MATHEMATICAL MODELS OF

INFECTIOUS DISEASES
Pej Rohani & John Drake

Odum School of Ecology

University of Georgia
GLOBAL CAUSES OF MORTALITY
Measles & pertussis account for
~300,000 and ~200,000 annual deaths

Total mortality
Infant mortality
MULTIFACETED APPROACH TO
UNDERSTANDING INFECTIOUS DISEASES
Medicine But these approaches don’t address
important questions at population
level ...
Microbiology

Genomics Immunology
Vaccines & Drugs
EMERGING PATHOGENS
SCHOOL OUTBREAK

300

#  Boys  confined  to  bed

250

200

Boarding  School,  England

150

Jan  1978 100

Raises  numerous  ques@ons:

50

• What  is  e@ological  agent? 0

0 2 4 6
Day
8 10 12

• Is  it  novel?
• Is  a  vaccine  available?
MODELING QUESTIONS I.
BASICS
300

250
Why  does  
epidemic  
What  does     turn  over?
200
growth  rate  
#  Boys  confined  to  bed

tell  us?

150

100

50

Why  did  it  

What   go  ex@nct?
determines   0
0 2 4 6 8 10 12
invasion? Day
MODELING QUESTIONS II.
CONTROL IMPLICATIONS
How  to   Random  or  
prevent   aimed  at  age/
spa@al   When  is  it   core  group?
spread? best  to  
implement  
controls? Drugs,  Vaccines  
Is  it   or  other  control  
evolving? measures?

How  
dras@c?

Probability  of  
How  to  prevent  
invasion  or  
invasion/
ex@nc@on
reinvasion?
WHAT IS A MODEL?

Different types of models:

A mathematical/computational model is an abstract model
that uses mathematical language to describe the behaviour of a
system
A Statistical model attempts to describe relationships between
observed quantities and independent variables

Developing a mechanistic model is different from statistical

analyses of data
ABSTRACTION

Purpose Components

Reality Conceptualization
Abstraction

Interpretation

Assumptions Limitations Validation

WHAT’S A ‘GOOD’ MODEL?

Choice of model depends crucially on focal question and available

data (hammer & chisel or pneumatic drill?)

Use model principally for

understanding nature
making predictions
JUDGING A MODEL…
Three fundamental features of models, often opposing forces:
Accuracy
Capture observed patterns (qualitative or quantitative?) and make
predictions
Increases with model complexity

Transparency
Ability to understand model components
Decreases with model complexity

Flexibility
How easily can model be adapted to new scenarios?
Decreases with model complexity
REALISM VS TRANSPARENCY
Transparency

Multi-Scale

Network
Resolution

Agent-Based
“Realism”

Structured
Homogeneous

Solution tools
‘HOW’ DO YOU MODEL?
Analy2cal  Models
Concentrate  on  problems  that  can  be  expressed  and  
analysed  fully  using  analy@cal  approaches.

Problem-­‐based  Models
Construct  most  “appropriate”  model  and  use  
whatever  combina@on  of  methods  for  analysis  and  
predic@on.

Ready-­‐Made  So+ware
ModelMaker
[email protected]/modelmaker/modelmaker.html
GLOBAL SIMULATORS
RESOURCE MATERIALS

Keeling & Rohani (2008)

Vynnycky & White (2010)

Anderson & May (1991)

Otto & Day (2007)

MATHEMATICAL MODELLING OF INFECTIOUS
DISEASES

Objective 1: Setting up simple models Objective 4: Heterogeneities

Different transmission modes Risk structure
Basic Reproduction Ratio (R₀), Simple Age-structured transmission
Epidemics, Invasion threshold & Realistic pathogenesis
extinction Seasonality
Stability analysis
Objective 5: Sensitivity & Variability
Objective 2: Control Stochastic implementation
Infection management Parameter uncertainty

Objective 3: Statistical estimation

R0 and other parameters
STEPS IN DEVELOPING A MODEL

Formulate problem/objectives

Conceptual model diagram

Dynamic equations

Computer code
THE SIMPLEST MODELS

Let’s develop a model for Boarding School influenza outbreak

Some important choices need to be made at outset
1. What do we want to keep track of?
Amount of virus in population?
Antibody titre of everyone in population (school)?
Cities in which infected people have been found?
CATEGORISING INDIVIDUALS
Healthy Incubating Diseased Clinical status

