We introduce the use of negative preferences to produce so- lutions that are acceptable to a grou... more We introduce the use of negative preferences to produce so- lutions that are acceptable to a group of users. This tech- nique takes advantage of the fact that discovering what a user does not like can be easier than discovering what the user does like. To illustrate the approach, we implemented Adaptive Radio, a system that selects music to play
We describe an interactive search algorithm inspired by the immune system. The algorithm learns w... more We describe an interactive search algorithm inspired by the immune system. The algorithm learns what parts of the search space are not useful to help a user ex- plore large parameter spaces ecien tly. The algorithm is capable of nding consensus solutions for parties with dieren t selection criteria. A simple implementation of the algorithm applied to selecting Biomorphs (Dawkins
Proceedings / IEEE Computer Society Bioinformatics Conference. IEEE Computer Society Bioinformatics Conference, 2003
We have constructed a computer model of the cytotoxic T lymphocyte (CTL) response to antigen and ... more We have constructed a computer model of the cytotoxic T lymphocyte (CTL) response to antigen and the maintenance of immunological memory. Because immune responses often begin with small numbers of cells and there is great variation among individual immune systems, we have chosen to implement a stochastic model that captures the life cycle of T cells more faithfully than deterministic models. Past models of the immune response have been differential equation based, which do not capture stochastic effects, or agent-based, which are computationally expensive. We use a stochastic stage-structured approach that has many of the advantages of agent-based modeling but is much more efficient. Our model can provide insights into the effect infections have on the CTL repertoire and the response to subsequent infections.
Based on the results of a computational model of thymic selection, we propose a mechanism that pr... more Based on the results of a computational model of thymic selection, we propose a mechanism that produces the observed wide range of T cell cross-reactivity. The model suggests that the cross-reactivity of a T cell that survives thymic selection is correlated with its affinity for self peptides. In order to survive thymic selection, a T cell with low affinity for all self peptides expressed in the thymus must have high affinity for major histocompatibility complex (MHC), which makes it highly cross-reactive. A T cell with high affinity for any self peptide must have low MHC affinity to survive selection, which makes it highly specific for its cognate peptide. Our model predicts that (1) positive selection reduces by only 17% the number of T cells that can detect any given foreign peptide, even though it eliminates over 95% of pre-selection cells; (2) negative selection decreases the average cross-reactivity of the pre-selection repertoire by fivefold; and (3) T cells responding to for...
Proceedings of the 2005 international ACM SIGGROUP conference on Supporting group work - GROUP '05, 2005
We introduce the use of negative preferences to produce solutions that are acceptable to a group ... more We introduce the use of negative preferences to produce solutions that are acceptable to a group of users. Using negative preference profiling, a system determines which solutions are unsatisfactory to individual users, and it is assumed that the remaining solutions are satisfactory. To satisfy all members of the group, the system can propose solutions that are not unsatisfactory to any of the group's members. This approach can find a large set of solutions that are acceptable to a group and simplify user profiling. To demonstrate these benefits, we implemented Adaptive Radio, a system that selects music to play in a shared environment. Rather than attempting to play the songs that users want to hear, the system avoids playing songs that they do not want to hear. Negative preferences can potentially be applied to other domains, such as information filtering, intelligent environments, and collaborative design.
Mathematical modeling can be a valuable tool for studying infectious disease outbreak dynamics an... more Mathematical modeling can be a valuable tool for studying infectious disease outbreak dynamics and simulating the effects of possible interventions. Here, we describe approaches to modeling cholera outbreaks and how models have been applied to explore intervention strategies, particularly in Haiti. Mathematical models can play an important role in formulating and evaluating complex cholera outbreak response options. Major challenges to cholera modeling are insufficient data for calibrating models and the need to tailor models for different outbreak scenarios.
