Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Edited by David Cox, Nuffield College, Oxford, United Kingdom, and approved December 22, 2010 (received for review June 22, 2010)
Evaluating the impact of different social networks on the spread sylvania to investigate how social networks and population struc-
of respiratory diseases has been limited by a lack of detailed data tures affect influenza transmission.
on transmission outside the household setting as well as appro-
priate statistical methods. Here, from data collected during a H1N1 Results and Discussion
pandemic (pdm) influenza outbreak that started in an elementary Outbreak Investigation. Fig. 1 presents the data that were col-
school and spread in a semirural community in Pennsylvania, we lected during the outbreak investigation. Demographic and
quantify how transmission of influenza is affected by social net- clinical information on 370 (81%) students from 295 (81%)
works. We set up a transmission model for which parameters are households and their 899 household contacts was collected
estimated from the data via Markov chain Monte Carlo sampling. during two rounds of phone interviews (May 16–21 and May 26–
ECOLOGY
Sitting next to a case or being the playmate of a case did not June 2). One hundred twenty-nine (35%) students and 141
significantly increase the risk of infection; but the structuring of (16%) household contacts were reported to have had acute re-
the school into classes and grades strongly affected spread. There spiratory illness (ARI, defined as at least two symptoms among
was evidence that boys were more likely to transmit influenza to fever, cough, sore throat, and runny nose) from late April to
other boys than to girls (and vice versa), which mimicked the ob- their last interview (Fig. 1A). Because fourth graders appeared to
served assortative mixing among playmates. We also investigated be the most affected group at the time the school was in-
the presence of abnormally high transmission occurring on specific vestigated (54% reported ARI over the study period), a survey
days of the outbreak. Late closure of the school (i.e., when 27% of was dedicated to this subset of individuals: Information on
students already had symptoms) had no significant impact on seating charts (Fig. 1B), activities (Tables S1 and S2), and social
spread. School-aged individuals (6–18 y) facilitated the introduc- networking (“Who are your playmates?”; Fig. 1D) was collected.
tion and spread of influenza in households, but only about one in Here, we set up a transmission model for which parameters are
five cases aged >18 y was infected by a school-aged household estimated from the data via Markov chain Monte Carlo sampling
member. This analysis shows the extent to which clearly defined and data augmentation techniques (Materials and Methods and
social networks affect influenza transmission, revealing strong SI Materials and Methods).
between-place interactions with back-and-forth waves of trans-
mission between the school, the community, and the household. Transmission Characteristics in Different Settings. Fig. 2A shows that
the structuring of the school in classes and grades had a strong
| |
epidemiology infectious diseases Bayesian statistics | data impact on transmission rates. Child-to-child transmission proba-
|
augmentation mathematical modelling bilities were estimated to be 3.5% [95% credibility interval (CI):
1.8%, 5.6%] within a class. Transmission probabilities between
Window
5
0
Apr 27
May 7
May 17
May 27
Door
ARI No ARI No ARI No ARI No ARI No ARI
Onset date
Teacher desk
C D
8
male
female
6
Number of cases
0
Apr 27
May 7
May 17
Onset date
Fig. 1. Epidemiological data collected in the school. (A) Number of acute respiratory illness (ARI) cases by date of symptom onset for different types of
individuals. (B–D) Survey of fourth graders with (B) seating charts and diagnosis for ARI in classroom C, (C) number of ARI cases by date of symptom onset and
sex among fourth graders, and (D) social networking among fourth graders based on the question “Who are your playmates?” [color of the nodes, red,
female; blue, male; color of the lines, red, girl–girl interaction; cyan, boy–boy interaction; green, boy–girl interaction (one symbol shape per class)]. The
algorithm used to draw the network aims at (i) distributing nodes evenly, (ii) making edge length uniform, (iii) minimizing edge crossings, and (iv) keeping
nodes from coming too close to edges (32, 33) (software: Netdraw). It does not use data on sex to position the nodes.