Susceptible Exposed/latent Infectious Recovered/Immune Infection status

Incubating Infectious, Infectious, Infectious,

latent symptomatic quarantined
THE SIMPLEST MODELS
Pragmatic choice: categorise individuals in population according to their
infection status, eg:

Susceptible
Infectious
Recovered/Immune
These are our
“system variables”
THE SIMPLEST MODELS
2. What model structure?
-- Determined by pathogen biology

Suscep@ble Infec@ous SI – signifies fatal infection

Suscep@ble Infec@ous Recovered SIR – recovery after infection

Suscep@ble Exposed Infec@ous Recovered SEIR – latency

Suscep@ble Infec@ous SIS – no immunity elicited

THE SIMPLEST MODELS
2. What model structure?
-- Determined by pathogen biology

Carrier

Suscep@ble Infec@ous Recovered SIR – with carriers

Suscep@ble Exposed Infec@ous Recovered

Infec@ous Exposed Suscep@ble Vectored transmission

THE SIMPLEST MODELS
What model structure?
Depends on what do we know about the pathogen (eg, influenza)
It’s directly transmitted (aerosol)
An acute infection
Lifelong immunity (to that strain)

Transmission Recovery

Suscep@ble Infec@ous Recovered

THE SIMPLEST MODELS
Transmission Recovery

Suscep@ble Infec@ous Recovered

Flow between classes/compartments determined by details of host population

structure and pathogen biology

Host population size

Contact rates These are our “parameters”
Pathogen infectivity
THE SIMPLEST MODELS
3. Deterministic or stochastic?

Deterministic 50 independent
stochastic
realizations

On average, stochastic simulations identical to deterministic

predictions, though individual realizations may be quite different
REALISM VS TRANSPARENCY

Multi-Scale

Network
Resolution

Agent-Based

Structured
Homogeneous

Solution tools
THE SIMPLEST MODELS
We’ve settled on a deterministic SIR model – now what?

How do we write down some equations to describe spread of ‘flu in this

population?
Assign each system variable a unique Roman letter, eg:
Susceptible, S (proportion) or X (number)
Infectious, I (proportion) or Y (number)
Recovered/Immune, R (proportion) or Z (number)
Assign parameters a unique (typically Greek) letter, eg:
Contact rate, κ
Pathogen infectivity, ν
VERY IMPORTANT!
NOTHING SPECIAL ABOUT MY CHOICE OF NOTATION – USE
OF PARTICULAR LETTERS HIGHLY IDIOSYNCRATIC

OTHER AUTHORS MAY USE DIFFERENT LETTERS TO

DENOTE SAME VARIABLES OR PARAMETERS.

YOU CANNOT AUTOMATICALLY ASSUME THAT β IN TWO

DIFFERENT PAPERS MEANS THE SAME THING!
3. MODEL EQUATIONS
BATH TUB EXAMPLE
Water inflow rate,
I(t)

Let W(t) be amount of water in bathtub

(ml)

Need a dynamic equation that tells us

how W(t) will change through time
Water outflow
rate, O(t)
Consider a small time interval, δt

Then,

W(t+ δt) = W(t) + Inflow rate × elapsed time - Outflow rate × elapsed time
BATH TUB EXAMPLE
Water inflow rate,
I(t)
W (t + t) = W (t) + I ⇥ t O⇥ t

Rearrange

W (t + t) W (t)
=I O
t Water outflow
rate, O(t)

Left hand side is a difference quotient for derivative of W with

respect to time

Let δt → 0 dW
=I O
dt
MANY BATHTUBS =
COMPARTMENT MODELS
MODEL EQUATIONS

If we knew Xt and Yt, could we predict Xt+δt and Yt+δt, where δt is

some (very short) time later?