The 2009 H1N1 influenza pandemic provides a unique opportunity for detailed examination of the sp... more The 2009 H1N1 influenza pandemic provides a unique opportunity for detailed examination of the spatial dynamics of an emerging pathogen. In the US, the pandemic was characterized by substantial geographical heterogeneity: the 2009 spring wave was limited mainly to northeastern cities while the larger fall wave affected the whole country. Here we use finely resolved spatial and temporal influenza disease data based on electronic medical claims to explore the spread of the fall pandemic wave across 271 US cities and associated suburban areas. We document a clear spatial pattern in the timing of onset of the fall wave, starting in southeastern cities and spreading outwards over a period of three months. We use mechanistic models to tease apart the external factors associated with the timing of the fall wave arrival: differential seeding events linked to demographic factors, school opening dates, absolute humidity, prior immunity from the spring wave, spatial diffusion, and their interactions. Although the onset of the fall wave was correlated with school openings as previously reported, models including spatial spread alone resulted in better fit. The best model had a combination of the two. Absolute humidity or prior exposure during the spring wave did not improve the fit and population size only played a weak role. In conclusion, the protracted spread of pandemic influenza in fall 2009 in the US was dominated by shortdistance spatial spread partially catalysed by school openings rather than long-distance transmission events. This is in contrast to the rapid hierarchical transmission patterns previously described for seasonal influenza. The findings underline the critical role that school-age children play in facilitating the geographic spread of pandemic influenza and highlight the need for further information on the movement and mixing patterns of this age group.
Killed, oral cholera vaccines have proven safe and effective, and several large-scale mass choler... more Killed, oral cholera vaccines have proven safe and effective, and several large-scale mass cholera vaccination efforts have demonstrated the feasibility of widespread deployment. This study uses a mathematical model of cholera transmission in Bangladesh to examine the effectiveness of potential vaccination strategies. We developed an age-structured mathematical model of cholera transmission and calibrated it to reproduce the dynamics of cholera in Matlab, Bangladesh. We used the model to predict the effectiveness of different cholera vaccination strategies over a period of 20 years. We explored vaccination programs that targeted one of three increasingly focused age groups (the entire vaccine-eligible population of age one year and older, children of ages 1 to 14 years, or preschoolers of ages 1 to 4 years) and that could occur either as campaigns recurring every five years or as continuous ongoing vaccination efforts. Our modeling results suggest that vaccinating 70% of the population would avert 90% of cholera cases in the first year but that campaign and continuous vaccination strategies differ in effectiveness over 20 years. Maintaining 70% coverage of the population would be sufficient to prevent sustained transmission of endemic cholera in Matlab, while vaccinating periodically every five years is less effective. Selectively vaccinating children 1-14 years old would prevent the most cholera cases per vaccine administered in both campaign and continuous strategies. We conclude that continuous mass vaccination would be more effective against endemic cholera than periodic campaigns. Vaccinating children averts more cases per dose than vaccinating all age groups, although vaccinating only children is unlikely to control endemic cholera in Bangladesh. Careful consideration must be made before generalizing these results to other regions.
The 2014 epidemic of Ebola virus disease in parts of west Africa defines an unprecedented health ... more The 2014 epidemic of Ebola virus disease in parts of west Africa defines an unprecedented health threat. We developed a model of Ebola virus transmission that integrates detailed geographical and demographic data from Liberia to overcome the limitations of non-spatial approaches in projecting the disease dynamics and assessing non-pharmaceutical control interventions. We modelled the movements of individuals, including patients not infected with Ebola virus, seeking assistance in health-care facilities, the movements of individuals taking care of patients infected with Ebola virus not admitted to hospital, and the attendance of funerals. Individuals were grouped into randomly assigned households (size based on Demographic Health Survey data) that were geographically placed to match population density estimates on a grid of 3157 cells covering the country. The spatial agent-based model was calibrated with a Markov chain Monte Carlo approach. The model was used to estimate Ebola virus...
Background: The 2014 West African Ebola Outbreak is so far the largest and deadliest recorded in ... more Background: The 2014 West African Ebola Outbreak is so far the largest and deadliest recorded in history. The affected countries, Sierra Leone, Guinea, Liberia, and Nigeria, have been struggling to contain and to mitigate the outbreak. The ongoing rise in confirmed and suspected cases, 2615 as of 20 August 2014, is considered to increase the risk of international dissemination, especially because the epidemic is now affecting cities with major commercial airports.