Relative susceptibility of adults to infection was estimated to be with the “next-step ahead” predictions giving for each day d the
about half that of children (41%; 95% CI, 21%, 78%; Fig. 2C) but number of infections predicted by the model given what has hap-
adults were as infectious as children when infected (infectiousness pened up to day d − 1. In general, there is good agreement between
of adults relative to children: 92%; 95% CI, 38%, 204%), in agree- the two distributions. However, the next-step ahead predictions
ment with another study on H1N1pdm (10). The mean household tend to largely underestimate the reconstructed number of cases
generation time of 2.3 d (95% CI: 1.4, 3.6) for individuals >10 y old among students from fourth grade class A in the time period May
was also consistent with that of other studies (Fig. 2D) (10, 15, 17). 6 and 7 (respectively, day 10 and day 11 of the outbreak). This is
With a mean of 3.7 d (95% CI: 2.3, 5.0), there was substantial the only group of individuals and the only 2 d for which trans-
evidence that children aged ≤10 had a longer household genera- mission is found to be abnormally high; i.e., there is <10% pos-
tion time than older individuals [Bayes factor (BF): 10.8; see SI terior probability P that the next-step ahead prediction is strictly
Materials and Methods for information on Bayes factors]. Our larger than the reconstructed number of infections (Fig. 3B). In an
analysis also suggests that the generation time in the school and the exploratory analysis described in SI Materials and Methods, dif-
community, with an estimated mean of 1.1 d (95% CI: 1.0, 1.7), was ferent mechanisms that could have been responsible of this phe-
substantially shorter than the household generation time (Fig. 2D; nomenon are explored. This model comparison also suggests that
BF = 64 for the comparison with adult household generation abnormally high transmission took place on those days (BF: 28)
time). This can be explained, for example, if sick (and infectious) (Table S3), although it is not conclusive concerning the mecha-
children are likely to stay home shortly after symptom onset, nisms that may have been involved. Overall, this analysis suggests
meaning that exposure to sick individuals in the school context is that abnormally high transmission may have taken place on May
likely to be truncated at an earlier time than would occur in 6 and 7 although we cannot rule out the possibility that discrep-
the household. ancies between reconstructed numbers of infections and next-step
ahead predictions were due to chance.
Detecting Events of Abnormally High Transmission. In an attempt to
detect abnormal transmission events, we consider the model in Sex-Related Mixing Patterns. Fig. 1D shows that sex is an important
which transmission rates do not change with time. For this model, determinant of social mixing between children of the same grade:
we plot in Fig. 3A the predictive distribution of the number of in- Children were four times more likely to play with children of the
fections (subsequently referred to as the “reconstructed” number same sex than with children of the opposite sex. We investigated
of infections) per day for different groups of individuals along whether this aspect of social networking affected transmission
5 20
4 15
3
10
2
1 5
0 0
Infec vity
0.6
80 from a different grade during his/her infectious period.
0.4
60 (B) Transmission probability in the household from an
0.2
40 infected child to an adult of the household during his/
0
20 0 1 2 3 4 5 6 7
her infectious period, as a function of household size.
0 Time since infec on (days) (C) Susceptibility of adults relative to children (≤10 y
School & Com. Adult in hous. Child in hous. old), ρadult. (D) Generation time in the school/commu-
nity, in the household for adults and children. (E)
E F Transmission to children from the other sex relative to
on trans. among students (%)
100 120
that to children from the same sex, ρsex. (F) Trans-
with other gender (%)
60
20 97.5% of the posterior distribution. The mathematical
40
0 definition of parameters is given in SI Materials and
ECOLOGY
Methods.
dynamics in the school. We considered the model where the on spread can be noted in the epidemic curve of fourth graders
transmission rate with the opposite sex was ρsex multiplied by the (Fig. 1C) where spread among boys (average time of onset: May
rate with children of the same sex. There was substantial evidence 6, 8 PM) significantly preceded spread among girls (average time
that the model ρsex < 1 accounting for the effect of sex-related of onset: May 9, 12 AM) (P = 0.023).
mixing patterns on spread had a better fit than the model ρsex = 1
that did not account for such an effect (BF: 9.7). We estimated Late Closure of the School. The school closed May 14–20 (days 18
ρsex = 32% (95% CI: 5%, 82%) (Fig. 2E). This effect of sex and 24 of the outbreak, respectively) because of the outbreak.
