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# Introduction to Infectious Disease

Modelling (EC06)
Module: EPM301 Epidemiology of Communicable Diseases
Course: PG Diploma/ MSc Epidemiology

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London School of Hygiene & Tropical Medicine September 2013 v1.0

## Section 1: EC06 Introduction to Infectious Disease Modelling

Aims:
To introduce the areas of application of models and the methods for setting up
models.
Objectives:
By the end of this session, you should:

## know some of the kinds of questions which might be addressed using

modelling.
be aware of the different types of models.
understand the principles of setting up models and some of the key
input parameters of models.

## This session should take 35 hours to complete.

Section 2: Introduction
Mathematical models are increasingly being used to interpret and predict the
dynamics and control of infectious diseases.
Applications include predicting the impact of vaccination strategies against common
infections such as measles and rubella, and determining optimal control strategies
against influenza, HIV and vectorborne diseases.
This session illustrates some of the areas of application of modelling and will
introduce you to some of the methods for setting up models.

## Section 3: What are models?

Definitions
According to the Oxford English dictionary, a model is any representation of a
designed or actual object
Models typically aim to recreate the transmission dynamics of an infection using
the smallest possible number of parameters and assumptions
In infectious disease epidemiology, two kinds of models have typically been
employed in the past:

## Physical or mechanical models

Mathematical models
Physical models
The classic example of the physical or mechanical model is the ReedFrost
teaching model, developed at Johns Hopkins during the 1930s to teach medical

students about the numbers of cases which are likely to be seen over time,
following the introduction of infectious cases into a population.
Interaction: Button: Reference (pop up box appears):
Fine (1977) A commentary on the mechanical analogue to the Reed-Frost epidemic
model. Am J Epidemiol, 1977, 106(2): 87-100
It is named after two famous infectious disease epidemiologists: Reed and Wade
Hampton Frost who developed the model.

## 3.1: What are models?

Physical models (cont)
The model consists of a roulette wheel or a trough and some coloured balls (see
right), representing susceptible individuals, cases and immune individuals (blue,
red and green balls respectively).
The balls are thrown into the trough or roulette wheel; the number of new cases
which occur in the next time interval equals the number of blue balls which are in
contact with a red ball. These blue balls are replaced with red balls (as they are
now "cases"); red balls are replaced with green balls (as they are now "immune").
The whole process of throwing balls is repeated until there are no more red balls in
the population.

Nowadays, this whole process of simulating an epidemic can be carried out using
mathematical equations, implemented on a computer, within a matter of seconds.

## 3.2: What are models?

Mathematical models (cont)
Mathematical models, as their name suggests, use mathematical equations to
describe the transmission dynamics of an infection in a population.
The following is an example of one of the simplest mathematical models of the
transmission dynamics of measles:
St + 1 = St Ct + 1 (+ Bt )

Ct + 1 = St Ct r

This particular model is based on reasoning by Hamer in 1906, and was designed
to interpret the biennial cycles in measles incidence which are seen in most
populations.
Interaction: Hyperlink: seen in most populations
Output: [pop up]:
Weekly measles notifications in England and Wales, 195079 (Fine and
Clarkson, 1982)

Output [pop up]:

## Hamer WH (1906) Epidemic disease in England: the evidence of variability and

persistence of type, Br Med J March 17:733739
Fine PEM and Clarkson JA (1982) Measles in England and Wales I: an analysis of
factors underlying seasonal patterns. Int J Epidemiol 11(1):514
In these equations:
Ct is the number of cases at time t;
St is the number of susceptible individuals at time t;

## Bt is the number of births into the population at time t;

r is defined as the proportion of total possible contacts between cases and
This model is simplistic in that it describes how the number of infectious individuals
changes from one generation to the next, taking time steps of 1 serial interval
(time interval between successive cases in a chain of transmission).
Interaction: button: Note
Output [pop up]:
This is a simple way of thinking conceptually about epidemics. For example, in a real
epidemic, generations of cases overlap each other, and so the model predictions do
not exactly correspond to what we would observe in a real outbreak.
We will illustrate how this particular model can be refined to allow generations of
cases to overlap later in this session.
End Note button interaction.
Interaction: button: References
Output [pop up]:
HopeSimpson RE (1948) The period of communicability of certain epidemic
diseases. Lancet (Nov 13), 755760.
Fine PE (2003). The Interval between successive cases of an infectious disease.
Am J Epidemiol 158, 10391047.

## 3.3: What are models?

As shown in the graph button opposite, this particular model, which incorporates
new susceptible individuals being born into the population, and susceptibles being
removed from the population, as a result of their becoming cases and then
immune, is able to recreate these cycles in incidence.
Number of cases and susceptibles over time predicted using Hamer's mass
action argument

Output:

## Section 4: Applications of modelling

Models have been applied to many problems in infectious disease epidemiology.
Their main (though not exclusive) use has been in predicting the impact of control
programs and the future numbers of cases.
However, models may also provide useful insight into the epidemiology of an
infection, since they (usually!) aim to recreate the transmission dynamics of an
infection using the smallest number of parameters.
Any discrepancy between the models output and real data may then help to
elucidate other factors which may be important in the epidemiology of that
infection.
We first describe the use of models for predicting the impact of control programs.

## Section 5: Applications of modelling predicting the critical

levels of treatment or vaccination coverage
The most obvious area of application of modelling is in predicting the impact of
control programs and the future number of cases.
Much of the work centres around the theme of thresholds and the idea that, in
order to control transmission, it is not necessary to treat all the cases or vaccinate
every susceptible individual: it is sufficient to reduce the numbers of cases or
susceptibles to a sufficiently low threshold level and transmission will eventually
cease.

This idea was first conceived by Ronald Ross in 1908, who reasoned that to control
malaria transmission, the density of mosquitoes in the population needed to be
reduced to a sufficiently low level.
Interaction: button: References (1):
Output:
Ross (1911) The Prevention of Malaria, 2nd ed., Murray, London.
End interaction.
This theme was subsequently developed by Kermack and McKendrick in 1927, and
then by Macdonald in 1957, who defined the basic reproduction rate as the average
number of secondary cases resulting from each infectious case when introduced into
a totally susceptible population.
Interaction: button: References (2):
Output:
Kermack WO and McKendrick AG (1927). Contributions to the mathematical theory
of epidemics. I Proceedings of the Royal Society of Medicine, 115A: 700721.
MacDonald G (1957). The Control of Epidemiology and Control of Malaria. Oxford
University Press, London.

## 5.1: Applications of modelling predicting the critical levels of

treatment or vaccination coverage
Macdonald referred to this
basic reproduction rate
Output:
Basic reproduction rate
Techinically, R0 is a number or ratio rather than a rate, since it has no time units.
Nowadays, epidemiologists refer to it as the basic reproduction number.
End interaction.
as Z0, which subsequently became known as R0 and is now more commonly
known as the basic reproduction number or ratio.
His observation that this quantity had to exceed 1 for malaria to persist in a
population led to optimism that malaria could be eradicated.

## Although this optimism proved to be shortlived, the reproduction number

concepts were developed and applied extensively during the 1980s to many
immunizing infections, such as measles, mumps, rubella, to calculate the
herd immunity threshold
Output:
Herd immunity threshold
The proportion of the population which needs to be immune in order to control
transmission, i.e., for the net reproduction number to equal 1. See EC03 if you
would like to revise this concept.
End interaction.
and hence the proportion of the population which needed to be vaccinated in order
to control transmission.
(See Anderson and May (1991) for a review.)
Interaction: Button: Reference (pop up box appears):
Anderson and May (1991)
Infectious Disease of Humans.
Dynamics and Control. Oxford
University Press. Oxford.

## 5.2: Applications of modelling predicting the critical levels of

treatment or vaccination coverage
As you saw in EC03, the herd immunity threshold is calculated using the equation:
Herd immunity threshold = 11/R0.
The panel opposite shows the relationship between R0 and the herd immunity
threshold, and the values for the herd immunity threshold for several infections.
Note the small value for the herd immunity threshold for smallpox, which, some
have argued, greatly facilitated the eradication of smallpox during the 1970s.
The R0 for malaria has been estimated to be very high (approaching 200)hence the
high value for its herd immunity threshold.