Pandemic influenza A (H1N1) 2009 (pandemic H1N1) is spreading throughout the planet. It has becom... more Pandemic influenza A (H1N1) 2009 (pandemic H1N1) is spreading throughout the planet. It has become the dominant strain in the southern hemisphere, where the influenza season is underway. Here, based on reported case clusters in the USA, we estimate the household secondary attack rate for pandemic H1N1 to be 27.3% (95% CI: 12.2%-50.5%). From a school outbreak, we estimate a school child infects 2.4 (95% CI: 1.8-3.2) other children within the school. We estimate the basic reproductive number, R 0 , to range from 1.3-1.7 and the generation interval to range from 2.6-3.2 days. We use a simulation model to evaluate the effectiveness of vaccination strategies in the USA for the Fall, 2009. If vaccine were available soon enough, vaccination of children, followed by adults, reaching 70% overall coverage, in addition to high risk and essential workforce groups, could mitigate a severe epidemic.
Proceedings of the National Academy of Sciences, 2011
In October 2010, a virulent South Asian strain of El Tor cholera began to spread in Haiti. Interv... more In October 2010, a virulent South Asian strain of El Tor cholera began to spread in Haiti. Interventions have included treatment of cases and improved sanitation. Use of cholera vaccines would likely have further reduced morbidity and mortality, but such vaccines are in short supply and little is known about effective vaccination strategies for epidemic cholera. We use a mathematical cholera transmission model to assess different vaccination strategies. With limited vaccine quantities, concentrating vaccine in high-risk areas is always most efficient. We show that targeting one million doses of vaccine to areas with high exposure to Vibrio cholerae, enough for two doses for 5% of the population, would reduce the number of cases by 11%. The same strategy with enough vaccine for 30% of the population with modest hygienic improvement could reduce cases by 55% and save 3,320 lives. For epidemic cholera, we recommend a large mobile stockpile of enough vaccine to cover 30% of a country's population to be reactively targeted to populations at high risk of exposure.
Background: Mathematical models have been used to study the dynamics of infectious disease outbre... more Background: Mathematical models have been used to study the dynamics of infectious disease outbreaks and predict the effectiveness of potential mass vaccination campaigns. However, models depend on simplifying assumptions to be tractable, and the consequences of making such assumptions need to be studied. Two assumptions usually incorporated by mathematical models of vector-borne disease transmission is homogeneous mixing among the hosts and vectors and homogeneous distribution of the vectors.
New strains of influenza spread around the globe via the movement of infected individuals. The gl... more New strains of influenza spread around the globe via the movement of infected individuals. The global dynamics of influenza are complicated by different patterns of influenza seasonality in different regions of the world. We have released an open-source stochastic mathematical model of the spread of influenza across 321 major, strategically located cities of the world. Influenza is transmitted between cities via infected airline passengers. Seasonality is simulated by increasing the transmissibility in each city at the times of the year when influenza has been observed to be most prevalent. The spatiotemporal spread of pandemic influenza can be understood through clusters of global transmission and links between them, which we identify using the epidemic percolation network (EPN) of the model. We use the model to explain the observed global pattern of spread for pandemic influenza A(H1N1) 2009-2010 (pandemic H1N1 2009) and to examine possible global patterns of spread for future pandemics depending on the origin of pandemic spread, time of year of emergence, and basic reproductive number (R 0 ). We also use the model to investigate the effectiveness of a plausible global distribution of vaccine for various pandemic scenarios. For pandemic H1N1 2009, we show that the biggest impact of vaccination was in the temperate northern hemisphere. For pandemics starting in the temperate northern hemisphere in May or April, vaccination would have little effect in the temperate southern hemisphere and a small effect in the tropics. With the increasing interconnectedness of the world's population, we must take a global view of infectious disease transmission. Our open-source, computationally simple model can help public health officials plan for the next pandemic as well as deal with interpandemic influenza.
