Stochastic epidemic models (SEMs) fit to incidence data are critical to elucidating outbreak dynamics, shaping response strategies, and preparing for future epidemics. SEMs typically represent counts of individuals in discrete infection states using Markov jump processes (MJPs), but are computationally challenging as imperfect surveillance, lack of subject-level information, and temporal coarseness of the data obscure the true epidemic. Analytic integration over the latent epidemic process is impossible, and integration via Markov chain Monte Carlo (MCMC) is cumbersome due to the dimensionality and discreteness of the latent state space. Simulation-based computational approaches can address the intractability of the MJP likelihood, but are numerically fragile and prohibitively expensive for complex models. A linear noise approximation (LNA) that approximates the MJP transition density with a Gaussian density has been explored for analyzing prevalence data in large-population settings, but requires modification for analyzing incidence counts without assuming that the data are normally distributed. We demonstrate how to reparameterize SEMs to appropriately analyze incidence data, and fold the LNA into a data augmentation MCMC framework that outperforms deterministic methods, statistically, and simulation-based methods, computationally. Our framework is computationally robust when the model dynamics are complex and applies to a broad class of SEMs. We evaluate our method in simulations that reflect Ebola, influenza, and SARS-CoV-2 dynamics, and apply our method to national surveillance counts from the 2013--2015 West Africa Ebola outbreak.

Stochastic epidemic models describe the dynamics of an epidemic as a disease spreads through a population. Typically, only a fraction of cases are observed at a set of discrete times. The absence of complete information about the time evolution of an epidemic gives rise to a complicated latent variable problem in which the state space size of the epidemic grows large as the population size increases. This makes analytically integrating over the missing data infeasible for populations of even moderate size. We present a data augmentation Markov chain Monte Carlo (MCMC) framework for Bayesian estimation of stochastic epidemic model parameters, in which measurements are augmented with subject-level disease histories. In our MCMC algorithm, we propose each new subject-level path, conditional on the data, using a time-inhomogeneous continuous-time Markov process with rates determined by the infection histories of other individuals. The method is general, and may be applied to a broad class of epidemic models with only minimal modifications to the model dynamics and/or emission distribution. We present our algorithm in the context of multiple stochastic epidemic models in which the data are binomially sampled prevalence counts, and apply our method to data from an outbreak of influenza in a British boarding school.

Mechanistic models fit to streaming surveillance data are critical to understanding the transmission dynamics of an outbreak as it unfolds in real-time. However, transmission model parameter estimation can be imprecise, and sometimes even impossible, because surveillance data are noisy and not informative about all aspects of the mechanistic model. To partially overcome this obstacle, Bayesian models have been proposed to integrate multiple surveillance data streams. We devised a modeling framework for integrating SARS-CoV-2 diagnostics test and mortality time series data, as well as seroprevalence data from cross-sectional studies, and tested the importance of individual data streams for both inference and forecasting. Importantly, our model for incidence data accounts for changes in the total number of tests performed. We model the transmission rate, infection-to-fatality ratio, and a parameter controlling a functional relationship between the true case incidence and the fraction of positive tests as time-varying quantities and estimate changes of these parameters nonparametrically. We compare our base model against modified versions which do not use diagnostics test counts or seroprevalence data to demonstrate the utility of including these often unused data streams. We apply our Bayesian data integration method to COVID-19 surveillance data collected in Orange County, California between March 2020 and February 2021 and find that 32--72\% of the Orange County residents experienced SARS-CoV-2 infection by mid-January, 2021. Despite this high number of infections, our results suggest that the abrupt end of the winter surge in January 2021 was due to both behavioral changes and a high level of accumulated natural immunity.

SignificanceMetagenomic pathogen sequencing offers an unbiased approach to characterizing febrile illness. In resource-scarce settings with high biodiversity, it is critical to identify disease-causing pathogens in order to understand burden and to prioritize efforts for control. Here, metagenomic next-generation sequencing (mNGS) characterization of the pathogen landscape in Cambodia revealed diverse vector-borne and zoonotic pathogens irrespective of age and gender as risk factors. Identification of key pathogens led to changes in national program surveillance. This study is a "real world" example of the use of mNGS surveillance of febrile individuals, executed in-country, to identify outbreaks of vector-borne, zoonotic, and other emerging pathogens in a resource-scarce setting.