## 5.3: Applications of modelling predicting the critical levels of

treatment or vaccination coverage
The basic reproduction number (and hence, the herd immunity threshold) is
straightforward to calculate from serological data if it can be assumed that
individuals mix randomly.
Output:

Everyone is as likely to contact, e.g. people of different ages, social groups, etc., as
they are to contact people of their own age, social group, etc. This is also referred
to as homogenous mixing.
End interaction.
See the tabs to revise these methods.
Calculating the R0
Interaction: tabs:
Tab 1:
Revision I
As you saw in EC03, if a population has a rectangular
Output:

End interaction.
age distribution (also known as a Type I distribution), such as that seen in many
Western populations, R0 can be calculated using the expression R0 = L/A
Here, L is the life expectancy and A is the average age at infection.
Tab 2:
Revision II
The expression for the R0 for a population with a negative exponential

Output:

End interaction.
age distribution (also known as a Type II distribution), such as that seen in some
developing countries is analogous to that for a population with a rectangular age
distribution:
R0 = 1 + L/A
Here, L is the average life expectancy and A is the average age at infection. See
Anderson and May (1991) for the derivation of this expression.
Interaction: Button: "References":
Anderson and May (1991)
Infectious Disease of Humans.
Dynamics and Control. Oxford
University Press. Oxford

## 5.4: Applications of modelling predicting the critical levels of

treatment or vaccination coverage
Estimates for the R0 based on assumptions of random mixing are helpful for
providing a rough estimate of the level of coverage required to control transmission.

## However, few populations mix randomly and estimates of the R0 based on

assumptions of random mixing may either under or overestimate the true proportion
of the population which would need to be vaccinated in order to control transmission.

## 5.5: Applications of modelling predicting the critical levels of

treatment or vaccination coverage
Example:
The diagram opposite shows the contact patterns in two populations (A and B).
In population A, each child contacts 1 other child and 1 adult and each adult
contacts 5 adults and 1 child.
In population B, individuals mix randomly: each child contacts the same number of
In both populations, each case leads to an average of 4 cases.

Question:
If vaccination is available only for children, is the level of coverage required to
control transmission in population A higher, equal to or lower than that in population
B?
Interaction: hotspots:
Hotspot 1:
Higher
Output [correct response]:
Correct
Control is easiest to achieve if it is targeted at the individuals who are the most
active transmitters. In population A, young individuals are responsible for a smaller
proportion of all the transmission events (2/8) than in population B (4/8). As a

## result, it will be harder to control transmission in population A through vaccinating

children than in population B. A higher proportion of children will therefore need to
be vaccinated in population A than in B in order to control transmission.
Hotspot 2:
Lower
Output [incorrect response]:
No, thats not right. Control is easiest to achieve if it is targeted at the individuals
who are the most active transmitters. In population A, young individuals are
responsible for a smaller proportion of all the transmission events (2/8) than in
population B (4/8) and therefore a higher proportion of individuals need to be
vaccinated in population A than in population B to control transmission.
Hotspot 3:
Equal
Output [incorrect response]:
No, thats not right. Control is easiest to achieve if its targeted at the individuals
who are the most active transmitters. In population A, young individuals are
responsible for a smaller proportion of all the transmission events (2/8) than in
population B (4/8) and therefore a higher proportion of individuals need to be
vaccinated in population A than in population B to control transmission.

## 5.6: Applications of modelling predicting the critical levels of

treatment or vaccination coverage
Estimates of the level of vaccination coverage which would be required to control
transmission need to take into account both how many people each child or adult
contacts and who they contact.
It can be shown (using modelling techniques which are beyond the scope of this
introductory session!) that approximately 81% of population A would need to be
vaccinated to control transmission, as compared with 75% of population B.
It is not necessary to use a model to see that control is easiest to achieve if its
targetted at the individuals who are the most active transmitters.
In fact, some control strategies e.g. shutting schools and thereby limiting contact
between schoolchildren (who are considered to be the most active transmitters of
influenza infection) have been introduced in some countries during influenza
epidemics, without any prior modelling being carried out.

## 5.7: Applications of modelling predicting the critical levels of

treatment or vaccination coverage
On the other hand, models are necessary to calculate the actual level of treatment
or vaccination coverage required to control transmission for a given assumption

Given that the true degree of contact between different population groups (e.g. the
young and the old) is poorly understood, in some countries e.g. the UK, models are
used to explore the effect of several different assumptions about contact between
individuals on the impact of vaccination against measles, pneumococcal,
meningococcal and other infections.
Interaction: tabs
Tab 1:
Example
In the UK, uptake of MMR vaccination has been variable (and sometimes below the
herd immunity threshold for measles), as a result of public concerns over its safety.
Changes in the proportion of individuals who are susceptible to measles infection, as
a result of MMR vaccination and ongoing transmission are used to calculate the
overall net reproduction number for different assumptions about contact between
individuals.
Interaction: Button: "References":
Gay NJ, Hesketh LM,
Morgan-Capner P, Miller E (1995)
Interpretation of serological
surveillance data for measles
using mathematical models:
implications for vaccine strategy.
Epidemiol Infect. 1995;
115(1): 139-56.
Tab 2:
Example (cont)
The size of the net reproduction number then provides an indication of the chance of
an outbreak of measles; models incorporating different assumptions about contact
can provide insight into the numbers of cases which might occur in different age
groups.

## Section 6: Applications of modelling predicting the impact of

control strategies
coverage, models can also be used to answer other policyrelated questions, such
as:
For how long do you need to vaccinate in order to control transmission?
Is mass vaccination at periodic intervals more effective at reducing transmission
than vaccinating a fixed proportion of individuals each year?

If no cases have been observed e.g. for 1 year, what is the probability that control
has been achieved?
These questions have been explored in relation to rubella, measles, and more
recently polio.
Interaction: Button: References
Output:
Anderson RM and Grenfell BT (1986). Quantitative investigation of different
vaccination policies for the control of congenital rubella syndrome (CRS) in the
UK. J Hyg. Camb, 96, 30533.
Anderson RM and May RM (1985). Agerelated changes in the rate of disease
transmission: implications for the design of vaccination programmes. J Hyg.
Camb, 94, 365436.
Eichner M, Hadeler KP, Ditz K. Stochastic models for the eradication of
poliomyelitis: minimum population size for polio virus persistence. Model for
Infectious Diseases: Their Structure and Relation to Data. Eds. V Isham, G
Medley. Cambridge University Press, 1996.
Trotter CL, Gay NJ, Edmunds WJ (2005). Dynamic models of meningococcal
carriage, disease, and the impact of serogroup C conjugate vaccination. Am J
Epidemiol. 2005, July 1; 162(1):89100.
End interaction.
To illustrate this use of modelling, we shall focus on one specific example, namely
the relationship between rubella, the incidence of Congenital Rubella Syndrome
and rubella vaccination coverage.

## 6.1: Applications of modelling predicting the impact of control

strategies
Background
Rubella is a mild immunizing infection. However, if a woman is infected with
rubella when pregnant, the child may be born with Congenital Rubella Syndrome
(CRS).
In countries in which the incidence of rubella is high, most women will have been
infected with rubella when young and will be immune by childbearing age. In such
countries, few women are newly infected with rubella during childbearing age and
the burden of CRS is typically low.
Exercise:
The following chart shows the agespecific proportion of individuals seropositive to
rubella antibodies in the UK and China during the 1980s.

Question: Assuming that neither country had introduced rubella or MMR vaccination
during the 1980s, in which country would you have expected to see a higher
incidence (per live birth) of Congenital Rubella Syndrome ?
Interaction: Buttons:
Button 1: UK
Output:
UK
Correct. The proportion of women of childbearing age who have antibodies (i.e.
immunity) to rubella is higher in China than in the UK. You might therefore expect
the number of new infections per capita among women in China to be lower than
that in the UK, and for the incidence of CRS per 1000 live births to be
correspondingly lower in China.
Button 2: China
Output:
China
Thats not quite right. The proportion of women of childbearing age who have
antibodies (i.e. immunity) to rubella is higher in China than in the UK. You might
therefore expect the number of new infections per capita among women in China to
be lower than that in the UK, and for the incidence of CRS per 1000 live births to be
correspondingly lower in China.
Button 3: References
Output:
Farrington CP (1990) Modelling forces of infection for measles, mumps and rubella.
Statistics in Medicine, 9, 95367.

Wannian (1985). Rubella in the Peoples Republic of China. Rev Inf Dis; 7 (S72).