Xt+δt = Xt – (νκ δt) Xt Yt/N

Yt+δt = Yt + (νκ δt) Xt Yt/N - (γ δt) Yt

And
Zt+δt = Zt + (γ δt) Yt

ν is probability of transmission given contact

κ is contact rate
BASIC QUESTIONS?
β=νκ

Xt+δt = Xt – (β δt) Xt Yt/N

Yt+δt = Yt + (β δt) Xt Yt/N - (γ δt) Yt
Zt+δt = Zt + (γ δt) Yt

Average infectious period given by 1/γ [why?]

MEAN LIFE TIME CALCULATION
t
Consider recovery of a single infectious individual I(t) = e
Z 1
t
c
1= ce dt =
o

Hence, probability density function is γe-γt

1
=

Z 1
For a random variable x, with probability density function f(x), thexfmean
(x)dxis given by
0
AN ODE MODEL

Consider the equation describing Susceptible dynamics

Xt+δt = Xt – (β δt) Xt Yt/N

Re-write as
Xt+δt - Xt = - (β δt) Xt Yt/N
(Xt+δt – Xt)/ δt = β Xt Yt/N

By fundamental theorem of calculus, as δt → 0,

dX/dt = - β X Y/N
AN ODE SIR MODEL

dX Y
= X
dt N
dY Y
= X Y
dt N
dZ
= Y
dt
o By definition, X+Y+Z = N
o These equations describe rates of change in state variables
o Parameters β, γ represent instantaneous rates
AN ODE SIR MODEL

dX
In my lectures Y
= (as X in K&R 2008),
dt N
variables X, Y & Z refer to the
dY Y
numbers=of individuals in each class.
X Y
Variables
dt S,NI, & R refer to the
proportionsdZof =
theYpopulation in
each
dt class
o These equations describe rates of change in state variables
o Parameters β, γ represent instantaneous rates
AN ODE SIR MODEL
dX Y
= X
dt N
dY Y
= X Y
dt N
dZ
= Y
dt
Important to notice: transmission rate is assumed to depend on
frequency of infecteds in population (Y/N). Hence, this is frequency-
dependent transmission
SIMULATING EPIDEMICS
Transmission rate, Transmission rate, Transmission rate, Transmission rate,
β = 10 yr-1
β = 10; 1/γ = 3d
β = 50 yr-1
β = 50; 1/γ = 3d
β = 100 yr-1
β = 1e+02; 1/γ = 3d
β = 200 yr-1
β = 2e+02; 1/γ = 3d
1

Infected
Susceptible

Infectious period (1/γ) = 3 days 0.5

0.1
0 0
0 0.5 1 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2

β = 10; 1/γ = 10d β = 50; 1/γ = 10d β = 1e+02; 1/γ = 10d β = 2e+02; 1/γ = 10d
1 1 1 0.8
0.9
0.8 0.8 0.8
0.6

Infected
0.7
Susceptible

0.6 0.6 0.6

Infectious period (1/γ) = 10 days 0.5
0.4
0.4
0.4
0.4
0.3
0.2 0.2
0.2 0.2
0.1
0 0 0 0
0 0.5 1 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2

β = 10; 1/γ = 20d β = 50; 1/γ = 20d β = 1e+02; 1/γ = 20d β = 2e+02; 1/γ = 20d
1 1 1

Infected
Susceptible

0.5 0.5
Infectious period (1/γ) = 20 days 0.5 0.4 0.5 0.5

0.2

0 0 0 0 0 0
0 0.5 1 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2

β = 10; 1/γ = 30d β = 50; 1/γ = 30d β = 1e+02; 1/γ = 30d β = 2e+02; 1/γ = 30d
1 1 1

0.8

Infected
Susceptible

0.6 0.5 0.5 0.5

Infectious period (1/γ) = 30 days 0.4
0.4 0.5 0.5
0.3
0.2
0.2
0.1
0 0 0 0 0 0
0 0.5 1 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2 0 0.05 0.1 0.15 0.2

Time (years) Time (years) Time (years) Time (years)

MODEL DYNAMICS

As parameters are varied, model predicts different

outcomes

Can we anticipate trajectories without resorting to

numerical integration?

Question: under what conditions will an infectious

disease invade a system?
THE INVASION THRESHOLD

When can an infectious disease invade a population?

