statistical methods for infectious diseases lecture...
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Outline Framework Concepts Simple SIR Models
Statistical Methods for Infectious DiseasesLecture 1
M. Elizabeth Halloran
Hutchinson Research Center andUniversity of Washington
Seattle, WA, USA
January 6, 2009
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Outline Framework Concepts Simple SIR Models
FrameworkTransmission and Dependent HappeningsDirect and Indirect EffectsVaccine efficacy and effectiveness
ConceptsTransmission probabilityTime Lines of InfectionBasic Reproductive Number, R0
Contact Structures; Mixing Patterns
Simple SIR ModelsEndemic versus Epidemic Models
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Outline Framework Concepts Simple SIR Models
FrameworkTransmission and Dependent HappeningsDirect and Indirect EffectsVaccine efficacy and effectiveness
ConceptsTransmission probabilityTime Lines of InfectionBasic Reproductive Number, R0
Contact Structures; Mixing Patterns
Simple SIR ModelsEndemic versus Epidemic Models
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Outline Framework Concepts Simple SIR Models
Transmission
� Transmission from one host to another is fundamental to thesurvival strategy of most infectious agents.
� Each infectious agent has its own life cycle, modes oftransmission, population dynamics, evolutionary pressures,and molecular and immunological interaction with the host.
� Transmission may involve an insect or other vector, and itsecology.
� Our focus is on underlying principles of dynamics and studydesign common to many infectious diseases.
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Outline Framework Concepts Simple SIR Models
Dependent versus Independent Happenings
� Sir Ronald Ross 1916
� 2nd Nobel Prize in Medicine : elucidation of mosquitos asmalaria transmitters
� Transmission models of malaria
� Theory of happenings
� In dependent happenings, the number of individuals becomingaffected depends on the number of individuals alreadyaffected.
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Outline Framework Concepts Simple SIR Models
Dependent Happenings and Vaccine Effects
� Due to the dependent happenings in infectious diseases (Ross1916), vaccination can produce several different kinds ofeffects
� At the individual level
� And at the population level.
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Outline Framework Concepts Simple SIR Models
Direct and Indirect Effects of Interventions
� Direct effects of interventions on those receiving theintervention, such as a protective vaccine
� Indirect effects of interventions, say in reducing infectiousnessof breakthrough infections or reducing the number ofinfectious people exposing others.
� Develop an appropriate terminology to describe differenteffects
� Interaction in assumptions about transmission dynamics andchoice of study design to evaluate the effect of interest
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Outline Framework Concepts Simple SIR Models
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Outline Framework Concepts Simple SIR Models
Vaccine efficacy and effectiveness
� generally estimated as one minus some measure of relativerisk, RR, in the vaccinated group compared to theunvaccinated group:
VE = 1− RR .
� The groups being compared could be composed of individualsor of populations or communities.
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Outline Framework Concepts Simple SIR Models
Historical Example: Typhoid inoculation efficacy
� Karl Pearson versus immunologist A.E. Wright BMJ (1904)
� compared correlation coefficient for typhoid inoculation (about0.1) with that of smallpox vaccination (0.578 to 0.769)
� claimed antityphoid inoculation should be stopped.
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Outline Framework Concepts Simple SIR Models
Vaccine efficacy: typhoid and cholera
� Greenwood and Yule (1915) (Proc Roy Soc Med)
� Thoughts on the statistics of evaluating vaccines in the field
� Pre-dates person-time analysis
� Discussion of “confounding”
� Problem of people being inoculated during epidemic
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Outline Framework Concepts Simple SIR Models
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Outline Framework Concepts Simple SIR Models
Pertussis vaccine efficacy
� Kendrick and Eldering (1939)
� Person-time analysis versus conditional on exposure toinfection
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Outline Framework Concepts Simple SIR Models
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Outline Framework Concepts Simple SIR Models
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Outline Framework Concepts Simple SIR Models
Polio vaccine trials
� Francis et al (1955)
� Observed Control Study, “to administer vaccine to children inthe second grade of school; the corresponding first and thirdgraders would not be inoculated, but would be kept underobservation for the occurrence of poliomyelitis in comparisonwith the inoculated second graders.”
� Placebo Control Study, “children of the first, second, andthird grades would be combined. One half would receivevaccine; the other matching half, serving as strict controls,would receive a solution of similar appearance....”
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Outline Framework Concepts Simple SIR Models
Transmission probability, p
� p = probability that, given a contact between an infectivesource (host) and susceptible host, successful transfer of theinfectious agent will occur so that the susceptible hostbecomes infected (or a carrier).
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Outline Framework Concepts Simple SIR Models
Infectioushost
Susceptiblehost
infectious agent
contact
Transmission probability depends on: • Type and definition of contact • Infectious agent • Infectious host • Susceptible host
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Outline Framework Concepts Simple SIR Models
Time Lines of Infection
Dynamics ofDisease
SusceptibleIncubation
periodSymptomatic
period
Non diseased- immune- carrier- dead- recovered
Time ofinfection
Appearanceof symptoms
Resolutionof infection
Time
Dynamics ofInfectiousness
SusceptibleLatentperiod
Infectiousperiod
Non infectious- removed- dead- recovered
Time ofinfection
Infectiontransmittable
Infection nottransmitable
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Outline Framework Concepts Simple SIR Models
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Disease RecognitionOnset of fever
Onset of macular
rash (day 4 of
fever)
Onset of papules
(day 3 of rash,
day 6 of fever)
Onset of vesicles (day 4 of
rash). In first period, all cases
recognized; contacts of
recognized cases & household
contacts of contacts
vaccinated, observed 12 days
for fever. 30% die on days 7-14
of fever (uniform dist.)Incubation Period
Infected
Day of
fever
Second period: All cases recognized
on day 3 of rash (day 6 of fever)
1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Infectiousness
Day of
fever
Latent period
1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Behavior
Day of
fever
At the end of the 1st day of fever:
47.5% withdraw to the home
47.5% go to the hospital
2x
4x
2x
One day before rash
Infected
Infected
Ordinary Smallpox
1x
One day after onset
of fever
At the end of the 3rd day of fever (beginning of 4th):
5% go to the hospital + those who withdrew to the home
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Infected
Distribution of
Incubation Period(Onset of Fever)
Day
Mean: 11.48 days
1st recognized case in hospital ! vacc. hosp. workers
Fig. 1
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Outline Framework Concepts Simple SIR Models
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Disease Recognition Onset of feverOnset of macularrash (day 4 offever)
Onset of papules(day 3 of rash,day 6 of fever)
Onset of vesicles (day 4 of rash).In first period, 75% of casesrecognized (remaining 25% onday 10 of fever); contacts ofrecognized cases & householdcontacts of contacts vaccinated,observed 12 days for fever. 10%die on days 7-14 of fever(uniform dist.)