Although there is no doubt that significant morbidity and mortality occur during annual influenza... more Although there is no doubt that significant morbidity and mortality occur during annual influenza epidemics, the role of contextual circumstances, which catalyze seasonal influenza transmission, remains unclear. Weather conditions are believed to affect virus survival, efficiency of transmission and host immunity, but seasonality may also be driven by a tendency of people to congregate indoors during periods of bad weather. To test this hypothesis, we combined data from a social contact survey in Belgium with local weather data. In the absence of a previous in-depth weather impact analysis of social contact patterns, we explored the possibilities and identified pitfalls. We found general dominance of day-type (weekend, holiday, working day) over weather conditions, but nonetheless observed an increase in long duration contacts (w1 hour) on regular workdays with low temperatures, almost no precipitation and low absolute humidity of the air. Interestingly, these conditions are often assumed to be beneficial for virus survival and transmission. Further research is needed to establish the impact of the weather on social contacts. We recommend that future studies sample over a broad spectrum of weather conditions and day types and include a sufficiently large proportion of holiday periods and weekends.
Background: Dengue is a mosquito-borne infectious disease that constitutes a growing global threa... more Background: Dengue is a mosquito-borne infectious disease that constitutes a growing global threat with the habitat expansion of its vectors Aedes aegyti and A. albopictus and increasing urbanization. With no effective treatment and limited success of vector control, dengue vaccines constitute the best control measure for the foreseeable future. With four interacting dengue serotypes, the development of an effective vaccine has been a challenge. Several dengue vaccine candidates are currently being tested in clinical trials. Before the widespread introduction of a new dengue vaccine, one needs to consider how best to use limited supplies of vaccine given the complex dengue transmission dynamics and the immunological interaction among the four dengue serotypes.
Mathematical and computer models of epidemics have contributed to our understanding of the spread... more Mathematical and computer models of epidemics have contributed to our understanding of the spread of infectious disease and the measures needed to contain or mitigate them. To help prepare for future influenza seasonal epidemics or pandemics, we developed a new stochastic model of the spread of influenza across a large population. Individuals in this model have realistic social contact networks, and transmission and infections are based on the current state of knowledge of the natural history of influenza. The model has been calibrated so that outcomes are consistent with the 1957/1958 Asian A(H2N2) and 2009 pandemic A(H1N1) influenza viruses. We present examples of how this model can be used to study the dynamics of influenza epidemics in the United States and simulate how to mitigate or delay them using pharmaceutical interventions and social distancing measures. Computer simulation models play an essential role in informing public policy and evaluating pandemic preparedness plans. We have made the source code of this model publicly available to encourage its use and further development.
Resistance to oseltamivir, the most widely used influenza antiviral drug, spread to fixation in s... more Resistance to oseltamivir, the most widely used influenza antiviral drug, spread to fixation in seasonal influenza A(H1N1) between 2006 and 2009. This sudden rise in resistance seemed puzzling given the low overall level of the oseltamivir usage and the lack of a correlation between local rates of resistance and oseltamivir usage. We used a stochastic simulation model and deterministic approximations to examine how such events can occur, and in particular to determine how the rate of fixation of the resistant strain depends both on its fitness in untreated hosts as well as the frequency of antiviral treatment. We found that, for the levels of antiviral usage in the population, the resistant strain will eventually spread to fixation, if it is not attenuated in transmissibility relative to the drugsensitive strain, but not at the speed observed in seasonal H1N1. The extreme speed with which the resistance spread in seasonal H1N1 suggests that the resistant strain had a transmission advantage in untreated hosts, and this could have arisen from genetic hitchhiking, or from the mutations responsible for resistance and compensation. Importantly, our model also shows that resistant virus will fail to spread if it is even slightly less transmissible than its sensitive counterpart-a finding of relevance given that resistant pandemic influenza (H1N1) 2009 may currently suffer from a small, but nonetheless experimentally perceptible reduction in transmissibility.
The opening of schools in late summer of 2009 may have triggered the fall wave of pandemic influe... more The opening of schools in late summer of 2009 may have triggered the fall wave of pandemic influenza A(H1N1) in the United States. We found that elevated percent of outpatient visits for influenza-like illness (ILI%) occurred an average of 14 days after schools opened in a state in the fall of 2009. The timing of these events was highly correlated (Spearman's correlation coefficient=0.62, p < 1.0 × 10 −5 ). This result provides evidence that transmission in schools catalyzes community-wide transmission. School opening dates can be useful for future pandemic planning, and influenza mitigation strategies should be targeted at school populations before the influenza season.