## 6.2: Applications of modelling predicting the impact of control

strategies
The introduction of any vaccination or treatment programme into a population
reduces the prevalence of infectious cases.
With the reduced opportunity for individuals to become infected, the risk of
infection goes down over time, and as a result, the average age at infection can
increase.
This is important for infections such as rubella.
If vaccination (such as the MMR vaccine) is provided at below the herd immunity
threshold and only among infants, then the proportion of individuals who reach
childbearing age still susceptible to infection increases over time. This, in turn,
may lead to an increase in the burden of Congenital Rubella Syndrome.
Question: Considering the rubella seroprevalence data which you saw on the
previous panel, might you be more cautious about introducing infant MMR
vaccination in China or in the UK?
Interaction: Buttons:
Button 1: UK
Output:
UK
(Probably!) incorrect. In the UK, the burden of CRS was likely to have been greater
in the absence of infant MMR vaccination than in China, where the burden was very
low or non existent.
In China, the introduction of infant MMR vaccination at below the herd immunity
threshold might therefore result in the emergence of a new problem of CRS and,
potentially, a greater relative increase in the burden of CRS than in the UK.
Button 2: China
Output:
China
(Probably!) correct. In the UK, the burden of CRS was likely to have been greater in
the absence of infant MMR vaccination than in China, where the burden was very low
or non existent.

In China, the introduction of infant MMR vaccination at below the herd immunity
threshold might therefore result in the emergence of a new problem of CRS and,
potentially, a greater relative increase in the burden of CRS than in the UK.

## 6.3: Applications of modelling predicting the impact of control

strategies
In practice, this question is very difficult to answer without using modelling
techniques e.g. setting up a model which describes rubella transmission in the
population and simulating the introduction of different levels of coverage.
For example, the incidence of CRS is proportional to:
(proportion of women of childbearing age who are susceptible)

risk of infection
The introduction of infant vaccination will lead to an increase in the proportion of
women of childbearing age who are susceptible.
On the other hand, it will lead to a reduction in the risk of infection.
The net effect on the incidence of CRS will depend on whether the increase in the
proportion of women of childbearing age who are susceptible outweighs the
reduction in the risk of infection

## 6.4: Applications of modelling predicting the impact of control

strategies
Extensive modelling work on this question was carried out by many researchers
(e.g. Anderson, Grenfell, Knox) during the 1980s, as shown in the diagrams
opposite.
According to Figure a, vaccination among infants is associated with decreases in
the CRS incidence, if the average age at infection before introduction of vaccination
is 12 years or more.
As shown in Figure b, for settings in which the average age at infection before the
introduction of vaccination is very low e.g. 3 years (such as that in The Gambia), the
introduction of vaccination at any level of coverage below 85% results in an
increased burden of CRS.
Predictions of the ratio between the numbers of cases of CRS after the
introduction of vaccination infants at different levels of coverage (x-axis)
and that before the introduction of vaccination (Anderson and May (1983)

## Interaction: button: Show

Output:

Typed out by M. A.
Predictions of the ratio between the numbers of cases of CRS after the
introduction of vaccination among infants at different levels of coverage (Xaxis) and that before the introduction of vaccination (Anderson and May
(1983)
Proportion vaccinated
End interaction.
The different lines are predictions for settings in which the average age at
infection before the introduction of vaccination ranged between 3 and 18
years.
Interaction: button: References
Output:

## Anderson RM and May RM (1983). Vaccination against rubella and measles:

quantitative investigations of different policies. J Hyg Camb. 90, 259325.

## 6.5: Applications of modelling predicting the impact of control

strategies
These predictions were proved correct during the 1990s in Greece, where MMR
vaccination had been available in the private sector since the mid 1970s.
As shown in the figure opposite, throughout this time, the proportion of pregnant
women who were susceptible increased from about 12% during the early 1970s to
This gradual increase in the proportion susceptible led to an increase in the incidence
of CRS during the 1990s, with an outbreak of 25 cases occurring in 1993. A further
outbreak occurred in 1999. In contrast, only 8 cases were reported during the
period 19801990.

## Interaction: button: references

Output:
occurrence after immunisation in Greece: retrospective survey and systematic
review. BMJ, 1999 Dec 4; 319 (7223):14627.

## 6.6: Applications of modelling predicting the impact of control

strategies
The issues discussed in relation to rubella are also relevant for other infections:
Polio increases in the incidence of paralytic polio were seen during the 1950s in
many Western populations.
(see e.g. Anderson and May (1991)).

These were attributed to improvements in hygiene and hence a reduction in the risk
of infection and an increasing proportion of individuals being infected with polio virus
for the first time when adults. (Note that infection during adulthood carries a greater
risk of paralytic polio than does infection as a child).
Interaction: button: references
Output:
Anderson and May (1991). Infectious Diesases of Humans: Dynamics and Control.
Oxford University Press, Oxford.
Mumps outbreaks of mumps have been seen among adolescents and young
adults in the UK and other Western countries since the year 2000.
This has been attributed to the introduction of MMR vaccination among young
children, leading to a reduced risk of infection in the overall population, with
individuals born before the introduction of vaccination reaching adult life still
susceptible to infection.
Interaction: button: references
Output:
Savage E, Ramsay M, White J, Beard S, Lawson H, Hunjan R, Brown D. Mumps
outbreaks across England and Wales in 2004: Observational study. BMJ,
2005;330(7500):111920.

## Section 7: Applications of modelling elucidating the

epidemiology of infection
Another use of modelling, which often receives little attention, is in providing useful
insight into the epidemiology of an infection.
For example, models (usually!) aim to recreate the transmission dynamics of an
infection using the smallest number of parameters and assumptions.
Any discrepancy between the models output and real data may therefore help to
elucidate other factors which may be important in the natural history of that
infection.
Interaction: tabs:
Tab 1:
This diagram
Output:

shows predictions of the Hamer model described earlier, adapted to take daily time
steps, rather than time steps of 1 serial interval.
Note that this model, which is more realistic than the Hamer model, predicts that the
cycles should ultimately damp out. The fact that this damping out is inconsistent
with the observed data, suggests that extrinsic factors, which had not been
incorporated in the model, help to sustain the cycles.
Tab 2:
The diagram
Output:

## shows predictions of the numbers of cases of CJD in the UK by Ghani et al during

the late 1990s.
Interaction: button: References
Output:
Ghani AC, Ferguson NM, Donnelly CA, Hagenaars TJ, Anderson RM. Epidemiological
determinants of the pattern and magnitude of the vCJD epidemic in Great Britain.
Proc Biol. Sci. 1998 Dec 22;265(1413):244352
End interaction.
Each of the scenarios shown were based on different assumptions, but led to
predictions of the numbers of cases seen until then, which were consistent with the
observed data.
The work highlighted the fact that too little was known about the epidemiology of
CJD in order to make reliable predictions of the likely scale of the epidemic.

## Section 8: Classification of models

More than 75% of published models have been socalled deterministic models,
as these are easiest to set up.

We will first describe what we mean by deterministic models and return to the other
kinds of models (stochastic models) later in this session.

## Section 9: Setting up deterministic models

Deterministic models describe what happens on average in a population.
The parameters in the model (e.g. the rate at which individuals recover, the
number of individuals contacted by each person per unit time etc) are fixed. Hence
the outcome (e.g. the number of cases seen at any given time) is predetermined.
The majority of deterministic models are compartmental models
Compartmental models stratify individuals into broad epidemiologically meaningful
categories, which depend on the disease, and describe the transitions between these
categories. We will focus mainly on compartmental models.

For immunizing infections, for example, it would be useful to stratify people into
those who are Susceptible, Infected (but not yet infectious), Infectious and
Immune, as follows:
Note that the InfEcted class is also sometimes referred to as the _xposed_class;
this however, can be confusing since everyone can be considered to be exposed.

## 9.1: Setting up deterministic models

Compartmental models describe the transmission dynamics in terms of the total
number of individuals in these categories.
Question: Which of the diagrams opposite might describe the model of the
transmission dynamics of an infection which does not confer complete immunity?
Model A is defined as a SIS model; Model B is referred to as a SIR model; Model C is
defined as a SEIR model and Model D is defined as a SIRS model.

