answer the questions on
the next cards.
15.3: Exercises
Interaction: Tabs: 1:
In the study, the investigators excluded the first 3 months of follow-up time.
Why do you think they did this?
Hint: see http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#C3
Interaction: Button: clouds picture (pop up box appears and text appears on
bottom LHS):
It may take 3 months from infection to the appearance of HBs antigen the
actual range of time for seroconversion is 2 weeks to 6-9 months (in rare cases).
The first 3 months were excluded because the vaccine might not be expected to
protect against infection acquired before first vaccination.
Was this decision justified by the data?
Interaction: Button: clouds picture (pop up box appears):
The data suggest that this decision was justified. The VE in the first 3 months
was low at 18%
[VE = (16.6 13.6)/16.6 x 100 = 18.1%], while after 3 months it was much
higher at 82%
[VE = (13.5 2.5)/13.5 x 100 = 81.5%].
The overall efficacy was
15.4: Exercises
The table below shows the incidence of HBs antigens according to the level of
anti-HBs antibodies after vaccination. Calculate the VE to the nearest percent for
each level of seroconversion and fill in the missing cells.
15.5: Exercises
Exercise 3
15.6: Exercises
Exercise 4
A RCT was conducted to estimate the efficacy of a vaccine against
meningococcal B disease. 700 schools were randomised to receive the vaccine
and 660 to receive a placebo. During the follow-up 26 cases were identified in
26 'placebo' schools and 14 cases in 13 'vaccinated' schools.
Calculate the vaccine efficacy, remembering to use the risk of having any
infection in a school.
Interaction: Button: clouds picture (pop up box appears and card appears on
right handside):
Vaccine efficacy was estimated as:
VE = 1 [(13/700) / (26/660)] = 57.1%
This is because the unit of randomisation was the school, so school outbreaks
rather than individual cases were counted. A more complex analysis could have
considered the number of cases and the number of person-years at risk in each
school.
Interaction: Tabs: Question i:
Which of the following does this VE measure?
Direct
Indirect
Direct and
indirect
Overall
15.7: Exercises
Exercise 5
The data in the table opposite are from a household contact study of pertussis
vaccine efficacy. The secondary attack rates (SARs) and vaccine efficacy (VE)
have been calculated for each age group.
Is 65% a good estimate of overall vaccine efficacy?
Interaction: Button: clouds picture (pop up box appears):
The VE calculated overall is higher than any of the age-specific VE estimates. It
is important to calculate a weighted-average summary estimate (e.g. using the
Mantel-Haenszel method). In addition, age is a confounding factor as the
unvaccinated young children have higher SARs, and also a lower vaccine
coverage. This will often be the case in vaccine studies, so it is important to
control for confounding factors!
Vaccine efficacy is the percent reduction in incidence (risk, rate, etc.) among
vaccinated (not necessarily immunised) individuals, which is attributable to
vaccination.
It is calculated using the following formulae, which are equivalent to each
other:
Vaccine efficacy (VE) = Iu Iv x 100
Iu
where:
Iu = incidence in unvaccinated individuals
Iv = incidence in vaccinated individuals
VE = (1 Relative Risk) x 100_
Methods to estimate vaccine efficacy 1
The following seven methods can be used to estimate vaccine efficacy.
1) Randomised controlled trials (RCTs):
Considered to be the ideal method
because they control for confounding
and biases. They are generally used
prior to licensing a vaccine and
measure vaccine efficacy under trial
conditions.
Methods to estimate vaccine efficacy 2_
2) Cohort studies: Not commonly used
and have problems of confounding
because of non-random allocation of
vaccines.
3) Outbreak investigations: Can be very
useful because there is usually a high
incidence of disease and homogenous
exposure to infection during an
outbreak. However, an outbreak may
be due to a local problem (such as a
cluster of vaccination failures), in
which case the results should not be
generalised.
Methods to estimate vaccine efficacy 3_
4) Contact studies: Especially used for
infections that are efficiently
transmitted within a household, and
have the advantage of homogeneous
exposure to infection.
5) Retrospective cross-sectional studies:
Used by EPI to assess the
effectiveness of vaccines in routine
programmes. The major drawback is