We introduce the use of negative preferences to produce so- lutions that are acceptable to a grou... more We introduce the use of negative preferences to produce so- lutions that are acceptable to a group of users. This tech- nique takes advantage of the fact that discovering what a user does not like can be easier than discovering what the user does like. To illustrate the approach, we implemented Adaptive Radio, a system that selects music to play
We describe an interactive search algorithm inspired by the immune system. The algorithm learns w... more We describe an interactive search algorithm inspired by the immune system. The algorithm learns what parts of the search space are not useful to help a user ex- plore large parameter spaces ecien tly. The algorithm is capable of nding consensus solutions for parties with dieren t selection criteria. A simple implementation of the algorithm applied to selecting Biomorphs (Dawkins
Proceedings / IEEE Computer Society Bioinformatics Conference. IEEE Computer Society Bioinformatics Conference, 2003
We have constructed a computer model of the cytotoxic T lymphocyte (CTL) response to antigen and ... more We have constructed a computer model of the cytotoxic T lymphocyte (CTL) response to antigen and the maintenance of immunological memory. Because immune responses often begin with small numbers of cells and there is great variation among individual immune systems, we have chosen to implement a stochastic model that captures the life cycle of T cells more faithfully than deterministic models. Past models of the immune response have been differential equation based, which do not capture stochastic effects, or agent-based, which are computationally expensive. We use a stochastic stage-structured approach that has many of the advantages of agent-based modeling but is much more efficient. Our model can provide insights into the effect infections have on the CTL repertoire and the response to subsequent infections.
Based on the results of a computational model of thymic selection, we propose a mechanism that pr... more Based on the results of a computational model of thymic selection, we propose a mechanism that produces the observed wide range of T cell cross-reactivity. The model suggests that the cross-reactivity of a T cell that survives thymic selection is correlated with its affinity for self peptides. In order to survive thymic selection, a T cell with low affinity for all self peptides expressed in the thymus must have high affinity for major histocompatibility complex (MHC), which makes it highly cross-reactive. A T cell with high affinity for any self peptide must have low MHC affinity to survive selection, which makes it highly specific for its cognate peptide. Our model predicts that (1) positive selection reduces by only 17% the number of T cells that can detect any given foreign peptide, even though it eliminates over 95% of pre-selection cells; (2) negative selection decreases the average cross-reactivity of the pre-selection repertoire by fivefold; and (3) T cells responding to for...
Proceedings of the 2005 international ACM SIGGROUP conference on Supporting group work - GROUP '05, 2005
We introduce the use of negative preferences to produce solutions that are acceptable to a group ... more We introduce the use of negative preferences to produce solutions that are acceptable to a group of users. Using negative preference profiling, a system determines which solutions are unsatisfactory to individual users, and it is assumed that the remaining solutions are satisfactory. To satisfy all members of the group, the system can propose solutions that are not unsatisfactory to any of the group's members. This approach can find a large set of solutions that are acceptable to a group and simplify user profiling. To demonstrate these benefits, we implemented Adaptive Radio, a system that selects music to play in a shared environment. Rather than attempting to play the songs that users want to hear, the system avoids playing songs that they do not want to hear. Negative preferences can potentially be applied to other domains, such as information filtering, intelligent environments, and collaborative design.
Mathematical modeling can be a valuable tool for studying infectious disease outbreak dynamics an... more Mathematical modeling can be a valuable tool for studying infectious disease outbreak dynamics and simulating the effects of possible interventions. Here, we describe approaches to modeling cholera outbreaks and how models have been applied to explore intervention strategies, particularly in Haiti. Mathematical models can play an important role in formulating and evaluating complex cholera outbreak response options. Major challenges to cholera modeling are insufficient data for calibrating models and the need to tailor models for different outbreak scenarios.