Initial conditions: X)0( = N, Y)0( = 1, Z)0( = 0

Invasion only if dY/dt > 0

ie, βXY/N – γY > 0 Y)βX/N - γ( > 0

If and only if X/N > γ/β

Since X=N, requires 1> γ/β
Or β/γ > 1
Kermack  &  McKendrick  (1927)
BASIC REPRODUCTIVE RATIO, R0
Ratio β/γ gives number of cases before infected individual recovers
Universally referred to as R0 or Basic Reproductive Ratio

Definition: Number of secondary cases generated by a typical infected in an

entirely susceptible population

R₀ < 1 R₀ =4
No invasion Successful invasion
R0 AND MODEL PARAMETERS

Transmission Rate (β, yr⁻¹)

R0 < 1

Infectious period (1/γ, days)

 R0 ESTIMATES OF R0
Hepatitis C

Seasonal Influenza

1918 Influenza

Ebola

SARS

Phocine Distemper

HIV (MSM)

HIV (FSW)

Mumps

Pertussis
THE DEATH OF AN EPIDEMIC

In SIR equations, let’s divide equation for dX/dt by dZ/dt:

dX/dZ = - (β X Y/N)/(γY)
= - R0 X/N

Integrate with respect to Z

X(t) = X(0) e –Z(t) R0/N

When epidemic is over, by definition, we have X(∞),Y(∞) (=0), and

Z(∞)

X(∞) = N – Z(∞) = X(0) e –Z(∞) R0/N

 THE DEATH OF AN EPIDEMIC

So, N – Z(∞) - X(0) e –Z(∞) R0/N = 0

Solve this numerically (‘transcendental’ equation)

Epidemic  dies  out  because  

there  are  too  few  infectives,  
not  because  of  too  few  
susceptibles

Kermack  &  McKendrick  (1927)

SIMPLE EPIDEMICS

β 1/Ɣ R₀

“Measles” 886 /yr 0.019 yr 17

“Influenza” 180 /yr 0.011 yr 2

“Chickenpox” 315 /yr 0.022 yr 7

“Rubella” 200 /yr 0.025 yr 5

FREQUENCY- OR DENSITY-DEPENDENT
TRANSMISSION?

Assumed contact rate, κ, constant: ‘mixing’ is independent of population

size: frequency-dependent transmission. Reasonable?
If we assume contact rate to be κN (increases with ‘crowding’), then
transmission rate is
dX/dt = -βXY
Called density-dependent transmission

κN
κ

Contact  Rate
Popula'on  Size
DOES IT MATTER?

Again, pathogen invasion if dY/dt > 0

If initially everyone susceptible (X=N),
βNY – γY>0 ⇒ Y(βN - γ) > 0
In this case, we define R0 = βN/γ, so need R0>1

Hence, for any particular β and γ, there’s now a threshold population

density required for invasion
INCORPORATING VIRULENCE

Assume infectious individuals die at rate α

dY
= ... Y ↵Y
dt
 TRANSMISSION & R0
Density Dependent Frequency Dependent
β=0.0426, γ=24, α=18, μ=0.02 β=426, γ=24, α=18, μ=0.02
NT = 1000 No invasion threshold
β = 0.0426; 1/γ = 15d β = 426; 1/γ = 15d
β = 426; 1/γ = 15d
10000 10000
10000

11

Size
Population Size

Population Size
10 10

Infected
9

Infected
Population
R0
5000 0 5000

R
5000 0

NT
1
0
0 0 00 100 200 300 400 500 600 700 800 900 1000
0 100 200 300 400 500 600 700 800 900 1000 0 100 200 300 400 500 600 700 800 900 1000
Time (years) Time
Time (years)
(years)

FD transmission → pathogen can wipe out

host
WHAT SHOULD WE DO?

If population size doesn’t change, FD & DD equivalent (βFD = N

x βDD)
Otherwise:
Frequency-dependence generally more appropriate in large
populations with heterogenous mixing, STDs, vector-borne
pathogens
Density-dependence representative of wildlife & livestock
diseases (especially with smaller population sizes)