## 9.2: Setting up deterministic models

Deterministic compartmental models can be set up using either difference
equations or differential equations.
We will first describe the approach based on difference equations.
Difference equations describe changes in the numbers of individuals in given
categories using discrete time steps e.g. of 1 day, 2 days etc.
Suppose that we would like to predict the average number of measles cases which
we might see in a closed population (i.e. in which there are no births, deaths or
immigrants or emigrants) following the introduction of a measles case into that
population.
As we are setting up a compartmental model, we first need to stratify individuals into
epidemiologically meaningful categories (compartments and decide on the
transitions between these categories.

## 9.3: Setting up deterministic models

Question: Based on the assumption that measles is an immunizing infection, which
of the diagrams opposite reflects a possible structure for our model?

## 9.4: Setting up deterministic models

Once the model structure has been decided, the next stage in the model
development involves writing down the equations for the number of susceptible,
infected, infectious and immune individuals at a given time t + 1 (e.g. tomorrow) in
terms of the number present at a previous time t (e.g. today).

Returning to our measles model, and considering the susceptible individuals, the
equations need to specify the fact that:
Number susceptible at time t + 1 =
Number susceptible at time t

## Number of individuals who are newly infEcted between t and t + 1

The number of individuals who are newly infEcted between t and t + 1, in turn, is
just the product of the risk that a susceptible individual is infEcted between time t
and t + 1 (traditionally denoted by the symbol) and the number of susceptible
individuals at time t. i.e. tSt

Output:
For example, if 10% (= t) of susceptible individuals are newly infected between
today and tomorrow, and we have 500 (St) susceptible individuals present today,
then the number of individuals who are newly infected between today and
tomorrow is 0.1 * 500 = 50.

## 9.5: Setting up deterministic models

The risk of infection (also referred to as the "force of infection", for historical
reasons) depends on the number of infectious individuals in the population and on
the extent to which they contact other individuals.
If its assumed that individuals mix randomly, then the number of individuals newly
infected in each time is given by the following expression: StIt
Here, is defined formally as the probability of an effective contact between two
specific individuals in each time step, and
It is the prevalence of infectious individuals in the population at time t.
We will return to the definition and derivation of later in this session.
This particular equation is known as the massaction equation, first used by
Hamer in 1906,
Output:
See also page 3 of 23, page of 3 of this session. [Note: this is exactly how this
text appears meaning uncertain!]
End interaction.
which considered individuals coming into contact with each other in the same
(random) way that gas molecules come into contact with each other.
As we shall see later in this session, though simplistic, this formulation leads to
reasonable predictions of time trends in the overall incidence of an immunizing
infection.

## 9.6: Setting up deterministic models

Equating the two expressions for the number of individuals who are newly
infEcted between time t and t + 1, i.e.
StIt = tSt
we see that, after cancelling St on both sides of this equation:
It = t

We can now formally write down the equations for the number of susceptible
individuals at time t + 1 as follows:
St + 1 = St tSt
or as
St + 1 = St StIt

## 9.7: Setting up deterministic models

Returning to our model diagram and now considering the individuals in the
infEcted category, we see that
the equations need to specify the fact that:
Number of individuals in the infEcted category at time t + 1
=
Number of individuals in the infEcted category at time t
+
Number of individuals who are newly infEcted between time t and t + 1

## Number of individuals who develop infectious disease between time t and t + 1.

The number of individuals who develop infectious disease between time infected
and t + 1, in turn, is just the product of the proportion of infected individuals who
develop infectious disease between time t and t + 1 (we will denote this
proportion by f for now) and the number of infected individuals at time t.
We will return to the definition and derivation of f later in this session.

## 9.8: Setting up deterministic models

We can now formally write down the equations for the number of infected
individuals at time t + 1 as follows:
E t + 1 = E t + t S t f E t
or

Et + 1 = Et + StIt f Et
Here we are assuming that the proportion of infected individuals who develop
infectious disease in each time step is the same over time we will return to this
assumption later.

## 9.9: Setting up deterministic models

Returning to our model diagram and now considering the individuals in the
infectious category, we see that the equations need to specify the fact that:
Number of individuals who are infectious at time t + 1
=
Number of individuals who were infectious at time t
+
Number of individuals who develop infectious disease between time t and
t + 1.

Number of individuals who recover from infectious disease between time t and t + 1
The number of individuals who recover from infectious disease between time t and
t + 1, in turn, is just the product of the proportion of infectious individuals who
recover from infectious disease between time t and t + 1 (we will denote this
proportion by r for now) and the number of infectious individuals at time t. i.e. r
It
We will return to the definition and derivation of r later in this session.

## 9.10: Setting up deterministic models

Exercise:
Write down the equation for the number of infectious individuals at time t + 1 in
Output:

It + 1 = It + fEt rIt
Exercise:
Write down the equation for the number of immune individuals at time t + 1 (Rt +
1) in terms of Rt, It and r, and check your answer by clicking on the answer box.
The equations need to specify the fact that:
Number of individuals who are immune at time t + 1 =
Number of individuals who were immune at time t
+
Number of individuals who recover from infectious disease between time t and t+1
Using mathematical notation, this equation can be written as:
Rt+1 = Rt + rIt

## The difference equations for this model can be summarized as follows:

St + 1 = St St It
Et + 1 = Et + St It fEt
It + 1 = It + fEt r It
Rt + 1 = Rt + r It

or equivalently

St + 1 = St tSt
Et + 1 = Et + tSt fEt
It + 1 = It + fEt r It
Rt + 1 = Rt + r It

At present, this model does not incorporate births entering the population or
individuals dying.

To incorporate births into the population, we would need to change the equation
for the number of susceptible individuals (assuming, for now, that individuals are
born susceptible as follows:
St + 1 = St St It + Bt
where Bt is the number of individuals born between time t and t + 1.

## 9.12: Setting up deterministic models

[diagram static]
Exercise: Rewrite the difference equations for the above model, incorporating the
assumption that the proportion of individuals who die during each time step (m) is
the same for the susceptible, infected, infectious and immune individuals (again,
this may not be realistic).
Output:
St + 1 = St St It + Bt mSt
Et + 1 = Et + St It fEt mEt
It + 1 = It + fEt r It mIt
Rt + 1 = Rt + r It mRt
If we assume that the proportion of individuals who die during each time step (m) is
the same for the susceptible, infected, infectious and immune individuals, then the
number of susceptible, infected, infectious and immune individuals who die between
time t and t + 1 is mSt, mEt, mIt, and mRt, respectively.
We therefore need to subtract mSt individuals from the susceptible population at
time t to adjust for the susceptible individuals dying.
Similarly, we need to subtract mEt individuals from the infected population at time t
to adjust for the infected individuals dying, etc.
Exercise
Write down the difference equations corresponding to the following model diagram,
assuming that no individuals are born into or die from the population.

Output:
The equations should be as follows:
St+1 = St tSt + r1Ct
Ct+1 = Ct + tSt + r1Ct fCt r2Ct
Dt+1 = Dt + fCt r3Dt
Rt+1 = Rt + r3Dt + r2Ct

## 9.13: Setting up deterministic models

Technical issue 1: Directions of the arrows
You should notice that the direction of the arrows linking the different
compartments in the model diagram determines whether individuals are added or
taken away from the number of individuals in that compartment.
For example, there is an arrow going out of the susceptible compartment and
entering the infected compartment, reflecting the fact that susceptible individuals are
being newly infected.
Hence, there is a minus sign in front of the term for the number of individuals who
are newly infected ( StIt) in the equation for the number of susceptible individuals
at time t + 1, and there is a plus sign in front of this term in the equation for the
number of infected individuals at time t + 1.

## 9.14: Setting up deterministic models

Technical issue 2: Check for population size
You should notice that if you add the four equations of the model for measles in a
closed population to each other, you obtain the result that:
St+1 +Et+1 + It+1 + Rt+1 = St + Et + It + Rt
i.e. the total population size remains constant over time.

This is a useful check to see whether your equations have any errors.

## 9.15: Setting up deterministic models

Technical issue 3: Risks versus rates
Technically, the input parameters which occur in difference equations are risks
since were using e.g. the proportion of infEcted individuals who develop
infectious disease in each time step, the proportion of infectious individuals who
recover in each time step, etc.
In practice, modellers tend to work with rates in difference equations, since these
are easier to calculate and are approximately equal to the risk. For example, you
may recall that risks and rates are related through the following equation:
risk = 1 erate
If the rate is small (see diagram)
Output:

End interaction.
then the risk is approximately equal to the rate.