4 4
3 60 60 60
3 3
2 40 40 40
2 2
1 20 20 20
1 1
0 0 0 0 0 0
Number of cases
0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35
0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35
grade 3 grade 4 A grade 4 B+C+D grade 3 grade 4 A grade 4 B+C+D
6 5 7 100 100 100
6
5 4 80 80 80
5
4
3 4 60 60 60
3
3 40 40 40
2
2 2
1 20 20 20
1 1
0 0 0 0 0 0
0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35
0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35
adult from hous. child from hous. adult from hous. child from hous.
15 7 100 100
6
80 80
5 reconstructed
10
4 next-step ahead 60 60
3 week−end
school closure 40 40
5
2
20 20
1
0 0 0 0
0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35
Fig. 3. Detection of abnormal transmission events in the different groups of individuals. (A) “Reconstructed” numbers of infections per day for different
groups of individuals (blue line) along with the “next-step ahead” predictions giving for each day t the number of infections predicted by the model given
what has happened up to day t − 1 (red line). Dashed lines give the 95% CI. The different groups of individuals are students from grades K, 1, 2, and 3 and
fourth graders from classroom A and from other classrooms (classrooms B, C, and D) and adult and child household contacts. (B) For each day and each group,
the posterior probability that the reconstructed number of infections is smaller or equal to the “next-step ahead” predictions. The blue line gives the 10%
limit below which adequacy is rejected. See Materials and Methods and SI Materials and Methods for details.
A B 40
Prop. of individuals infected (%)
by any case
40
by any household case
Prop. student cases infected
30
by 6−18 yr old household case Fig. 4. Reconstruction of the trans-
by people from (%)
ECOLOGY
individuals facilitated the introduction and spread of influenza in
on, the school outbreak needed repeated introductions from
households, but most cases were not infected by school-aged
outside and/or abnormally high transmission events to be sus-
tained. This result is confirmed in Fig. 4D, which shows a trans- household members. Such detailed outbreak investigations are
mission tree drawn from the predictive distribution and where critically needed to improve our understanding of disease spread
back-and-forth waves of transmission between the school, the in human populations. It is also important that the agent-based
community, and the households are visible. The global re- simulation models that are now commonly used to inform policy
production number for a “typical” case (i.e., averaged over cases (1, 3) are properly calibrated on the basis of the type of analysis
of the dataset) was 1.3 (95% CI: 1.2, 1.4) in the first 2 wk and presented here.
moved below 1 on the fourth week of the outbreak.
Materials and Methods
Sensitivity Analysis. In a sensitivity analysis (SI Materials and Data Collection. The outbreak investigation was performed by the teams from
Methods, and Tables S5–S9), we explored the robustness of our the Centers for Disease Control and Prevention (CDC) and the Pennsylvania
results to a set of modeling assumptions and prior specifications. Department of Health. During May 16–21, the team attempted to conduct
Estimates appeared to be robust to most of them. The household a telephone interview with a parent or guardian in each student household.
generation time was sensitive to prior specification with a mean During May 26–June 2, all student households were contacted by phone ex-
in the range 2.3–2.8 d for adults and 3.7–4.6 d for children; cept those that refused further participation in the investigation when they
were contacted for the rapid questionnaire. For fourth graders, documents
however, the difference between child and adult generation
such as seating charts, school activity schedules, school calendars, bus sched-
times (1.4–1.8 d) was relatively robust to the prior specification.
ules, nurse logs, and absentee records were collected and reviewed. During
June 2 and 3, investigation team members administered questionnaires to
Limitations and Conclusion. The study was subject to the following
fourth graders who had obtained permission to participate in the study.
