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MD 03
MD 03
diseases
EPM302 Modelling and the Dynamics of Infectious Diseases
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OVERVIEW
The previous sessions introduced methods for setting up simple models of the
transmission dynamics of immunising infections. This session discusses the insights into
the dynamics of infections provided by these models, and subsequently relates model
predictions to data.
OBJECTIVES
By the end of this session you should:
Understand what determines whether the number of new infections will increase or
decrease over time;
Be aware of methods for calculating R0 for an infection from the growth rate of an
epidemic or outbreak;
Understand the factors that lead to cycles in the incidence of immunising infections;
Be able to calculate the inter-epidemic period for an immunising infection;
Know some of the insights into the epidemiology of immunising infections that are
provided by simple models.
This session should take 2-5 hours to complete
This session comprises two parts. Part 1 (1-2 hours) introduces the insights that models
provide into the dynamics of infections; Part 2 (1-3 hours) consists of a practical exercise
using models set up in Berkeley Madonna, during which you will study the cycles in
incidence of immunising infections in detail.
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Section 2: Introduction
page 2 of 78
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The following diagram shows the structure of the models that you worked with during the
last two sessions.
The models that you used are among the simplest models that are used to describe the
long-term transmission dynamics of an immunising infection. We assumed that individuals
mix randomly and that the population size remains unchanged over time. We have also
not stratified the population by age, sex or any other subgroup.
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2.1: Introduction
page 3 of 78 2.1
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2.2: Introduction
page 4 of 78 2.1
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However, the fact that the model predicts that peaks in the epidemics become
progressively less pronounced ("damped") over time, but that we do not see this in the
actual data, suggests that other factors that are not in the model are needed to sustain the
epidemic cycles.
Before discussing the cycles and damping in further detail, we will discuss some of the
other insights into the dynamics of infections provided by this model, specifically:
1. What determines whether or not the number of infectious individuals increases
following the introduction of an infectious person into a totally susceptible
population?
2. How fast might we expect the number of infectious individuals to increase following
the introduction of an infectious person into a totally susceptible population and what
can we infer from it?
3. Why does the incidence of an immunising infection cycle over time?
4. What other factors lead to cycles in the incidence of immunising infections?
5. What inter-epidemic period might we expect to see for immunising infections?
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You may remember from previous sessions that if the basic reproduction number (R0)
of a pathogen is greater than 1, the introduction of one infectious person into a susceptible
population should result in an increase in the number of infectious individuals and the
persistence of the infection in the population.
This result can be obtained relatively easily from the differential equations used to describe
the transmission dynamics of immunising infections that you have used previously. We will
illustrate the derivation of this result by considering a "closed" population, i.e. one in which
there are no births into or deaths out of the population. The model has the following
structure:
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When deriving the result, we will use the following equation, which we met in MD01
=
next
R0
ND
This expression can be rearranged to give the following expression for the basic
reproduction number:
R0 = ND
or, equivalently,
R0 =
N
r
Equation 1
We will show that for the number of infectious individuals to increase following the
introduction of an infectious person into a totally susceptible population, ND must be
greater than 1, and that this expression has the literal definition of R0, , i.e. as the average
number of secondary infectious individuals resulting from one infectious person following
his/her introduction into a totally susceptible population.
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We begin by noting that if the number of infectious individuals increases following the
introduction of an infectious person into a totally susceptible population then the rate of
change in the number of pre-infectious and infectious individuals must be positive, i.e.
dE
dl
> 0 and
>0
dt
dt
As shown in MD02 , the expressions for the rate of change in the number of preinfectious and infectious individuals for the model described on page 5 are:
dE
=S(t)l(t)- fE(t)
dt
Equation 2
dl
=fE(t)-rl(t)
dt
Equation 3
where f is the rate at which pre-infectious individuals become infectious and r is the rate at
which the infectious individuals recover to become immune.
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Combining the logic in the last two expressions , the number of individuals who are
newly infected per unit time must also be larger than the number of individuals who
recover per unit time, i.e.
S(t)I(t) > rI(t)
After dividing both sides of this expression by the number of infectious individuals in the
populations, I(t), we see that for the rate of change in the number of infected individuals to
be positive and therefore for the number of infected individuals to increase, the following
condition must hold:
S(t) > r
Equation 4
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Notice that when the infection is introduced into the population, the number of individuals
who are susceptible, S(t), is the size of the total population, N. Substituting N for S(t) into
the last expression , we see that for the number of infectious individuals to increase
following the introduction of an infectious person into a totally susceptible population, the
following must hold:
N > r
If we divide both sides of this expression by the recovery rate r, we see that the following
condition must hold:
N
>1
r
Equation 5
Substituting for D = 1/r into this expression, we obtain the result that ND >1 for the
number of infectious individuals to increase after the introduction of one infectious person
into a totally susceptible population. You should recognize that the left side of this
expression is the same as that of the basic reproduction number, as presented on page 6
.
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On average, each infectious person effectively contacts N other individuals per unit time.