## Section 10: Setting up deterministic models: Excel exercise 1

Given estimates for the model parameters, such as and the proportions of infected
and infectious individuals who develop infectious disease and recover in each time

step , the model can be set up in a spreadsheet to predict the total number of
individuals present in each of the compartments over time.
We shall now illustrate how this is done in further detail.

## 10.1: Setting up deterministic models: Excel exercise 1

Step 1: Open up the spreadsheet measles1.xls.
The model in this spreadsheet is designed to simulate the effect of introducing 1
infectious measles case into a population comprising 99,999 susceptible individuals,
assuming that no individuals are born into or die from the population.
You will see some:
a) yellow cells which hold the size of the time step in the model and the total
population size (cells F4 and F5);
b) blue cells which hold the key input parameters (rows 1116) we shall discuss
the derivation of these values later;
c) purple cells (rows 4225594) which will (eventually) hold the equations for the
number of susceptible, infected, infectious and immune individuals over time.
d) a graph (currently empty) which will show the numbers of susceptible, infectious
and immune individuals over time.

## 10.2: Setting up deterministic models: Excel exercise 1

Look at the equations for the number of susceptible and infected individuals for
day 1: you should notice that theyre expressed in terms of the number present
on day 0.
Step 2: Set up appropriate equations for the number of infected and immune
individuals on day 1 in cells D45 and E45, assuming, for now, that no individuals
are born into or die from the population.
Step 3: Copy all the equations for day 1 down until day 200.
Check Excel expression for infectious individuals for day 1
Output:
= D44+C44*dis_rateD44*rec_rate

Check Excel expression for immune individuals for day 1
Output:
= E44=D44*rec_rate
Compare your graph of the number of susceptible, infectious and immune
individuals to the graph here.
Output:

If the two differ, refer to spreadsheet measles1solna.xls to check that you have
typed in the equations correctly.
The graph shows the classic epidemic curve, i.e. after a peak in the incidence of
infectious cases, no further cases arise in the population.
This is attributable to the depletion of susceptible individuals: all have been infected,
have developed disease and are immune to further infection.

## 10.3: Setting up deterministic models: Excel exercise 1

We will now alter the model to incorporate births and deaths. At present, we are
assuming that the population remains constant over time, with the mortality rate
per capita equalling the birth rate per capita.
Step 4: Using the contents of the cells labelled m_rate and num_births, alter the
equations for the number of susceptible, infEcted, infectious and immune

individuals on day 1 to incorporate births into and deaths out of the population
(assuming, for now, that individuals are born susceptible.
Step 5: Copy all the equations for day 1 down until day 25550 (i.e. 70 years).
Interaction: button: Example
Output:
Check Excel expressions for day 1:
Susceptible individuals:
= B44+beta *B44*D44+num_births-B44*m_rate
Infected individuals:
= C44+beta *B44*D44-dis_rate*C44-C44*m_rate [Note: yes, it is C44-C44]
Infectious individuals:
= D44+C44*dis_rate-D44*rec_rate-D44*m_rate
Immune individuals
=E44+D44*rec_rate-E44*m_rate
Step 6: Select rows 18 and 37 together, click with your right mouse button and
choose the unhide option.
NB To select two rows together, click on the grey row header for the first row that
you're interested in, and either hold down the left mouse button and drag the
mouse down to the grey row header for the next row, OR hold the shift key down
and click on the grey row header for the second row.
You should now see the following graph
Output:

of the numbers of susceptible and immune individuals over time. If your graph
differs from this graph, check your equations against the equations in
measles1solnb.xls.
The graph shows that the numbers of susceptible and immune individuals cycle over
time.

## 10.4: Setting up deterministic models: Excel exercise 1

This cycling is attributable to the fact that susceptible individuals are being
a) added to the population as a result of new births and
b) removed from the population as they become infected and subsequently
immune.
The number of susceptible individuals
a) decreases when the number of susceptibles being removed (as a result of their
becoming cases and subsequently immune) is larger than the number being added
through new births;
b) increases when the number of susceptibles being removed is less than the
number being added through new births.

## 10.5: Setting up deterministic models: Excel exercise 1

This cycling in the numbers of susceptible and immune individuals also leads to
cycling in the infectious disease incidence.

Step 7: To see this, double click with your mouse on the righthand yaxis in the
figure showing the longterm trends in the spreadsheet and change the scale to go
from zero to 20.
We shall discuss the relationship between the peaks in the disease incidence and
the numbers of susceptible individuals, after we have considered the derivation of
the input parameters in the model.

## Section 11: Input parameters for models:

is the most important parameter in infectious disease models, but at the same
time, it is the most difficult to estimate.
It is defined formally as the:
probability of an effective contact between two specific individuals per unit time,
and is referred to by various names (which are not always consistent with its
formal definition!) such as the transmission probability, transmission
coefficient, transmission parameter, transmission rate, etc.
An effective contact is defined as one which is sufficient to lead to infection of a
susceptible individual if it occurs between a susceptible and an infectious individual.
As a result, the definition of an effective contact depends on both the method of
transmission (e.g. sexual vs respiratory vs. vectorborn vs. faecaloral etc) and the
infection considered.

## 11.1: Input parameters for models:

For tuberculosis, for example, casual contact is unlikely to lead to transmission, as
shown in the Figure opposite.
The highly infectious nature of measles, on the other hand, means that contact
between individuals can be less intimate than that for TB in order for transmission to
occur.

## Interaction: Button: References:

van Geuns HA, Meijer J, Styblo K
(1975) Results of contact
examination in Rotterdam,
1967-1969. Bull Int Union
Tuberc, 50:107-121

## 11.2: Input parameters for models:

depends further on other factors such as age and setting.
For example, children probably contact more individuals (who are also likely to be
children) than do adults; individuals living in urban areas probably have many
more effective contacts than do those living in rural areas.

Question:
Which of the bars in the above figure are likely to reflect the seroprevalence among
females in rural areas?
Interaction: Buttons:
Button 1: White Bars
Output:
White Bars
Correct. For each age group, the seropositivity is lower among individuals reflected
in the white bars than for the individuals reflected in the black bars, suggesting that
these individuals face a correspondingly lower risk of infection, i.e. they probably live
in rural areas.
Button 2: Black Bars
Output:
Black Bars
Thats not quite right. For each age group, the seropositivity is lower among
individuals reflected in the white bars than for the individuals reflected in the black
bars, suggesting that these individuals face a correspondingly lower risk of infection,
i.e. they probably live in rural areas.
Button 3: References
Output:
Dowdle WR, Ferrera W, De Salles Gomes LF, King D, Kourany M, Madalengoitia J,
Pearson E, Swanston WH, Tosi HC, Vilches AM. WHO collaborative study on the
seroepidemiology of rubella in Carribbean and Middle and South American
populations in 1968. Bull World Health Organ. 1970; 42(3):41922.

## 11.3: Input parameters for models:

may also change over time: as a result of reduction in crowding in living
conditions,
Interaction: hyperlink: reduction in crowding in living conditions
Output:
During the second part of the 19th century, ~8% of the UK population lived in
accommodation with more than 2 individuals per room, as compared with 5.5% by
1901 and ~1% by 1951. By 1991, only 0.25% of the population lived in
accommodation with more than 1.5 individuals per room.
End interaction.

individuals living in many Western countries in the year 1900 probably contacted
more individuals than their counterparts who are alive today.
Interaction: Button: References:
Hunt S. Housing-related
disorders. In: Charlton J, Murphy
M (eds.), The health of adult
Britain, 1841-1994. Volume 1;
chap. 10, 157-70. The Stationery
Office; London 1997.
may also change over time as a result of changes in behaviour or interventions.
During past influenza pandemics, for example, the amount of contact between
individuals changed over time, e.g. with theatres and concert halls shutting and
office closing hours being staggered to avoid the congregation of individuals.
is difficult to measure directly for the majority of infections, excepting possibly,
those involving a vector or sexual transmission. Consequently, it is typically
calculated using indirect methods involving analysis of seroprevalence data and/or
the basic reproduction number.

## 11.4: Input parameters for models:

For example, for immunizing infections, and assuming that individuals mix
randomly, can be formally calculated from the basic reproduction number, using
the expression
= R0 / (Nd),
where N is the total population size and d is the duration of infectiousness.
Interaction: Hyperlink: = R0 / (Nd)
For an infection for which all infected individuals develop infectious disease, the R0
reflects the number of effective contacts made by each person over a time period
which is equal to the infectious period of an infectious case.
R0/d reflects the number of effective contacts made by each person per unit time.
Dividing this by N gives the probability of an effective contact between 2 specific
individuals per unit time.
Exercise:
The basic reproduction number of measles and rubella in some populations has
been estimated to be 13 and 7 respectively.
The duration of infectiousness for measles is 7 days and 11 days for rubella.