The 2009 H1N1 influenza pandemic provides a unique opportunity for detailed examination of the sp... more The 2009 H1N1 influenza pandemic provides a unique opportunity for detailed examination of the spatial dynamics of an emerging pathogen. In the US, the pandemic was characterized by substantial geographical heterogeneity: the 2009 spring wave was limited mainly to northeastern cities while the larger fall wave affected the whole country. Here we use finely resolved spatial and temporal influenza disease data based on electronic medical claims to explore the spread of the fall pandemic wave across 271 US cities and associated suburban areas. We document a clear spatial pattern in the timing of onset of the fall wave, starting in southeastern cities and spreading outwards over a period of three months. We use mechanistic models to tease apart the external factors associated with the timing of the fall wave arrival: differential seeding events linked to demographic factors, school opening dates, absolute humidity, prior immunity from the spring wave, spatial diffusion, and their interactions. Although the onset of the fall wave was correlated with school openings as previously reported, models including spatial spread alone resulted in better fit. The best model had a combination of the two. Absolute humidity or prior exposure during the spring wave did not improve the fit and population size only played a weak role. In conclusion, the protracted spread of pandemic influenza in fall 2009 in the US was dominated by shortdistance spatial spread partially catalysed by school openings rather than long-distance transmission events. This is in contrast to the rapid hierarchical transmission patterns previously described for seasonal influenza. The findings underline the critical role that school-age children play in facilitating the geographic spread of pandemic influenza and highlight the need for further information on the movement and mixing patterns of this age group.
Killed, oral cholera vaccines have proven safe and effective, and several large-scale mass choler... more Killed, oral cholera vaccines have proven safe and effective, and several large-scale mass cholera vaccination efforts have demonstrated the feasibility of widespread deployment. This study uses a mathematical model of cholera transmission in Bangladesh to examine the effectiveness of potential vaccination strategies. We developed an age-structured mathematical model of cholera transmission and calibrated it to reproduce the dynamics of cholera in Matlab, Bangladesh. We used the model to predict the effectiveness of different cholera vaccination strategies over a period of 20 years. We explored vaccination programs that targeted one of three increasingly focused age groups (the entire vaccine-eligible population of age one year and older, children of ages 1 to 14 years, or preschoolers of ages 1 to 4 years) and that could occur either as campaigns recurring every five years or as continuous ongoing vaccination efforts. Our modeling results suggest that vaccinating 70% of the population would avert 90% of cholera cases in the first year but that campaign and continuous vaccination strategies differ in effectiveness over 20 years. Maintaining 70% coverage of the population would be sufficient to prevent sustained transmission of endemic cholera in Matlab, while vaccinating periodically every five years is less effective. Selectively vaccinating children 1-14 years old would prevent the most cholera cases per vaccine administered in both campaign and continuous strategies. We conclude that continuous mass vaccination would be more effective against endemic cholera than periodic campaigns. Vaccinating children averts more cases per dose than vaccinating all age groups, although vaccinating only children is unlikely to control endemic cholera in Bangladesh. Careful consideration must be made before generalizing these results to other regions.
The 2014 epidemic of Ebola virus disease in parts of west Africa defines an unprecedented health ... more The 2014 epidemic of Ebola virus disease in parts of west Africa defines an unprecedented health threat. We developed a model of Ebola virus transmission that integrates detailed geographical and demographic data from Liberia to overcome the limitations of non-spatial approaches in projecting the disease dynamics and assessing non-pharmaceutical control interventions. We modelled the movements of individuals, including patients not infected with Ebola virus, seeking assistance in health-care facilities, the movements of individuals taking care of patients infected with Ebola virus not admitted to hospital, and the attendance of funerals. Individuals were grouped into randomly assigned households (size based on Demographic Health Survey data) that were geographically placed to match population density estimates on a grid of 3157 cells covering the country. The spatial agent-based model was calibrated with a Markov chain Monte Carlo approach. The model was used to estimate Ebola virus...
Background: The 2014 West African Ebola Outbreak is so far the largest and deadliest recorded in ... more Background: The 2014 West African Ebola Outbreak is so far the largest and deadliest recorded in history. The affected countries, Sierra Leone, Guinea, Liberia, and Nigeria, have been struggling to contain and to mitigate the outbreak. The ongoing rise in confirmed and suspected cases, 2615 as of 20 August 2014, is considered to increase the risk of international dissemination, especially because the epidemic is now affecting cities with major commercial airports.