When the population is entirely susceptible, each of these contacts will generate a new
infection. Multiplying N by the infectious period D (or 1/r), we obtain the total number of
individuals effectively contacted by the infectious person during their infectious period.
Using this literal definition for R0 in Equation 5 , we conclude that for the introduction of
an infectious person into the population to lead to an increase in the number of infectious
individuals, the basic reproduction number or ND must be greater than 1.
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Using the result on the previous page, we can see that the number of infected individuals
increases ifND >1. Similarly, the force of infection also increases if ND >1, since the
rate at which susceptible individuals are infected is directly proportional to the number of
infectious individuals, i.e.
(t) = I(t)
This is equivalent to Equation 1
in MD01.
We might expect that when the number of infectious individuals increases (or decreases),
the infection incidence rate, (t)S(t)=I(t)S(t), will also increase (or decrease). However,
whilst this relationship approximately holds, it is not quite exact, since an increase in
infected individuals corresponds to a fall in susceptible individuals, and both I(t) and S(t)
appear in the expression for incidence. If we consider outbreaks that only result in
relatively small fluctuations in numbers of susceptible individuals, we can say that,
approximately, incidence increases whenND >1.
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We can use the logic described on the last few pages to derive the result that the
proportion of a population that needs to be susceptible for the number of infected
individuals to increase at a given time must be greater than 1/R0.
Q1.1 Derive the above result using Equation 4
Hint: Divide both sides of Equation 4 by the total population size (N) and and use the
result that R0 =
.
Answer
Kermack and McKendrick first discussed these results in papers published in 1927 2 ,
although, at the time, they weren't expressed in terms of the basic reproduction number,
which was first defined by Macdonald during the early 1950s3-4 .
For the purposes of this module, you do not need to read these references.They are
mentioned here because of their historical importance.
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Note that the expression ND for the basic reproduction number does not account for
deaths that may occur during the pre-infectious or infectious periods. Anderson and May
(1992, Ch 1-4) 5 provide the details for expressions that account for deaths. For most
common immunising infections, the pre-infectious and infectious periods are generally a
few days, whereas the life expectancy (in industrialised populations) is about 70 years. As
such, since the mortality rate is much smaller than the rate at which individuals become
infectious and recover, the effects of these adjustments on the estimate for R0 are
relatively small.
The logic described in this section can be extended to obtain the equations for R0 to
account for mortality or for non-immunising infections (see e.g. the recommended course
text, Panel 8.26 ).
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It can be shown that, following the introduction of an infectious person into a totally
susceptible population, the number of infectious individuals will increase at a rate (),
given by the following expression:
R0 - 1
D
Equation 6
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Equation 6
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R0 D+1
Equation 7
Therefore, given empirical estimates of the growth rate of an epidemic or outbreak (), it
should be possible to infer the R0 of a pathogen. Methods for estimating the growth rate
are provided in section 4.2.3.1 of the recommended course text 6 . These estimates of R0
can then be used to infer future trends in infection incidence.
Equation 7 (and its variants) has been used to derive estimates of the basic reproduction
number for HIV during the early stages of the HIV epidemic in Kenya and Uganda9 ,
which ranged between 4 and 11. As shown on the next page, this theory has been applied
for Severe Acute Respiratory Syndrome (SARS ), which was caused by a newly
emergent infectious agent which was first identified in 2003.
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A variant of Equation 7 was used in studies estimating the basic reproduction number of
Severe Acute Respiratory Syndrome (SARS ), which was caused by a newly emergent
infectious agent that was first identified in 2003. The analyses used estimates of the
average serial interval (calculated as 8.4 days using data from Singapore) and the growth
rate in the cumulative numbers of cases 7 (see Figure 3). In these analyses, R0 for SARS
was estimated to be in the range 2.0 - 3.6.
If you are interested in seeing the derivation of this result, please read section 4.2.3.2.1 of
the recommended course text, which provides a simplified description6 . This low value
for R0 in comparison with that for other infections such as measles or mumps (see MD04
), together with the fact that the peak infectiousness of cases occurs after the onset of
symptoms, suggested that SARS might be controllable.
Figure 3. a) Number and b) cumulative number of probable or reported cases of SARS in Hong Kong in 2003.
Data source: http://www.who.int/csr/sars/country/en/index.html .
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During the first part of the 20th century there were two main theories for the occurrence of
cycles in the numbers of measles cases:
1. The cycles reflected cycles in infectivity of the measles virus, or
2. The cycles resulted from changes in the prevalence of susceptible individuals, as a
result of a constant influx of susceptibles born into the population, and susceptible
individuals becoming immune after becoming infected10 .
Experimental studies in mice populations carried out in the 1930s found no evidence for
changes in the infectivity11 , and the second argument has since become accepted.
Before discussing how changes in the prevalence of susceptible individuals lead to
epidemic cycles for immunising infections, we will first review the relationship between the
net reproduction number (Rn), the trend in incidence and the proportion of individuals in the
population who are susceptible.