Considering population of a given size, is the value for greater for measles or for
rubella?
Interaction: button: Measles
Output:
Measles
Correct. In a population comprising 100 individuals, the value for is 0.019 per
day for measles and 0.0064 per day for rubella.
Interaction: button: Rubella
Output:
Rubella
Thats not quite right. In a population comprising 100 individuals, the value for is
0.019 per day for measles and 0.0064 per day for rubella, i.e. it is higher for
measles than for rubella.

## 11.5: Input parameters for models:

Alternatively, (and other parameters) can be obtained by fitting model
predictions of disease incidence to observed data on the numbers of cases seen
over time.
For more complicated assumptions about mixing e.g. assuming that contact between
individuals is agedependent, is calculated separately for each age group, using
an approach based on fitting to observed seroprevalence data.
Unfortunately, those methods are beyond the scope of this session However,
further details are provided in the following reference:
Anderson RM and May RM (1991) Infectious Diseases of Humans. Dynamics and
Control, Ch 9. Oxford University Press.

## Section 12: Input parameters for models rate at which

individuals develop infectious disease, recover, etc.
An assumption which is often made in infectious disease models is that, once
infected, individuals develop infectious disease at a constant rate, or that once
infectious, individuals recover and become immune at a constant rate.
This assumption is convenient, since
a) the rate at which something occurs is equal to 1/(average time to that event).
b) The average latent and infectious periods are usually known (at least for
immunizing infections).

For example, the average infectious period for measles is 7 days; the rate at which
infectious individuals recover from infectious disease is 1/7 = 0.143 per day.

## 12.1: Input parameters for models rate at which individuals

develop infectious disease, recover, etc.
The assumption that individuals develop or recover from infectious disease at a
constant rate may not be realistic, since it implies that the latent or infectious
periods follow the negative exponential distribution.
Output:

End interaction.
Distribution of the time interval between infection and onset of
infectiousness, assuming that individuals develop infectious disease at a
constant rate of 0.143/day
Days since infection
It is possible to refine this assumption e.g. to assume that the rate of infectious
disease onset depends on time since infection.
In practice, the level of complexity incorporated in the model usually depends on

## One rule in modelling is to keep models as simple as possible, and no simpler. If

model predictions fail to match the observed data, then this is a strong indicator that
the model is too simplistic and some assumptions need to be changed!

## Section 13: Setting up deterministic models Excel exercises II

(measlesfin1.xls) and incorporate these expressions for the input parameters and
explore how they influence the disease incidence.
Step 1: Select rows 5 and 10 of this spreadsheet together, click with the right mouse
button and choose the unhide option.
You should now see some yellow cells, containing values for the average latent and
infectious periods, the life expectancy and the basic reproduction number.
Step 2. Set up appropriate equations for beta, dis_rate, rec_rate and m_rate in the
corresponding cells.
At this stage, your graphs should remain unchanged. If they change, check your
equations against the contents of measles1solnc.xls.

## 13.1: Setting up deterministic models Excel exercises II

The model currently incorporates the latent and infectious periods and the R0 for
measles.
Step 3: Change the latent and infectious periods and the R0 to be those for rubella
(10 days, 11 days and 7 respectively).
Question: How does changing the input parameters in the model to reflect those of
rubella affect the:
a) epidemic curve during the first 200 days following the introduction of the
infectious case into the population?
b) the cycles in the numbers of immune and susceptible individuals?
(The answer is on the next slide)

## 13.2: Setting up deterministic models Excel exercises II

a) The epidemic curve for rubella
The epidemic peaks later for rubella than it does for measles, as you can see by
clicking on the graph button below.
You would expect this to happen, since the latent period is longer for rubella than it
is for measles. It therefore takes longer for a rubella case to appear in the
population after infection than for a measles case.

You should also notice that, as for measles, all individuals are immune in the
population by the end of the first 200 days following the introduction of the infectious
case.
Interaction: button: Graph
Output:

## Predictions of the daily incidence of measles and rubella following the

introduction of one infectious individual into a totally susceptible population
comprising 100,000 individuals

## 13.3: Setting up deterministic models Excel exercises II

b) The cycles in the numbers of
susceptible and immune individuals
for rubella
The numbers of susceptible and immune individuals cycle more slowly for rubella
than they do for measles.
You might have expected this to occur, since the R0 for rubella is smaller than that
for measles. Since each rubella case removes fewer susceptible individuals than
does each measles case, it takes longer to deplete the susceptible population for
rubella than it does for measles.
We shall now discuss the relationship between the R0 and these cycles in more
detail.

## Section 14: The relationship between the R0 and the cycles in

disease incidence: Excel exercises III
From your previous epidemiological training, you will recall that the size of the net
reproduction number (Rn) determines whether or not the disease incidence
increases or decreases in a given population (see EC03 p11).

If Rn is bigger than one (i.e. each infectious case is leading to more than one
secondary infectious case), then the disease incidence should increase.
If Rn is less than one (i.e. each infectious case is leading to less than one secondary
infectious case), then the disease incidence should decrease.
We will now use our spreadsheet model to explore this relationship further.
Step 1: Open up the spreadsheet measles2.xls. It is very closely related to the
spreadsheet you have just been using, except that we now have some cells set up
for the proportion of susceptible and immune individuals in the population for day
1.
Step 2. Set up an appropriate expression for the net reproduction number on day 1
and copy this expression down until the 18250th day.
Interaction: Button: Hint:
The expression for the net reproduction number on day 1 should be: =G81*R0

## 14.1: The relationship between the R0 and the cycles in disease

incidence: Excel exercises III
Step 3: Select the columns I and V together, click with your right mouse button
and select the unhide option.
You should now see Figure 1
Output:

(end interaction)
which plots the Rn on the left hand yaxis and the disease incidence on the right

hand yaxis in the population. The xaxis goes from the 14600th day (ie the 40th
year) to the 18250th day (ie the 50th year). The gridlines on the xaxis occur at 2
year intervals.
(If Figure 1 in your spreadsheet does not resemble this Figure, you may like to check
Question: What is the value of the Rn when the disease incidence peaks or reaches
a trough?
Interaction: hotspots (set 1):
Hotspot 1: ~>1
Thats not quite right. At the peak or trough of the disease incidence, Rn is
approximately equal to 1.
Hotspot 2: ~<1
Thats not quite right. At the peak or trough of the disease incidence, Rn is
approximately equal to 1.
Hotspot 3: =1
Correct. At the peak or trough of the disease incidence, Rn is approximately equal
to 1.
End hotspots (set 1).
Question: What is happening to the disease incidence when Rn~<1?
Interaction: hotspots (set 2):
Hotspot 1: Increasing

Thats not quite right. When Rn~<1, the disease incidence is increasing.
Hotspot 2: Decreasing
Correct. When Rn~<1, the disease incidence is increasing.
Hotspot 3: Unchanging
Thats not quite right. When Rn~<1, the disease incidence is increasing.
Question: What is happening to the disease incidence when Rn~>1?
Interaction: hotspots (set 3)
Hotspot 1: Increasing
Correct. When Rn~>1, the disease incidence is increasing.
Hotspot 2: Decreasing
Thats not quite right. When Rn~>1, the disease incidence is increasing.
Hotspot 3: Unchanging
Thats not quite right. When Rn~>1, the disease incidence is increasing.

## 14.2: The relationship between the R0 and the cycles in disease

incidence: Excel exercises III
Step 2: Select rows 22 and 43 together, click with the right mouse button and
select the unhide option.
You should now see Figure 2,
Output:

(end interaction)
which plots the proportion susceptible on the left hand yaxis and the disease
incidence on the right hand yaxis.
Question. What proportion of the population is susceptible to infection when the
disease incidence peaks or troughs?
Output:
At a peak or trough in disease incidence, the proportion of individuals which are
susceptible is approximately 0.077.
You should remember from previous sessions that, for transmission of an infectious
disease to persist in a population, the proportion of the population which is immune
to infection has to be below the herd immunity threshold(HIT), which is given by:
HIT = 1 1/R0
Question: According to this expression, what should be the herd immunity threshold
for the infection in this model?
Output:
The R0 is 13, so the herd immunity threshold is 11/R0 which is approximately
equal to 92.3%.