limitations. We used a syndromic definition to identify possible
The school has a population of 456 students from 364 households. Three
influenza cases and most cases were not laboratory confirmed.
hundred thirteen households (86.0%) completed at least one of the two
It is therefore likely that some cases were not infected by
surveys. Of those, 18 (5.8%) were excluded from the analysis because the age
H1N1pdm (see sensitivity analysis in SI Materials and Methods,
of at least 1 household contact was unknown. The analysis was therefore
Fig. S4, and Table S9.). However, among the 36 cases with in- performed on data collected from 295 (81%) households with 370 students
fluenza-like illness (fever and cough or sore throat or both) that (81% of the students of the school) and 899 household contacts (i.e., any
were tested, the proportion who were infected by H1N1pdm was person residing in the respondent’s household since May 1). A more detailed
high (72%) (20). Conversely, some individuals that did not meet summary of the data that were collected and the way they were processed
the clinical definition were likely to have been infected (21). The can be found in SI Materials and Methods. Children were defined as indi-
survey data were self-reported and the main caregiver provided viduals aged ≤10 y.
information for all of the household members. Interview with the
school nurse, reviews of nurse logs, and absentee records in- Statistical Inference. Assuming that individuals with ARI were infected with
dicated that the first clinical cases among students occurred the influenza virus, we built a statistical model to estimate from the data how
around late April/early May. The surveys therefore focused on social networks (i.e., structuring of the school in classes and grades, struc-
symptoms occurring from that period onward. Students with turing of the population in households, and sex-related mixing patterns)
symptoms before this period would have been detected from the affected transmission dynamics.
data gathered in the school; but it is possible that some very early Transmission model. We build a transmission model for the force of infection
cases among household contacts were missed. The sample of exerted on individual i at time t,
interviewed households was not a representative sample of the N
community (see above). λi ðtÞ ¼ ∑ λ j→i ðt j xj ; xi Þ;
j:tj < t
It is likely that a substantial proportion of transmission among
students of the school took place in the school. However, in the where λ j→i ðtj xj ; xi Þ is the instantaneous hazard of transmission from in-
eventuality where students also met and transmitted the virus to dividual j to individual i at time t:
1. Ferguson NM, et al. (2005) Strategies for containing an emerging influenza pandemic 18. Cauchemez S, et al. (2009) Closure of schools during an influenza pandemic. Lancet
in Southeast Asia. Nature 437:209–214. Infect Dis 9:473–481.
2. Ferguson NM, et al. (2006) Strategies for mitigating an influenza pandemic. Nature 19. Cowling BJ, et al. (2008) Effects of school closures, 2008 winter influenza season,
442:448–452. Hong Kong. Emerg Infect Dis 14:1660–1662.
3. Germann TC, Kadau K, Longini IM, Jr., Macken CA (2006) Mitigation strategies for 20. Bhattarai A, et al. (2011) Viral shedding duration of pandemic influenza A H1N1 virus
pandemic influenza in the United States. Proc Natl Acad Sci USA 103:5935–5940. during an elementary school outbreak - Pennsylvania, May–June 2009. CID 52(S1):
4. Longini IM, Jr., et al. (2005) Containing pandemic influenza at the source. Science S102–S108.
309:1083–1087. 21. Miller E, et al. (2010) Incidence of 2009 pandemic influenza A H1N1 infection in
5. Eubank S, et al. (2004) Modelling disease outbreaks in realistic urban social networks. England: A cross-sectional serological study. Lancet 375:1100–1108.
Nature 429:180–184. 22. Cauchemez S, et al. (2006) Investigating heterogeneity in pneumococcal transmission:
6. Riley S, Ferguson NM (2006) Smallpox transmission and control: Spatial dynamics in A Bayesian-MCMC approach applied to a follow-up of schools. J Am Stat Assoc 101:
Great Britain. Proc Natl Acad Sci USA 103:12637–12642. 946–958.