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The net reproduction number (Rn ) is defined as the average number of secondary
infectious individuals resulting from each infectious person in a given population (in which
some individuals may be immune). Rn is related to R0 as follows:
Rn = R0 s
Equation 8
where s is the proportion of the population that is susceptible. For example, if each
infectious person generates 4 secondary infectious individuals in a totally susceptible
population, then in a population in which only 25% of individuals are susceptible, the
infectious person will generate only 1 (= 4 0.25) secondary infectious individuals.
When the number of infected individuals is increasing, Rn > 1; when the number of infected
individuals is decreasing, Rn < 1; and when the number of infected individuals is stable, Rn
= 1. As discussed on page 12, we can approximately say that when the incidence is
increasing, Rn > 1; when the incidence is decreasing, Rn < 1; and when the incidence is
stable, Rn = 1.
Given Equation 8 and the relationship between the trend in incidence and the net
reproduction number, we can now infer what proportion of the population is likely to be
susceptible when the incidence is increasing, decreasing, or at a peak.
For example, when the incidence is increasing, Rn > 1 and therefore, using the fact that Rn
= R0 s, we can say that:
R0 s > 1
Rearranging this expression, we see that whilst the incidence is increasing:
s >1/R0
Equation 9
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Q1.2 Given Equation 8 and the relationship between Rn and the trend in incidence,
what can we say about the proportion of the population which is susceptible when the
incidence is
a) Decreasing?
Answer
b) Stable?
Answer
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b) Decreasing?
Answer
c) At a peak?
Answer
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Figure 4. Predictions of the number of new infectious individuals per day (red line, right hand axis) and the
number of susceptible and immune individuals following the introduction of an infectious person with measles into
a totally susceptible population, assuming that R0 = 13, the pre-infectious period = 8 days, the infectious period =
7 days and the total population size = 100,000.
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The previous exercise highlights the fact that the proportion of the population which is
susceptible has to be above a certain threshold value (1/R0) for the incidence (or the
number of new infections or infectious individuals) to increase, and it has to be below the
same threshold for the incidence (or the number of new infections or infectious individuals)
to decrease. When the proportion of individuals who are susceptible equals this threshold
value, the incidence is stable.
Table 1 and Figure 5 summarise the relationship between trends in incidence and the size
of the net reproduction number and the proportion of the population that is susceptible.
Incidence (or
number of
new
infections or
infectious
individuals)
Rn
Proportion susceptible
Increasing
>1
>1/R0
Decreasing
<1
<1/R0
Peaking
=1
=1/R0
Figure 5.Relationship between Rn , the proportion susceptible and number of new infectious individuals per day.
See the caption to Figure 4 for details of the assumptions in the model.
We will now apply the above results to explain why the incidence of immunising infections
cycles over time.
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During the course of an epidemic following the introduction of an infectious person into a
totally susceptible population, we see that the following events occur in succession:
1. The number of new infectious individuals increases as there are sufficient numbers
of susceptible individuals for each infectious person to lead to >1 secondary
infectious people.
2. The proportion of individuals that are susceptible in the population decreases.
3. Once this proportion is sufficiently low (<1/R0) each infectious person leads to <1
infectious person, and the number of new infectious individuals starts to decrease.
Without the entry of new susceptibles into the population (e.g. as a result of births or
immigration), the proportion of the population that is susceptible would remain consistently
below the threshold level (i.e. <1/R0) and transmission would eventually cease.
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The entry of new susceptibles as a result of new births into the population, however,
means that the following occurs:
Stage 1. The proportion of susceptible individuals(s) will eventually start to increase once a
sufficient number of births have been added (see Figure 6).
Figure 6. Explanation for the epidemic cycles in measles - the relationship between the proportion susceptible
and the number of new infectious individuals. Stages 4 and 5 are identical to the stages discussed on pages 2426 and are greyed out. We will discuss these stages again once we have discussed stage 3.
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Stage 2. At some point, the proportion of susceptible individuals(s) is sufficiently large (i.e.
>1/R0) for each infectious person to generate >1 infectious people. Once this occurs the
number of new infectious individuals starts to increase, as shown in Figure 7.
Figure 7. Explanation for the epidemic cycles in measles - the relationship between the proportion susceptible
and the number of new infectious individuals
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Stage 3. At some point, the number of susceptibles who are being removed by infectious
individuals exceeds the number being added to the population through new births. Once
this occurs, the increase in the proportion of susceptible individuals slows and then
reverses (Figure 8).
Figure 8. Explanation for the epidemic cycles in measles - the relationship between the proportion susceptible
and the number of new infectious individuals
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Stage 4. Once the proportion of the population that is susceptible has decreased to reach
1/R0, the number of new infectious individuals peaks (so we have now returned to Stage 4
in Figures 6-8).
Stage 5. The continuing reduction in the susceptible population means that eventually, the
proportion of the population that is susceptible becomes sufficiently low (<1/R0) that each
infectious person generates <1 secondary infectious people. Consequently, the number of
new infectious individuals starts to decrease, illustrated in Figure 9.