Incubation Period
Infected
Day offever
Second period: All cases recognizedon day 3 of rash (day 6 of fever)
1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Infectiousness
Day offever
Latent period
Behavior
Day offever
At the end of the first day of fever: 25% withdraw to the home 25% go to the hospital
0.33(2x)
0.33(4x)
0.33(2x)
One day before rash
Infected
Infected
Modified Smallpox50% of those born before 1971
0.33x
One day after onsetof fever
At the end of the 3rd day (beginning of 4th day) of fever: 50% go to the hospital + those who withdrew to the home
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Infected
Day
Mean: 11.48 days
Distribution ofIncubation Period(Onset of Fever)
1st recognized case in hospital → vacc. Hosp. workers
Fig. 2
1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14
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Outline Framework Concepts Simple SIR Models
-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Disease Recognition Onset of feverOnset of bleeding(day 4 of fever)
Incubation Period
Infected
Day offever
1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Infectiousness
Day offever
Latent period
1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Behavior
Day offever
At the end of the 1st day of fever: 100% withdraw to the hospital
5(2x)
5(4x)
5(2x)
One day before bleeding
Infected
Infected
Hemorrhagic Smallpox5% of non-modified smallpox
5x
One day after onsetof fever
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Infected
Day
Mean: 10.24 days
All hemorrhagicsmallpox cases die at endof 7th day after onset ofbleeding
Distribution ofIncubation Period(Onset of Fever)
1st recognized case in hospital → vacc. Hosp. workers
First period: 50% of cases recognized on day 2 of bleeding (day 5 of fever.)Second period: all cases recognized on day 1 of bleeding (day 4 of fever.)
Fig. 3
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Outline Framework Concepts Simple SIR Models
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Outline Framework Concepts Simple SIR Models
Basic Reproductive Number, R0
� the average number of new infectious hosts that a typicalinfectious host will produce during his or her infectious period
� in a large population (absence of density-dependent effects)
� if the population were completely susceptible
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Outline Framework Concepts Simple SIR Models
Basic Reproductive Number, R0
� heuristically, thought of as product of� contact rate, c� transmission probability, p� duration of infectious period, d
� R0 = cpd
� tricky to measure, but important public health concept
� interventions act on components of R0
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Outline Framework Concepts Simple SIR Models
Basic Reproductive Number, R0
� average, or expectation
� particular population
� all susceptible (or absence of intervention)
� microparasitic diseases (in contrast to macro-parasiticdiseases)
� dimensionless
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Outline Framework Concepts Simple SIR Models
(Net or effective) Reproductive Number, R
� if not all susceptible, or after intervention
� need R > 1 for an epidemic to take off or sustainedtransmission
� at equilibrium, R = 1
� goal is to reduce R, and if possible < 1
� monitoring R in real-time can aid in evaluating success ofintervention
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Outline Framework Concepts Simple SIR Models
R0 in Macroparasitic Infections
� macroparasites are larger, such as helminths
� related to R0 in general population theory
� average number of reproducing female offspring that oneadult female will produce in the absence of crowding
� generally require distributional theory and different approachesfor study of macroparasites
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Outline Framework Concepts Simple SIR Models
Generation time, Tg
� The expected time between the infection of a person and theinfection of the persons infected by the initial person.
� Case serial interval: expected time between onset of a caseand the onset of cases produced by an initial case.
� subtle differences in definitions
� different variability
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Outline Framework Concepts Simple SIR Models
Contact Structures; Mixing Patterns
� homogeneous mixing
� heterogeneous mixing
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Outline Framework Concepts Simple SIR Models
Population Heterogeneities
� m mutually exclusive groups that form a partition, e.g., agegroups, gender
� number of people in group i , where∑
i ni = n
� Overlapping subgroups, e.g., households, schools, workplaces,neighborhoods, where a person can belong to more than onegroup.
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Outline Framework Concepts Simple SIR Models
Hazard Function for Infection: Force of Infection
� Let I (t) be number of infectious people.
� Homogeneous mixing:
λ(t) =1
ncpI (t)
� Heterogeneous mixing, m group partition
λi (t) =1
ni
∑j
cijpij Ij(t)
� contrast λ(t) and R(t)
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Outline Framework Concepts Simple SIR Models
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Outline Framework Concepts Simple SIR Models
Simple S-I-R Model
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Outline Framework Concepts Simple SIR Models
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Outline Framework Concepts Simple SIR Models
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Outline Framework Concepts Simple SIR Models
Differences in diseases
� Smallpox versus polio
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Outline Framework Concepts Simple SIR Models
Thank you!