Using genetic data to identify transmission risk factors: Statistical assessment and application to tuberculosis transmission.

Identifying host factors that influence infectious disease transmission is an important step toward developing interventions to reduce disease incidence. Recent advances in methods for reconstructing infectious disease transmission events using pathogen genomic and epidemiological data open the door for investigation of host factors that affect onward transmission. While most transmission reconstruction methods are designed to work with densely sampled outbreaks, these methods are making their way into surveillance studies, where the fraction of sampled cases with sequenced pathogens could be relatively low. Surveillance studies that use transmission event reconstruction then use the reconstructed events as response variables (i.e., infection source status of each sampled case) and use host characteristics as predictors (e.g., presence of HIV infection) in regression models. We use simulations to study estimation of the effect of a host factor on probability of being an infection source via this multi-step inferential procedure. Using TransPhylo-a widely-used method for Bayesian estimation of infectious disease transmission events-and logistic regression, we find that low sensitivity of identifying infection sources leads to dilution of the signal, biasing logistic regression coefficients toward zero. We show that increasing the proportion of sampled cases improves sensitivity and some, but not all properties of the logistic regression inference. Application of these approaches to real world data from a population-based TB study in Botswana fails to detect an association between HIV infection and probability of being a TB infection source. We conclude that application of a pipeline, where one first uses TransPhylo and sparsely sampled surveillance data to infer transmission events and then estimates effects of host characteristics on probabilities of these events, should be accompanied by a realistic simulation study to better understand biases stemming from imprecise transmission event inference.

Confidence intervals for prevalence estimates from complex surveys with imperfect assays.

There are established methods for estimating disease prevalence with associated confidence intervals for complex surveys with perfect assays, or simple random sample surveys with imperfect assays. We develop and study methods for the complicated case of complex surveys with imperfect assays. The new methods use the melding method to combine gamma intervals for directly standardized rates and established adjustments for imperfect assays by estimating sensitivity and specificity. One of the new methods appears to have at least nominal coverage in all simulated scenarios. We compare our new methods to established methods in special cases (complex surveys with perfect assays or simple surveys with imperfect assays). In some simulations, our methods appear to guarantee coverage, while competing methods have much lower than nominal coverage, especially when overall prevalence is very low. In other settings, our methods are shown to have higher than nominal coverage. We apply our method to a seroprevalence survey of SARS-CoV-2 in undiagnosed adults in the United States between May and July 2020.

Semi-parametric modeling of SARS-CoV-2 transmission using tests, cases, deaths, and seroprevalence data.

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.