Figure 9. Explanation for the epidemic cycles in measles - the relationship between the proportion susceptible
and the number of new infectious individuals
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Section 6: Exercise
page 32 of 78
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Q1.4 Figure 10 shows how the number of new infectious individuals per unit time changes
as the proportion of the population that is susceptible changes. Copy this figure onto a
piece of paper.Add plots of the following as they change with the number of new infectious
individuals per unit time and the proportion susceptible:
a) The net reproduction number
b) The proportion of the population that is immune
Figure 10. The relationship between the cycles in incidence or the number of new infectious individuals per unit
time, the proportion susceptible and the net reproduction number.
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You should have plotted something similar to the plot in Figure 11:
Figure 11. The relationship between the cycles in the numbers of new infectious
individuals, the proportion susceptible and the net reproduction number
a) Note that the net reproduction number follows the same pattern as the proportion of the
population that is susceptible, i.e. the two statistics peak, decrease or reach a trough
simultaneously. This follows from the fact that the net reproduction number is directly
proportional to the proportion susceptible, through the relationship:
Rn = R0 s
Also, at a peak or trough in the number of new infectious individuals, Rn is equal to 1;
whilst the number of new infectious individuals is increasing Rn is greater than 1 and
whilst the number of new infectious individuals is decreasing Rn is less than 1.
b) The plot of the proportion of the population that is immune is just the mirror image of the
plot of the proportion susceptible. This follows from the fact that the proportion immune
is approximately equal to 1-proportion susceptible.This approximation follows from the
(reasonable) assumption that, for an immunising infection, the number of infectious or
pre-infectious individuals is typically small in a population, in comparison with the
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Hamer used a similar argument to that presented on the previous pages to explain the
cycles in measles deaths seen during the early part of the 20th century. His argument,
employing the "mass action" principle, was based implicitly on the following difference
equations:
Ct+1 = kC tS t
Equation 10
S t+1 = B + S t - Ct+1
Equation 11
where:
Ct and S t are the number of cases and susceptibles, respectively, at time t;
k is the proportion of the total possible contacts that actually lead to new cases 1 ,
B is the number of births in each time step.
The time step used in this original model was the serial interval for the infection.
The difference between this model and the other models that we have used so far is that
the generations of cases in this model do not overlap. In other words, all cases have onset
and infect each other at time steps of 1 serial interval.
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Hamer argued that when the number of susceptible individuals was at a peak or a trough
(i.e. reached a maximum or a minimum), the number of new measles cases occurring in
the population equalled the number of births into the population.
Q1.5 Look at the equations for Hamer's model
this result.
Hint: Use the result that when the number of susceptible individuals is at a peak or a
trough at time t, the number of susceptible individuals at time t+1 equals that at time t (i.e.
S t+1 =St).
Answer
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Figure 12 shows the number of susceptibles and cases predicted by Hamer's model over
time.
In contrast with the models used so far in this module, this model predicts that the cycles in
the numbers of cases should never damp out .
Further theoretical elaborations by Soper (1929) 12 found that when the simple mass
action model was adapted to assume that the infectious period was not fixed and followed
a variable distribution, the cycles damped out. Therefore, the simple mass action model
did not include sufficient assumptions to fully explain the cycles in incidence for immunising
infections.
Figure 12. Number of cases and susceptibles over time predicted using Hamer's mass action model, assuming
that C0 = 50, S 0 = 1200, B = 50 and k = 0.001 per serial interval. See the Excel file massact.xls
this model.
for details of
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As we saw in Figure 1 , the model that we worked with during the last few sessions
predicted that the cycles in the number of new infectious individuals damp out, which is
inconsistent with the data observed in many populations. For example, as shown in Figure
2 , measles epidemics occurred regularly every two years in England and Wales before
the introduction of vaccination. This discrepancy between model predictions and the
observed data has led to suggestions that other factors must have a role in sustaining
these cycles. These factors are discussed in detail in Anderson and May (1991) 1 ; we
discuss the main factors on the next few pages.
You will also find it helpful to read section 4.3.2 of the recommended course text 6 .
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Seasonality in transmission
Seasonal transmission is the most obvious factor that is likely to lead to cycles in the
incidence of immunising infections. There have been many modelling and observational
studies investigating the effect of seasonality on incidence. Analyses by Fine and Clarkson
(1982) 1 have found evidence for seasonal transmission of measles in England and
Wales, occurring as a result of intense mixing between children during term-time, and less
intense mixing during the school holidays (Figure 13).
These analyses used a model-based approach, calculating the transmission parameter k,
in Hamer's simple mass action model (i.e. the proportion of the total possible contacts that
actually lead to new cases), using the ratio between the number of cases observed in the
UK each week over the time period 1950-77, and the estimates of the number of
susceptible individuals.
As shown in Figure 13B , the transmission parameter was lowest during the school
holidays.
Figure 13. Analysis of average biennial measles patterns, based on data from the UK (1950-55).Shaded blocks indicate school summer
and Christmas holiday periods 1 .
a) Average number of cases notified per week;
b) Calculated weekly transmission parameters;
c) Estimated numbers of susceptible individuals.
