A resampling-based test to detect person-to-person transmission of infectious disease

Early detection of person-to-person transmission of emerging infectious diseases such as avian influenza is crucial for containing pandemics. We developed a simple permutation test and its refined version for this purpose. A simulation study shows that the refined permutation test is as powerful as or outcompetes the conventional test built on asymptotic theory, especially when the sample size is small. In addition, our resampling methods can be applied to a broad range of problems where an asymptotic test is not available or fails. We also found that decent statistical power could be attained with just a small number of cases, if the disease is moderately transmissible between humans.Comment: Published at http://dx.doi.org/10.1214/07-AOAS105 in the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Molecular Infectious Disease Epidemiology: Survival Analysis and Algorithms Linking Phylogenies to Transmission Trees

Recent work has attempted to use whole-genome sequence data from pathogens to reconstruct the transmission trees linking infectors and infectees in outbreaks. However, transmission trees from one outbreak do not generalize to future outbreaks. Reconstruction of transmission trees is most useful to public health if it leads to generalizable scientific insights about disease transmission. In a survival analysis framework, estimation of transmission parameters is based on sums or averages over the possible transmission trees. A phylogeny can increase the precision of these estimates by providing partial information about who infected whom. The leaves of the phylogeny represent sampled pathogens, which have known hosts. The interior nodes represent common ancestors of sampled pathogens, which have unknown hosts. Starting from assumptions about disease biology and epidemiologic study design, we prove that there is a one-to-one correspondence between the possible assignments of interior node hosts and the transmission trees simultaneously consistent with the phylogeny and the epidemiologic data on person, place, and time. We develop algorithms to enumerate these transmission trees and show these can be used to calculate likelihoods that incorporate both epidemiologic data and a phylogeny. A simulation study confirms that this leads to more efficient estimates of hazard ratios for infectiousness and baseline hazards of infectious contact, and we use these methods to analyze data from a foot-and-mouth disease virus outbreak in the United Kingdom in 2001. These results demonstrate the importance of data on individuals who escape infection, which is often overlooked. The combination of survival analysis and algorithms linking phylogenies to transmission trees is a rigorous but flexible statistical foundation for molecular infectious disease epidemiology.Comment: 28 pages, 11 figures, 3 table

Estimating within-household contact networks from egocentric data

Acute respiratory diseases are transmitted over networks of social contacts. Large-scale simulation models are used to predict epidemic dynamics and evaluate the impact of various interventions, but the contact behavior in these models is based on simplistic and strong assumptions which are not informed by survey data. These assumptions are also used for estimating transmission measures such as the basic reproductive number and secondary attack rates. Development of methodology to infer contact networks from survey data could improve these models and estimation methods. We contribute to this area by developing a model of within-household social contacts and using it to analyze the Belgian POLYMOD data set, which contains detailed diaries of social contacts in a 24-hour period. We model dependency in contact behavior through a latent variable indicating which household members are at home. We estimate age-specific probabilities of being at home and age-specific probabilities of contact conditional on two members being at home. Our results differ from the standard random mixing assumption. In addition, we find that the probability that all members contact each other on a given day is fairly low: 0.49 for households with two 0--5 year olds and two 19--35 year olds, and 0.36 for households with two 12--18 year olds and two 36+ year olds. We find higher contact rates in households with 2--3 members, helping explain the higher influenza secondary attack rates found in households of this size.Comment: Published in at http://dx.doi.org/10.1214/11-AOAS474 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Estimating within-school contact networks to understand influenza transmission

Many epidemic models approximate social contact behavior by assuming random mixing within mixing groups (e.g., homes, schools and workplaces). The effect of more realistic social network structure on estimates of epidemic parameters is an open area of exploration. We develop a detailed statistical model to estimate the social contact network within a high school using friendship network data and a survey of contact behavior. Our contact network model includes classroom structure, longer durations of contacts to friends than nonfriends and more frequent contacts with friends, based on reports in the contact survey. We performed simulation studies to explore which network structures are relevant to influenza transmission. These studies yield two key findings. First, we found that the friendship network structure important to the transmission process can be adequately represented by a dyad-independent exponential random graph model (ERGM). This means that individual-level sampled data is sufficient to characterize the entire friendship network. Second, we found that contact behavior was adequately represented by a static rather than dynamic contact network.Comment: Published in at http://dx.doi.org/10.1214/11-AOAS505 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Preclinical Assessment of HIV Vaccines and Microbicides by Repeated Low-Dose Virus Challenges

BACKGROUND: Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against “real life” exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses. METHODS AND FINDINGS: Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success. CONCLUSION: Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions

Optimizing Vaccine Allocation at Different Points in Time during an Epidemic

For current pandemic influenza H1N1, vaccine production started in the early summer, and vaccination started in the fall. In most countries, by the time vaccination started, the second wave of H1N1 was already under way. With limited supplies of vaccine, it might be a good strategy to vaccinate the high-transmission groups earlier in the epidemic, but it might be a better use of resources to protect instead the high-risk groups later on. We develop a deterministic epidemic model with two age-groups (children and adults) and further subdivide each age group in low and high risk. We compare optimal vaccination strategies started at various points in time in two different settings: a population in the United States (US) where children account for 24% of the population, and a population in Senegal, where children make up for the majority of the population, 55%. For each of these populations, we minimize mortality and we find an optimal vaccination vector that gives us the best vaccine allocation given a starting vaccination date and vaccine coverage level. We find that there is a switch in the optimal vaccination strategy at some time point just before the peak of the epidemic. For instance, with 25% vaccine coverage, it is better to protect the high-transmission groups before this point, but it is optimal to protect the most vulnerable groups afterward

Predictive Modeling of Cholera Outbreaks in Bangladesh

Despite seasonal cholera outbreaks in Bangladesh, little is known about the relationship between environmental conditions and cholera cases. We seek to develop a predictive model for cholera outbreaks in Bangladesh based on environmental predictors. To do this, we estimate the contribution of environmental variables, such as water depth and water temperature, to cholera outbreaks in the context of a disease transmission model. We implement a method which simultaneously accounts for disease dynamics and environmental variables in a Susceptible-Infected-Recovered-Susceptible (SIRS) model. The entire system is treated as a continuous-time hidden Markov model, where the hidden Markov states are the numbers of people who are susceptible, infected, or recovered at each time point, and the observed states are the numbers of cholera cases reported. We use a Bayesian framework to fit this hidden SIRS model, implementing particle Markov chain Monte Carlo methods to sample from the posterior distribution of the environmental and transmission parameters given the observed data. We test this method using both simulation and data from Mathbaria, Bangladesh. Parameter estimates are used to make short-term predictions that capture the formation and decline of epidemic peaks. We demonstrate that our model can successfully predict an increase in the number of infected individuals in the population weeks before the observed number of cholera cases increases, which could allow for early notification of an epidemic and timely allocation of resources.Comment: 43 pages, including appendices, 5 figures, 1 table in the main tex

Neuraminidase Inhibitor Resistance in Influenza: Assessing the Danger of Its Generation and Spread

Neuraminidase Inhibitors (NI) are currently the most effective drugs against influenza. Recent cases of NI resistance are a cause for concern. To assess the danger of NI resistance, a number of studies have reported the fraction of treated patients from which resistant strains could be isolated. Unfortunately, those results strongly depend on the details of the experimental protocol. Additionally, knowing the fraction of patients harboring resistance is not too useful by itself. Instead, we want to know how likely it is that an infected patient can generate a resistant infection in a secondary host, and how likely it is that the resistant strain subsequently spreads. While estimates for these parameters can often be obtained from epidemiological data, such data is lacking for NI resistance in influenza. Here, we use an approach that does not rely on epidemiological data. Instead, we combine data from influenza infections of human volunteers with a mathematical framework that allows estimation of the parameters that govern the initial generation and subsequent spread of resistance. We show how these parameters are influenced by changes in drug efficacy, timing of treatment, fitness of the resistant strain, and details of virus and immune system dynamics. Our study provides estimates for parameters that can be directly used in mathematical and computational models to study how NI usage might lead to the emergence and spread of resistance in the population. We find that the initial generation of resistant cases is most likely lower than the fraction of resistant cases reported. However, we also show that the results depend strongly on the details of the within-host dynamics of influenza infections, and most importantly, the role the immune system plays. Better knowledge of the quantitative dynamics of the immune response during influenza infections will be crucial to further improve the results

Estimating Influenza Vaccine Efficacy From Challenge and Community-based Study Data

In this paper, the authors provide estimates of 4 measures of vaccine efficacy for live, attenuated and inactivated influenza vaccine based on secondary analysis of 5 experimental influenza challenge studies in seronegative adults and community-based vaccine trials. The 4 vaccine efficacy measures are for susceptibility (VES), symptomatic illness given infection (VEP), infection and illness (VESP), and infectiousness (VEI). The authors also propose a combined (VEC) measure of the reduction in transmission in the entire population based on all of the above efficacy measures. Live influenza vaccine and inactivated vaccine provided similar protection against laboratory-confirmed infection (for live vaccine: VES  = 41%, 95% confidence interval (CI): 15, 66; for inactivated vaccine: VES  = 43%, 95% CI: 8, 79). Live vaccine had a higher efficacy for illness given infection (VEP  = 67%, 95% CI: 24, 100) than inactivated vaccine (VEP  = 29%, 95% CI: −19, 76), although the difference was not statistically significant. VESP for the live vaccine was higher than for the inactivated vaccine. VEI estimates were particularly low for these influenza vaccines. VESP and VEC can remain high for both vaccines, even when VEI is relatively low, as long as the other 2 measures of vaccine efficacy are relatively high