7. Meyers LA, Pourbohloul B, Newman MEJ, Skowronski DM, Brunham RC (2005) 23. Gilks WR, Richardson S, Spiegelhalter DJ (1996) Markov Chain Monte Carlo in Practice
Network theory and SARS: Predicting outbreak diversity. J Theor Biol 232:71–81.
(Chapman & Hall, London).
8. Newman MEJ (2002) Spread of epidemic disease on networks. Phys Rev E Stat Nonlin
24. Green PJ (1995) Reversible jump Markov chain Monte Carlo computation and
Soft Matter Phys 66:016128.
Bayesian model determination. Biometrika 82:711–732.
9. Cauchemez S, Carrat F, Viboud C, Valleron AJ, Boëlle PY (2004) A Bayesian MCMC
25. Cori A, Boëlle PY, Thomas G, Leung GM, Valleron AJ (2009) Temporal variability and
approach to study transmission of influenza: Application to household longitudinal
social heterogeneity in disease transmission: The case of SARS in Hong Kong. PLoS
data. Stat Med 23:3469–3487.
Comput Biol 5:e1000471.
10. Cauchemez S, et al. (2009) Household transmission of 2009 pandemic influenza A
26. O’Neill PD (2002) A tutorial introduction to Bayesian inference for stochastic epidemic
(H1N1) virus in the United States. N Engl J Med 361:2619–2627.
models using Markov chain Monte Carlo methods. Math Biosci 180:103–114.
11. Longini IM, Jr., Koopman JS (1982) Household and community transmission parameters
27. O’Neill PD, Balding DJ, Becker NG, Eerola M, Mollison D (2000) Analyses of infectious
from final distributions of infections in households. Biometrics 38:115–126.
disease data from household outbreaks by Markov chain Monte Carlo methods. J R
12. Longini IM, Jr., Koopman JS, Haber M, Cotsonis GA (1988) Statistical inference for
infectious diseases. Risk-specific household and community transmission parameters. Stat Soc C 49:517–542.
Am J Epidemiol 128:845–859. 28. O’Neill PD, Roberts GO (1999) Bayesian inference for partially observed stochastic
13. Longini IM, Jr., Koopman JS, Monto AS, Fox JP (1982) Estimating household and epidemics. J R Stat Soc Ser A Stat Soc 162:121–129.
community transmission parameters for influenza. Am J Epidemiol 115:736–751. 29. Walker PG, et al. (2010) A Bayesian approach to quantifying the effects of mass
14. Yang Y, Halloran ME, Longini IM, Jr. (2009) A Bayesian model for evaluating influenza poultry vaccination upon the spatial and temporal dynamics of H5N1 in Northern
antiviral efficacy in household studies with asymptomatic infections. Biostatistics 10: Vietnam. PLoS Comput Biol 6:e1000683.
390–403. 30. Lessler J, et al. (2009) Incubation periods of acute respiratory viral infections: A
15. Lessler J, et al.; New York City Department of Health and Mental Hygiene Swine systematic review. Lancet Infect Dis 9:291–300.
Influenza Investigation Team (2009) Outbreak of 2009 pandemic influenza A (H1N1) 31. Moser MR, et al. (1979) An outbreak of influenza aboard a commercial airliner. Am J
at a New York City school. N Engl J Med 361:2628–2636. Epidemiol 110:1–6.
16. Calatayud L, et al. (2010) Pandemic (H1N1) 2009 virus outbreak in a school in London, 32. Davidson R, Harel D (1996) Drawing graphs nicely using simulated annealing. ACM
April-May 2009: An observational study. Epidemiol Infect 138:183–191. Trans Graph 15:301–331.
17. Ghani AC, et al. (2009) The early transmission dynamics of H1N1pdm influenza in the 33. Kamada T, Kawai S (1991) A general framework for visualizing abstract objects and
United Kingdom. PLoS Curr 1:RRN1130. relations. ACM Trans Graph 10:1–39.