Reproduced from Fine PEM and Clarkson JA (1982) Measles in England and Wales I - an analysis of factors underlying seasonal
patterns. Int J Epidemiol 11(1):5-14 1 ,. By permission of Oxford University Press.
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Figure 14. Seasonal patterns in measles and pertussis notifications (left and right-hand figures respectively),
based on weekly case reports in England and Wales, 1941-1991. Based on Figure 11 in Anderson et al (1984)13
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Stochastic effects
The models discussed so far have been deterministic and do not take account of the fact
that individuals come in integer (not fractional!) quantities. The work of Bartlett (1956) 15
and Anderson and May (1986) 16 have shown that models that are amended to deal with
discrete (integer) numbers of individuals and that allow for stochastic variation in
transmission predict regular cycles in incidence (so long as the population size is
sufficiently large), as shown in Figure 15. See chapter 6 of the recommended course text 6
for further discussion of stochastic models.
Figure 15. Comparison between the observed notification rates of measles in the UK and Greenland and those
predicted using a stochastic model (Anderson and May, 1986)16 .
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Equation 12
where A is the average age at infection, D' and D are the average pre-infectious and
infectious periods, respectively.
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We can adapt equation 12 to express T in terms of R0. For example, in the absence of
vaccination or control programs, the average age at infection A, the average life
expectancy L and the basic reproduction number are related through the following
expression for some types of populations:
R0 1 + L/A
We will discuss the derivation of this expression in MD04.
This equation can be re-arranged to give the expression A L/(R0- 1). If we substitute this
expression for A into Equation 12, the equation for the inter-epidemic period in the
absence of control becomes:
T 2
L(D+D')
R0 - 1
Equation 13
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Table 2. Estimates of the observed and predicted inter-epidemic periods for different infections in various
locations (extracted from Anderson and May (1991)5 ).
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Equation 12
Equations 12
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This session has mainly focused on simple immunising infections (such as measles,
mumps and rubella), for which the pre-infectious and infectious periods are measured in
days, and are therefore short relative to the lifetime of individuals. The pattern seen for
these infections does not necessarily hold for non-immunising infections. Similarly, the
logic is not easily extendible to diseases such as tuberculosis, for which the interval
between infection and disease may be long (e.g. decades), as conditions (such as the
number of individuals contacted by each infectious person) have probably changed over
time.
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We suggest that you now read Chapter 4 of the recommended course text 6 , where the
issues covered in this session are explained in further depth.
Some of the issues presented in this session are discussed in further detail in the following
articles:
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The rest of this session (the practical component) is likely to take 1 - 3 hours
may wish to take a short break before starting it.
next
. You
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OVERVIEW
We will now start parts 2 and 3 of this session, which consist of a practical using models
set up in Berkeley Madonna.
Part 2 of this session revises the relationship between the basic and net reproduction
numbers (R0 and Rn), the herd immunity threshold and the trends in the number of new
infectious individuals. Part 3 (which is optional) explores how the size of the basic
reproduction number affects the inter-epidemic period.
OBJECTIVES
By the end of the practical part of this session you should understand the relationship
between:
The basic and net reproduction numbers and the herd immunity threshold;
The peaks in the number of new infectious individuals for an immunising infection
and the prevalence of susceptible and immune individuals in the population;
The basic reproduction number and the inter-epidemic period.
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The relationship between the net reproduction number and trends in the
number of new infectious individuals
We will first focus on how the net reproduction number, Rn changes during the epidemic
cycles for a simple immunising infection. As discussed on page 20 ,
Rn= R0 * proportion susceptible
1. Start up Berkeley Madonna and open the file 'measles2 equations.mmd ' , or
'measles2 flowchart.mmd ' depending on whether you prefer to work with the
equation or flowchart editor versions of the models. Unless otherwise stated, the
instructions for this practical are identical for both files.
The structure of the model is as follows:
You should recognise that this model is identical to the model you created in the last
session, except that it has 2 new variables (prop_sus and prop_imm). You can see
these variables by viewing the equations window (for those using the equation
editor) or by clicking on the globals button in the flowchart window (for those using
the flowchart editor). prop_sus and prop_imm are defined as the proportion of the
population that is susceptible and immune respectively and we are using the
approximation that prop_imm 1- prop_sus. Please see page 33 for the basis of
this assumption.
Note that the R0 is currently equal to 13.
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2. If you are using the equation editor, set up Rn in the equations window using the
appropriate expression. If you are using the flowchart editor, set up a new variable
called Rn in the globals window for the net reproduction number using the
appropriate expression.
3. Open the parameters window and run the model, which has been set to run for
73,000 days.
Click here to check your expression.
Click here to see the figure that you should have obtained.
PLEASE AVOID CLICKING ON THE BUTTON ON THE
TOP RIGHT
HAND CORNER OF THE FIGURES WINDOW during this session, as this
will result in the contents of the figures window being deleted.