Pandemic influenza A (H1N1) 2009 (pandemic H1N1) is spreading throughout the planet. It has becom... more Pandemic influenza A (H1N1) 2009 (pandemic H1N1) is spreading throughout the planet. It has become the dominant strain in the southern hemisphere, where the influenza season is underway. Here, based on reported case clusters in the USA, we estimate the household secondary attack rate for pandemic H1N1 to be 27.3% (95% CI: 12.2%-50.5%). From a school outbreak, we estimate a school child infects 2.4 (95% CI: 1.8-3.2) other children within the school. We estimate the basic reproductive number, R 0 , to range from 1.3-1.7 and the generation interval to range from 2.6-3.2 days. We use a simulation model to evaluate the effectiveness of vaccination strategies in the USA for the Fall, 2009. If vaccine were available soon enough, vaccination of children, followed by adults, reaching 70% overall coverage, in addition to high risk and essential workforce groups, could mitigate a severe epidemic.
Proceedings of the National Academy of Sciences, 2011
In October 2010, a virulent South Asian strain of El Tor cholera began to spread in Haiti. Interv... more In October 2010, a virulent South Asian strain of El Tor cholera began to spread in Haiti. Interventions have included treatment of cases and improved sanitation. Use of cholera vaccines would likely have further reduced morbidity and mortality, but such vaccines are in short supply and little is known about effective vaccination strategies for epidemic cholera. We use a mathematical cholera transmission model to assess different vaccination strategies. With limited vaccine quantities, concentrating vaccine in high-risk areas is always most efficient. We show that targeting one million doses of vaccine to areas with high exposure to Vibrio cholerae, enough for two doses for 5% of the population, would reduce the number of cases by 11%. The same strategy with enough vaccine for 30% of the population with modest hygienic improvement could reduce cases by 55% and save 3,320 lives. For epidemic cholera, we recommend a large mobile stockpile of enough vaccine to cover 30% of a country&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s population to be reactively targeted to populations at high risk of exposure.
Background: Mathematical models have been used to study the dynamics of infectious disease outbre... more Background: Mathematical models have been used to study the dynamics of infectious disease outbreaks and predict the effectiveness of potential mass vaccination campaigns. However, models depend on simplifying assumptions to be tractable, and the consequences of making such assumptions need to be studied. Two assumptions usually incorporated by mathematical models of vector-borne disease transmission is homogeneous mixing among the hosts and vectors and homogeneous distribution of the vectors.
New strains of influenza spread around the globe via the movement of infected individuals. The gl... more New strains of influenza spread around the globe via the movement of infected individuals. The global dynamics of influenza are complicated by different patterns of influenza seasonality in different regions of the world. We have released an open-source stochastic mathematical model of the spread of influenza across 321 major, strategically located cities of the world. Influenza is transmitted between cities via infected airline passengers. Seasonality is simulated by increasing the transmissibility in each city at the times of the year when influenza has been observed to be most prevalent. The spatiotemporal spread of pandemic influenza can be understood through clusters of global transmission and links between them, which we identify using the epidemic percolation network (EPN) of the model. We use the model to explain the observed global pattern of spread for pandemic influenza A(H1N1) 2009-2010 (pandemic H1N1 2009) and to examine possible global patterns of spread for future pandemics depending on the origin of pandemic spread, time of year of emergence, and basic reproductive number (R 0 ). We also use the model to investigate the effectiveness of a plausible global distribution of vaccine for various pandemic scenarios. For pandemic H1N1 2009, we show that the biggest impact of vaccination was in the temperate northern hemisphere. For pandemics starting in the temperate northern hemisphere in May or April, vaccination would have little effect in the temperate southern hemisphere and a small effect in the tropics. With the increasing interconnectedness of the world's population, we must take a global view of infectious disease transmission. Our open-source, computationally simple model can help public health officials plan for the next pandemic as well as deal with interpandemic influenza.