## 14.3: The relationship between the R0 and the cycles in disease

incidence: Excel exercises III
Step 3: Select rows 49 and 70 together, click with the right mouse button and
select the unhide option.

## You should now see graph: Figure 3

Output:

(end interaction)
which plots the proportion immune in the population together with the disease
incidence.
Question: What proportion of the population is immune when the disease
incidence peaks or troughs?
Output:
At a peak or a trough in the disease incidence, the proportion of the population
which is immune is approximately 0.923, i.e. equal to the herd immunity threshold.
(Note that this is equal to 1 0.077, the proportion of the population which is
susceptible at this time, as we saw earlier on EC06p15c3)
End interaction.
Question: What do you notice about the proportion of the population which is
immune when the disease incidence is a) declining? b) increasing?
Output:

When the disease incidence is declining, the proportion of the population which is
immune is always above 0.923, i.e. above the herd immunity threshold.
Output:
When the disease incidence is increasing, the proportion of the population which is
immune is always below 0.923, i.e. above the herd immunity threshold.

## Section 15: The relationship between the R0 and the cycles in

disease incidence: summary
The spreadsheet exercise which you have just completed should help to reinforce
the theory that you learnt in previous sessions: for the incidence of an infectious
disease to increase or decrease, the proportion of the population which is immune
must be below or above the threshold respectively, given by:
1 1/R0
This is equivalent to saying that the proportion of the population which is susceptible
must be above or below the threshold 1/R0 for the disease incidence to increase or
decrease respectively.

The exercise also highlights the fact that cycles in the incidence of an immunizing
infection occur because of cycles in the proportion of individuals who are susceptible
and immune.

## 15.1: The relationship between the R0 and the cycles in disease

incidence: summary
For example, as shown in this graph,
Output:

## A summary of the process underlying the cycles in measles incidence

Disease incidence
Proportion susceptible
A. Numbers of new births added to popn ~>number of susceptibles being
removed, resulting in an increase in proportion of susceptibles
B. Proportion susceptible now sufficiently large (i.e. ~> 1/Ro) for each
case to start to lead to ~> 1 secondary case = ~> increase disease
incidence
C. Increased proportion susceptible slows and then reverses, since no.
susceptible being removed ~> no. being born
D. Proportion susceptible is now so low (i.e. ~< 1/Ro) that each case
leads to ~< 1 secondary case and the disease incidence starts to
decrease
the proportion of susceptible individuals in the population increases if the number
of births entering the population exceeds the number of susceptibles being
removed, as they become cases and then immune. (point A).
The disease incidence starts to increase once the proportion susceptible starts to
exceed 1/R0. (point B)

## 15.2: The relationship between the R0 and the cycles in disease

incidence: summary
This increase in the incidence (and hence prevalence) of infectious cases, in turn,
slows down and eventually reverses the increase in the proportion of individuals

who are susceptible i.e. more susceptibles are being removed than are being added
to the population. (point C)
Once the proportion of susceptible individuals has decreased to be below 1/R0, each
case starts to lead to less than one secondary case and the disease incidence
decreases (point D).
Interaction: button: Graph
Output:

## A summary of the process underlying the cycles in measles incidence

Disease incidence
Proportion susceptible
A. Numbers of new births added to popn ~> number of susceptibles
being removed, resulting in an increase in proportion of susceptibles
B. Proportion susceptible now sufficiently large (i.e. ~> 1/Ro) for each
case to start to lead to ~> 1 secondary case = ~> increase disease
incidence
C. Increased proportion susceptible slows and then reverses, since
number susceptibles being removed ~> no. being born
D. Proportion susceptible is now so low (i.e. ~< 1/Ro) that each case
leads to ~< 1 secondary case and the disease incidence starts to
decrease

## 15.3: The relationship between the R0 and the cycles in disease

incidence: summary
The interepidemic period
It can be shown that the interepidemic period for an immunizing infection is
related to its basic reproduction number through the following expression:

T 2

L( D + D' )
R 0 1

Here, L is the average life expectancy, and D and D are the durations of the latent
and infectious periods respectively. is the universal constant, given approximately
by 3.14.
Use this formula to calculate the interepidemic period in a population in which the
life expectancy is 60 years for
a) measles (R0=13, D=8 days, D=7 days)
b) rubella (R0=7, D=10 days, D=11 days)

Output:

T 2 x3.14

60 x365(7 + 8)
= 1039days = 2.85 years
13 1

Output:

T 2 x3.14

60 x365(11 + 10)
= 1739days = 4.76 years
7 1

## 15.4: The relationship between the R0 and the cycles in disease

incidence: summary
You should find that the values obtained using the formula for the interepidemic
period should be consistent with the values predicted by the spreadsheet model
that you were working with, once the cycles have settled down.
However, if the spreadsheet model is extended to make predictions
Output:

## Predictions of the daily incidence of measles cases, following the

introduction of 1 infectious case into a totally susceptible population
Number of cases per day per 100,000 population
Time (years)
for a prolonged time period e.g. over 100 years, then the cycles eventually damp out
(although they can still be seen if the yaxis scale is refined sufficiently).
Since this damping out is inconsistent with what is observed in reality for
immunizing infections, it suggests that other extrinsic factors must be important in
sustaining these cycles.
The most likely factor is seasonal contact, which occurs as a result of children
contacting each other intensively during school terms and less so during the school
holidays.
Interaction: button: References
Output:
Fine PEM and Clarkson JA (1982) Measles in England and Wales I: an analysis of
factors underlying seasonal patterns. Int J Epidemiol 11(1):514.

## 15.5: The relationship between the R0 and the cycles in disease

incidence: summary
There is also a discrepancy between model predictions of disease incidence for
influenza and the observed data.
For example, application of the formula
Output:
For influenza, the average latent and infectious periods are both roughly 2 days, and
the R0 has been estimated to be approximately 2.
End interaction.
for the interepidemic period suggests that the peaks in the incidence of influenza
should occur roughly every 56 years, whereas, in reality, in most European
countries, influenza epidemics occur almost every winter.
This discrepancy suggests that the model would need to be changed to be
consistent with the observed data, e.g. incorporating changes in the strain of
influenza in circulation, so that individuals are not completely immune to the new
strain, if its introduced into the population.
In addition, the predicted interepidemic period would change if the model were to
incorporate seasonal contact between individuals or seasonality in the
transmissibility of the influenza strain.

## Section 16: Beyond difference equations: time step sizes and

differential equations
As you have just seen, difference equations describe the numbers of individuals in
different categories using discrete time steps e.g. of 1, 2, 3 days etc.
Such models can be set up in any spreadsheet, although using it to make longterm
predictions (e.g. for 100 years) can become difficult as the spreadsheet can become
large.
To reduce this problem, the size of the time step used in the model can be
increased.
To see an example of how this can be achieved, open up the spreadsheet
measles3.xls.
This spreadsheet is similar to the models that we have been using so far, except
that and the transition, birth and mortality rates have been reexpressed to take
account of the size of the time step.

Step 1: Change the size of the time step (in cell F4) to be 0.5, 2, 3, 4 and 5 days
and look at predictions of the longterm disease incidence.

## 16.1: Beyond difference equations: time step sizes and

differential equations
You should notice that predictions of disease incidence based on time step sizes of
0.54 days, as shown in the graph in the spreadsheet, are very similar.
However, if the time step is 5 days then the model fails to make reliable predictions.
This results from the fact that the size of is now so large that, between day 50
and 55 more individuals are predicted to become infected than were susceptible on
day 50.
This, in turn, leads to negative numbers of susceptible individuals on day 55, which,
in the current model, leads to negative numbers of infectious individuals and
ultimately, the model fails to make sensible predictions.

## 16.2: Beyond difference equations: time step sizes and

differential equations
A way of ensuring that models make reliable longterm predictions and avoiding
the problems with inaccuracies in using large step sizes is to use differential
equations.
Differential equations use time step sizes which are infinitesimally small and
therefore describe the transmission dynamics in continuous time.
Such equations can be set up in specialist software packages (e.g. ModelMaker,
Berkeley Madonna), which convert differential equations into difference equations,
but then adjust for the error resulting from using discrete time steps rather than
continuous time.