Unfortunately, the figures are then irrecoverable and will need to be set
up again, unless you use one of the solution files that are available in
this session.
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We first focus on the relationship between Rn and the daily number of infectious individuals
over time.
4. Set up a new figure (called page 2) by clicking on the "New Page" button
toolbar of the figures page. We will now add a plot of Rn to this figure.
on the
The simplest way to add another variable, such as Rn to the graph is to select the
appropriate button for that variable at the bottom of the window. Berkeley Madonna
automatically includes buttons for the first few variables in the model, but has not
included a button for Rn. We therefore need to add a button for Rn manually.
5. Follow the instructions provided here
At present, it is difficult to see how Rn changes with the number of new infectious
individuals per day. We will therefore change the scales on the x- and y-axes before
trying to interpret the figure.
6. Change the scale on the y-axis for Rn to range from 0 to 1.5. Click here
instructions if you don't recall how to do this.
for
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14.3
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7. We are interested in how the net reproduction number changes during an epidemic
cycle (e.g. over a 10 year period). Therefore, in a similar way, change the x-axis to
go from time t = 14600 days (i.e. year 40) to time t = 18250 days (i.e. year 50).
The axis settings window should now look as follows:
Once you have entered the appropriate options into the axis settings window, click on OK
to continue.
Click here to see the output you should have by this stage.
If your output does not resemble this figure, you can check your settings against those in
the files measles2 - equations_solna.mmd or measles2 - flowchart_solna.mmd .
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Q2.1 How does the net reproduction number change over time? What is the value of the
net reproduction number when the number of new infectious individuals per day peaks?
What is the value when the number of new infectious individuals per day reaches a
trough?
Answer
Q2.2 What is the trend in the number of new infectious individuals per day when
a) Rn <1?
b) Rn >1?
c) Rn =1?
Are these trends reasonable?
Answer
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We will now explore how the number of new infectious individuals per day changes with
the proportion of the population that is susceptible.
8. Copy the figure on Page 2 to Page 3 by clicking on the "New Page" button . Add
prop_sus to the new plot (on the left hand y-axis) by clicking on the prop_sus button
at the bottom of the figure window. Remove Rn from the plot by clicking on the Rn
button at the bottom of the window.
9. Change the scale of the left hand y-axis to range from 0 to 0.15, in the same way
that you did before.
Click here if you need to remind yourself of how you can change the scales on axes in
Berkeley Madonna.
Click here to see the output you should have by this stage.
If your output does not resemble this figure, you can check your settings against those in
the files measles2 - equations_solnb.mmd or measles2 - flowchart_solnb.mmd .
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Q2.3 What proportion of the population is susceptible to infection when the number of new
infectious individuals per day is at a peak or trough? Is this what you would expect and
why?
Answer
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For transmission of an infection to cease, the proportion of the population which is immune
must be kept higher than the herd immunity threshold (H), which is given by the following
expression:
H = 1 - 1/R0
Q2.4 What is the herd immunity threshold in the population in the model?
Answer
1. Copy the figure on Page 3 to a new page (called Page 4). Add prop_imm to the plot
on the left hand y-axis and remove prop_sus from the plot. Change the scale of the
left-hand y-axis to range from 0.8 to 1.0 to see the prop_imm.
Click here to see the output you should have by this stage.
If your output does not resemble this figure, you can check your settings against those in
the files measles2 - equations_solnc.mmd or measles2 - flowchart_solnc.mmd .
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Q2.5 What is the value of the proportion immune when the number of new infectious
individuals per day peaks or reaches a trough? What do you notice about the value of
prop_imm when the number of new infectious individuals per day is declining or when it is
increasing? How does this relate to your estimated value for the herd immunity threshold?
Answer
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We will now adapt the model to explore how vaccinating a fixed proportion of the
population at a level of coverage close to the herd immunity threshold affects transmission.
Before continuing, deselect prop_imm and prop_sus from the plot on Page 1 of the Figure
window.
1. Set up a new parameter (in the Equation window if you're using the equation editor
or in the Globals window if you're using the flowchart editor) called prop_vacc,
reflecting the vaccination coverage in the population. Set this equal to 0.75.
We will assume that vaccination is introduced some time (e.g. 50 years) after
the infection has started circulating in the population.
2. Add the following text to your model on the line immediately after the definition for
prop_vacc:
eff_cov = if (time>18250) then prop_vacc else 0
This indicates that the parameter eff_cov (which we will take to reflect the
proportion of newborns which are effectively vaccinated) takes the value of
prop_vacc 18250 days (i.e. 50 years) after the start of the simulations;
otherwise the value is zero.
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The following is the general structure of the model that we are currently working with:
3. On a separate piece of paper, draw arrow(s) to show how you would change the
model diagram to show newborns being vaccinated.
Answer
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Q2.7 Set up the equation for the following in terms of the total population, birth rate, and
effective coverage:
a)The number of newborns entering the population per day who are
susceptible (denoted by the arrow "Susceptible births").
b)The number of newborns entering the population per day who are immune
(denoted by the arrow "Immunised births").