Although there is no doubt that significant morbidity and mortality occur during annual influenza... more Although there is no doubt that significant morbidity and mortality occur during annual influenza epidemics, the role of contextual circumstances, which catalyze seasonal influenza transmission, remains unclear. Weather conditions are believed to affect virus survival, efficiency of transmission and host immunity, but seasonality may also be driven by a tendency of people to congregate indoors during periods of bad weather. To test this hypothesis, we combined data from a social contact survey in Belgium with local weather data. In the absence of a previous in-depth weather impact analysis of social contact patterns, we explored the possibilities and identified pitfalls. We found general dominance of day-type (weekend, holiday, working day) over weather conditions, but nonetheless observed an increase in long duration contacts (w1 hour) on regular workdays with low temperatures, almost no precipitation and low absolute humidity of the air. Interestingly, these conditions are often assumed to be beneficial for virus survival and transmission. Further research is needed to establish the impact of the weather on social contacts. We recommend that future studies sample over a broad spectrum of weather conditions and day types and include a sufficiently large proportion of holiday periods and weekends.
Background: Dengue is a mosquito-borne infectious disease that constitutes a growing global threa... more Background: Dengue is a mosquito-borne infectious disease that constitutes a growing global threat with the habitat expansion of its vectors Aedes aegyti and A. albopictus and increasing urbanization. With no effective treatment and limited success of vector control, dengue vaccines constitute the best control measure for the foreseeable future. With four interacting dengue serotypes, the development of an effective vaccine has been a challenge. Several dengue vaccine candidates are currently being tested in clinical trials. Before the widespread introduction of a new dengue vaccine, one needs to consider how best to use limited supplies of vaccine given the complex dengue transmission dynamics and the immunological interaction among the four dengue serotypes.
Mathematical and computer models of epidemics have contributed to our understanding of the spread... more Mathematical and computer models of epidemics have contributed to our understanding of the spread of infectious disease and the measures needed to contain or mitigate them. To help prepare for future influenza seasonal epidemics or pandemics, we developed a new stochastic model of the spread of influenza across a large population. Individuals in this model have realistic social contact networks, and transmission and infections are based on the current state of knowledge of the natural history of influenza. The model has been calibrated so that outcomes are consistent with the 1957/1958 Asian A(H2N2) and 2009 pandemic A(H1N1) influenza viruses. We present examples of how this model can be used to study the dynamics of influenza epidemics in the United States and simulate how to mitigate or delay them using pharmaceutical interventions and social distancing measures. Computer simulation models play an essential role in informing public policy and evaluating pandemic preparedness plans. We have made the source code of this model publicly available to encourage its use and further development.
Resistance to oseltamivir, the most widely used influenza antiviral drug, spread to fixation in s... more Resistance to oseltamivir, the most widely used influenza antiviral drug, spread to fixation in seasonal influenza A(H1N1) between 2006 and 2009. This sudden rise in resistance seemed puzzling given the low overall level of the oseltamivir usage and the lack of a correlation between local rates of resistance and oseltamivir usage. We used a stochastic simulation model and deterministic approximations to examine how such events can occur, and in particular to determine how the rate of fixation of the resistant strain depends both on its fitness in untreated hosts as well as the frequency of antiviral treatment. We found that, for the levels of antiviral usage in the population, the resistant strain will eventually spread to fixation, if it is not attenuated in transmissibility relative to the drugsensitive strain, but not at the speed observed in seasonal H1N1. The extreme speed with which the resistance spread in seasonal H1N1 suggests that the resistant strain had a transmission advantage in untreated hosts, and this could have arisen from genetic hitchhiking, or from the mutations responsible for resistance and compensation. Importantly, our model also shows that resistant virus will fail to spread if it is even slightly less transmissible than its sensitive counterpart-a finding of relevance given that resistant pandemic influenza (H1N1) 2009 may currently suffer from a small, but nonetheless experimentally perceptible reduction in transmissibility.
The opening of schools in late summer of 2009 may have triggered the fall wave of pandemic influe... more The opening of schools in late summer of 2009 may have triggered the fall wave of pandemic influenza A(H1N1) in the United States. We found that elevated percent of outpatient visits for influenza-like illness (ILI%) occurred an average of 14 days after schools opened in a state in the fall of 2009. The timing of these events was highly correlated (Spearman's correlation coefficient=0.62, p < 1.0 × 10 −5 ). This result provides evidence that transmission in schools catalyzes community-wide transmission. School opening dates can be useful for future pandemic planning, and influenza mitigation strategies should be targeted at school populations before the influenza season.
Uploads
Papers by Dennis Chao