## 16.3: Beyond difference equations: time step sizes and

differential equations
The notation for differential equations
Output:

for the measles model we were discussing earlier differs from that for the
difference equations.
Output:

These differences are discussed in the optional reading section for this session.

## As we have seen, deterministic models describe what happens on average in a

population.
As such, they are unlikely to provide a reliable answer to questions involving small
populations, where chance might play an important role in the outcome.
using a deterministic model:
If we introduce 1 infectious case of MRSA into a ward comprising 20 susceptible
individuals, how many cases are we likely to see?
What is the probability that transmission will cease?
What is the 95% confidence interval in the number of cases that we will see?
On the other hand, these kinds of questions could be answered using a stochastic
model.

## 17.1: Beyond difference equations: stochastic models

Stochastic models incorporate chance variation e.g. in the number of individuals
infected during each time step.
They are therefore analogous to the ReedFrost mechanistic model which you saw
in one of the earlier slides
In the same way that the outcome from one simulation run of that model was not
interpretable, stochastic models have to be used to run many simulations in order for
the findings to be useful.
This is illustrated in the spreadsheet stoch1.xls which shows an example of a
stochastic model.
This model describes the transmission dynamics of an infection following the
introduction of 1 infectious case into a population of 10 susceptible individuals.
The status of each individual at the end of each time step (taken to be one serial
interval) is described in the orange cells and is determined by the size of the
random number drawn in the adjacent pink cell.
If this random number is less than the risk of infection, then the person becomes a
case; otherwise that person remains susceptible.

## 17.2: Beyond difference equations: stochastic models

You will notice that pressing the F9 (or any other) key leads to a new set of
random numbers and hence to new predictions of the numbers of cases in the
population.

If a stochastic model is run many (e.g. 1000) times, then the average result from all
of these runs should be very similar to the outcome from a deterministic model.

## Section 18: Final conclusions: how complex do models have to

be?
As you have seen in the Excel exercises, the simple models of the transmission of
an immunizing infection such as measles were able to recreate the cycles in
incidence which are seen in reality.
These models also help to provide insight into how the basic reproduction number
influences these cycles and they can be extended to explore the effect of vaccinating
infants on the overall incidence.
However, this model as it stands, has limited use, if, for example, we would like to
know the numbers of cases in various age groups, or the effect of agedependent
mixing on the impact of an intervention.
Additional complexities can be built in to examine these issues (e.g. stratifying the
population by age and incorporating an agedependent parameter.
The methods for doing this are, unfortunately, beyond the scope of this session.
This then leads on to the question of how complex does a model need to be?

## 18.1: Final conclusions: how complex do models have to be?

The development of fast computers has meant that it is now possible to have
models which are as realistic as possible.
An example of such a model is the ONCHOSIMmodel, which was developed during
the 1990s and described the transmission dynamics of onchocerciasis explicitly for
every individual and every parasite in a given village population.
Interaction: Button: References
Output:
Palasier AP, von Oortmarssen G, Habbema JDF, Remme J, Alley ES. ONCHOSIM: a
model and computer simulation program for the transmission and control of
onchocerciasis. Computer Methods and Programs in Biomedicine, 1990; 31;4356.
A more recent example is the model (published in 2005) describing the
transmission dynamics of pandemic influenza in Thailand at the individual level,
also accounting for movement patterns of individuals to work and elsewhere.
Interaction: Button: References

Output:
Ferguson NM, Cummings DA, Cauchemez S, Fraser C, Riley S, Meeyai A,
Iamsirlthaworn S, Burke DS. Strategies for containing and emerging influenza
pandemic in Southeast Asia. Nature. 2005 Sep 8;437(7056):20914.
End interaction.
The main drawback of complex models is that, because they incorporate many
different parameters and assumptions, the individual effect of a particular factor on
the model prediction becomes difficult to understand.

## 18.2: Final conclusions: how complex do models have to be?

An alternative approach is that reflected in a quote by Einstein, namely that:
a model should be as simple as possible and no simpler i.e. the complexity of a
model should depend on the question being answered
Ultimately, models are often useful for informing policy and providing insight into
the epidemiology of an infection.
However, they should only be used as a guide: the input parameters and
assumptions should be questioned before the output is accepted

## Section 19: Summary

This is the end of EC06. When you are happy with the material covered here please
move on to session EC07.
The main points of this session will appear below as you click on the relevant title.
Applications of models
There are two main areas of application of modelling:
a) Predicting the level of treatment or vaccination coverage for control and the
future numbers of cases
b) Providing insight into the natural history of an infection

19.1: Summary
Models are classified into those which are deterministic and those which are
stochastic.
Deterministic models describe what happens on average in a population.
Stochastic models incorporate chance variation in e.g. the number of individuals
infected and might be used to address questions such as:

what is the probability of an outbreak following the introduction of one case into a
given population?

19.2: Summary
Deterministic models can be set up using either difference equations of differential
equations.
Difference equations describe the transmission dynamics of an infection using
discrete time steps of e.g. 1, 2 days etc.
Differential equations describe the transmission dynamics using continuous time.
Interaction: tabs:
Tab 1: Difference Equations
An example of a model for an immunizing infection set up using difference
equations:

## Tab 2: Differential Equations

An example of a model for an immunizing infection set up using differential
equations:

19.3: Summary
The most important parameter in infectious disease models is , defined as the
probability of an effective contact between two specific individuals per unit time.
For an immunizing infection in a randomly mixing population, it can be calculated
using the expression:
R0/(ND)
where N is the population size and D is the duration of infectiousness.
For simple models, the transition rates, (e.g. rates of infectious disease onset, the
recovery rate) can be calculated using the expressions:
1/(average latent period)
or
1/(average duration of infectiousness)
assuming that these rates are constant over time.

19.4: Summary
The level of complexity incorporated in a model depends on the question being
For example, a simple model of the transmission dynamics of measles following the
introduction of 1 infectious case into a totally susceptible population can provide
useful insight into the factors underlying the cycles in incidence e.g. the basic
reproduction number.

On the other hand, such a model would need to be extended to make predictions
about the numbers of cases in specific age groups, or the effect of nonrandom
mixing on the impact of control strategies.

## Section 20: Optional reading: writing down differential equations

The first distinction between difference and differential equations lies in the
notation.
For example, as shown in the diagram opposite, the number of susceptible
individuals at time t is denoted by the symbol S(t) rather than St, reflecting the fact
that were considering events occurring in continuous time, rather than taking
discrete time steps.
Difference equation model:

## 20.1: Optional reading: writing down differential equations

When describing the transmission using continuous time, it is usually not possible
to express the number of susceptibles at a given time in terms of that at a previous
time.
Instead, we use the notation shown opposite we shall now describe the
interpretation of these equations.

## 20.2: Optional reading: writing down differential equations

Technically, differential equations describe the rate of change of a given quantity.
The rate of change in the number of individuals in a given category is just given by
the difference between the number of individuals entering the category and the
number of individuals moving out per unit time
or
+ the number entering the category per unit time
the number leaving the category per unit time

Returning to the above model and considering the susceptible category, for
example, as noone enters the susceptible class, the rate of change in the
number of susceptible individuals is given by the expression:

the number of susceptible individuals who become newly infected per unit
time
Using mathematical notation, this would be written as:
dS(t)
= -S(t)I(t)

dt

## 20.3: Optional reading: writing down differential equations

Considering the infected category in the same model, newly infected individuals
enter this category and diseased individuals exit this category.
The rate of change in the number of infected individuals is given by the expression:
+ the number of susceptible individuals who become newly infected per unit time
the number of infected individuals who develop infectious disease per unit time.
Using mathematical notation, the rate of change in the number of infected
individuals would be written as:
dE(t)
= -S(t)I(t)-fE(t)
dt

## 20.4: Optional reading: writing down differential equations

Exercise:
Considering the above model, write down the differential equations for the rate of
change in the number of
Interaction: Button: (a)infectious individuals
Output:

A total of fE(t) Infection individuals enter this category per unit time and rI(t) exit
this category per unit time. The rate of change in the number of infectious
individuals is therefore given by:

dl (t )
= fE (t ) rl (t )
dt
Interaction: Button: (b) immune individuals
Output:
A total of rI(t) Infectious individuals enter this category per unit time and no
individuals exit this category per unit time. The rate of change in the number of
immune individuals is therefore given by:

dR(t )
= rl (t )
dt
Exercise:
Write down the differential equations corresponding to the following model
diagram, assuming that no individuals are born into or die from the population.