Use the terms provided in the drop down menus to complete the expressions that you
might use in your model for these terms. Terms may be used more than once or not at all.
Susceptible births =
Immunised births =
Answer
Choose...
Choose...
Choose...
Choose...
Choose...
Choose...
Choose...
Choose...
Choose...
Choose...
Choose...
Choose...
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Q2.8 Identify the correct differential equations from the list below that incorporate i)
immunised newborns and ii) susceptible newborns entering the population.
a)d/dt(Susceptible) = beta*Susceptible*Infectious - total_popn*b_rate*(1eff_cov) - Susceptible*m_rate
b)d/dt(Susceptible) = beta*Susceptible*Infectious - total_popn*b_rate*(1eff_cov) + Susceptible*m_rate
c)d/dt(Susceptible) = -beta*Susceptible*Infectious + total_popn*b_rate*(1eff_cov) - Susceptible*m_rate
d)d/dt(Susceptible) = -beta*Susceptible*Infectious + total_popn*b_rate*(1eff_cov) + Susceptible*m_rate
e)d/dt(Immune) = Infectious*rec_rate - Immune*m_rate +
total_popn*b_rate*eff_cov
f) d/dt(Immune) = Infectious*rec_rate + Immune*m_rate +
total_popn*b_rate*eff_cov
g)d/dt(Immune) = - Infectious*rec_rate + Immune*m_rate +
total_popn*b_rate*eff_cov
h)d/dt(Immune) = - Infectious*rec_rate - Immune*m_rate +
total_popn*b_rate*eff_cov
Answer
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4. Change the model (either in the equations or flowchart editor, depending on which
approach you're working with) so that:
a)A proportion eff_cov of newborn individuals are effectively vaccinated (i.e.
enter the immune compartment) after they are born.
b)The remaining proportion (1 - eff_cov) of newborns enter the susceptible
compartment.
Click the show button below to check your model if you are using the flowchart editor.
Show
Click here to check your model if you are using the equation editor.
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5. Run the model. Your output on Page 1 of the Figures window should resemble the
following at this stage - you should notice that the epidemic cycles change after
vaccination of 75% of newborns is introduced on day 18250.
If your model is failing to run or your figure looks different from this figure, clickmeasles equations_solnd.mmd or measles - flowchart_solnd.mmd to access the file that
you should have developed by this stage.
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6. Run the model for values of prop_vacc that are either above or below the herd
immunity threshold, either by setting up and using the sliders or by changing the
value in the parameter window. If you are using the sliders, set the maximum to
equal 1.0 and the increment for prop_vacc to equal 0.01.
Click here
Q2.9 Look at Page 1 of the Figures window. What happens to the number of new
infectious individuals per day if the proportion of the population which is effectively
vaccinated is above the herd immunity threshold? What happens to the number of new
infectious individuals per day if the value is below the herd immunity threshold?
Answer
If you have time, try Part 3 of this session, in which we explore how R0 and other factors
(e.g. the vaccination coverage and the birth rate in the population) affect the epidemic
cycles. Please save your Berkeley Madonna files before continuing.
Figure 16. Model predictions of the effect of different levels of effective vaccination coverage among newborns,
introduced in year 50, on the long-term number of new infectious individuals per day.
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1. Reset the proportion of the population which is vaccinated to be zero. Re-run the
model and look at Page 1 of the figures window.
Q3.1 What is the inter-epidemic period 50-100 years following the introduction of one
infectious person into this population? Note that we are focusing on the time period 50 100 years after the introduction of one infectious person since at this time, the cycles
should have stabilized and epidemics should be occurring at approximately regular
intervals.
Hint: How many cycles in the number of new infectious individuals per day occur in each
10 year period?
You may wish to change the x-axis to use annual, rather than daily time units.
Click here
Answer
to remind yourself of how you can change what is plotted on the x-axis.
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Anderson and May (1992) 5 , provide the following formula for estimating the interepidemic period for immunising infections:
T 2
L(D+D')
R0 - 1
Equation 14
where D' is the average duration of the pre-infectious period, D is the average duration of
infectiousness, L is the life expectancy and is the constant (3.14...).
Q3.2 Are your results from Q3.1 consistent with this formula? Note that the life
expectancy currently equals 70 years.
Answer
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2. Run the model for values of R0 of 5 and 18. R0 of measles was estimated to be 5-6
in Kansas (US 1918-9), 13-14 in Cirencester (UK 1947-50) and 18 in England and
Wales (1950-68).
Q3.3 How does the inter-epidemic period resulting from an R0 of 18 compare against that
resulting from an R0 of 5? Why might this occur?
Note that, as mentioned in MD02 , you can see the effect of changing a given parameter
value on model predictions by clicking on the overlay button
and then running the
model.
Answer
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Q3.4 How should the introduction of vaccination affect the inter-epidemic period? Check
your answer by changing the value of prop_vacc and re-running the model.
Answer
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Q3.5 How should the birth rate in the population influence the inter-epidemic period? Test
your hypothesis by changing the birth rate assuming that the population size remains
constant over time.
Answer
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Q3.6 Would you expect the inter-epidemic period for measles to be longer or shorter than
that for:
a)Chickenpox?
b)Mumps?
c)Rubella?
Hint: R0 for measles is typically higher than that for rubella and mumps; the average preinfectious and infectious periods for these infections are shorter than those for measles.
Answer
3. Change the parameters in the model to be those for influenza (pre-infectious and
infectious period = 2 days, R0 = 2). Reset the birth rate to be that in the original
model (i.e. corresponding to a life expectancy of 70 years) and, making sure that no
one is vaccinated in the population, run the model.
Q3.7 Why might you be cautious about using the predictions of the inter-epidemic period
for influenza from this model?
Answer
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To consolidate your understanding, we suggest that you try the exercises associated with
the model files for chapter 4 in the recommended course text 6 .
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1. For immunising infections, for the numbers of infectious individuals to increase once
an infectious person enters a totally susceptible population, the basic reproduction
number, R0, which is given by the expression ND, must be bigger than 1.
Here N is the total population size, D is the duration of infectiousness and is the
rate at which two specific individuals come into effective contact per unit time.
2. During the early stages of an epidemic of a new infection, R0 can be estimated from
the epidemic growth rate () using the expression: R0 1+D, and variants of this
expression.
3. These equations have been used to estimate R0 for HIV during the 1980s, for SARS
when it first emerged and for pandemic influenza.
4. For an immunising infection, the proportion of the population susceptible for the
number of infectious individuals to increase (or equivalently, for an epidemic to
occur) must be bigger than 1/R0. This result can be obtained by using the facts that:
For the number of infectious individuals to increase, the net reproduction
number, Rn (defined as the average number of secondary infectious
individuals resulting from an infectious person in a given population) must be
bigger than 1.
Rn is related to R0 and the proportion of the population that is susceptible (s)
through the equation Rn = R0 s.
If Rn>1, then R0 s must be bigger than 1 for the number of infectious
individuals to increase. Rearranging the expression R0 s >1 leads to the result
that s>1/R0 for the number of infectious individuals to increase.
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20.1: Summary
page 74 of 78 20.1
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5. In general, for the incidence or the number of new infectious individuals to decrease
for an immunising infection, the proportion of the population that is susceptible has to
be below1/R0.
6. The following table summarises the relationship between trends in incidence or the
number of new infections per unit time, Rn, the proportion susceptible and the
proportion immune:
Incidence
(or number
of new
infections
or
infectious
individuals)
Rn
Proportion Proportion
susceptible
immune
Increasing
>1
>1/R0
<1-1/R0
Decreasing
<1
<1/R0
>1-1/R0
Peaking
=1
= 1/R0
= 1-1/R0
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L(D+D')
R0 - 1
11. This approximation is obtained by using the fact that, in the absence of vaccination
R0, A and L are related through R01+L/A (see EP301 and discussed further in
MD04 ), or after rearranging, AL/(R0 -1), where L is defined as the average life
expectancy. After substituting the latter expression for A into the approximation
described in point 9 above, we obtain the equation:
T 2
L(D+D')
R0 - 1
12. These approximations have usually led to estimates of the inter-epidemic period
which are reasonably consistent with those observed for many infections.
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20.3: Summary
page 76 of 78 20.1
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Section 21: Working with graphs in Berkeley Madonna summary of key features
page 77 of 78
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1. Double click in the middle of the graph. This opens a new window called "Choose
Variables".
2. Double click on the variable that you would like to plot from the variables list on the
left hand side of this window, so that the variable appears in the list under the "Y
Axes" section on the right hand side. This section lists the variables for which
buttons will be set up at the bottom of the figures window.
3. Click on "OK" to continue and re-run the model. Your selected variable should now
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References
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1. Fine, P.E. and J.A. Clarkson, Measles in England and Wales--I: An analysis of
factors underlying seasonal patterns. Int J Epidemiol, 1982. 11(1): p. 5-14.
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4. Macdonald G. The epidemiology and control of malaria. London: Oxford University
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7. Lipsitch, M., et al., Transmission dynamics and control of severe acute respiratory
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8. Wearing, H.J., P. Rohani, and M.J. Keeling, Appropriate models for the management
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10. Hamer, W.H., Epidemic disease in England - the evidence of variability and of
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12. Soper, M.A., The interpretation of periodicity in disease prevalence. J.R. Stat. Soc.
Ser. A, 1929. 92: p. 34-61.
13. Anderson RM, Grenfell BT, May RM. Oscillatory fluctuations in the incidence of
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1984 Dec;93(3):587-608.
14. Schenzle, D., An age-structured model of pre- and post-vaccination measles
transmission. IMA J Math Appl Med Biol, 1984. 1(2): p. 169-91.
15. Bartlett, M., On theoretical models for competitive and predatory biological systems.
Biometrika, 1957. 44: p. 27-42.
16. Anderson, R.M. and R.M. May, The invasion, persistence and spread of infectious
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