Spatial heterogeneity of extensively drug resistant-tuberculosis in Western Cape Province, South Africa.

Tuberculosis (TB) remains a leading infectious disease killer globally. Treatment outcomes are especially poor among people with extensively drug-resistant (XDR) TB, until recently defined as rifampicin-resistant (RR) TB with resistance to an aminoglycoside (amikacin) and a fluoroquinolone (ofloxacin). We used laboratory TB test results from Western Cape province, South Africa between 2012 and 2015 to identify XDR-TB and pre-XDR-TB (RR-TB with resistance to one second-line drug) spatial hotspots. We mapped the percentage and count of individuals with RR-TB that had XDR-TB and pre-XDR-TB across the province and in Cape Town, as well as amikacin-resistant and ofloxacin-resistant TB. We found the percentage of pre-XDR-TB and the count of XDR-TB/pre-XDR-TB highly heterogeneous with geographic hotspots within RR-TB high burden areas, and found hotspots in both percentage and count of amikacin-resistant and ofloxacin-resistant TB. The spatial distribution of percentage ofloxacin-resistant TB hotspots was similar to XDR-TB hotspots, suggesting that fluoroquinolone-resistace is often the first step to additional resistance. Our work shows that interventions used to reduce XDR-TB incidence may need to be targeted within spatial locations of RR-TB, and further research is required to understand underlying drivers of XDR-TB transmission in these locations.

Estimation of the generation interval using pairwise relative transmission probabilities.

The generation interval (the time between infection of primary and secondary cases) and its often used proxy, the serial interval (the time between symptom onset of primary and secondary cases) are critical parameters in understanding infectious disease dynamics. Because it is difficult to determine who infected whom, these important outbreak characteristics are not well understood for many diseases. We present a novel method for estimating transmission intervals using surveillance or outbreak investigation data that, unlike existing methods, does not require a contact tracing data or pathogen whole genome sequence data on all cases. We start with an expectation maximization algorithm and incorporate relative transmission probabilities with noise reduction. We use simulations to show that our method can accurately estimate the generation interval distribution for diseases with different reproductive numbers, generation intervals, and mutation rates. We then apply our method to routinely collected surveillance data from Massachusetts (2010-2016) to estimate the serial interval of tuberculosis in this setting.

What Can Genetic Relatedness Tell Us About Risk Factors for Tuberculosis Transmission?

BACKGROUND: To stop tuberculosis (TB), the leading infectious cause of death globally, we need to better understand transmission risk factors. Although many studies have identified associations between individual-level covariates and pathogen genetic relatedness, few have identified characteristics of transmission pairs or explored how closely covariates associated with genetic relatedness mirror those associated with transmission. METHODS: We simulated a TB-like outbreak with pathogen genetic data and estimated odds ratios (ORs) to correlate each covariate and genetic relatedness. We used a naive Bayes approach to modify the genetic links and nonlinks to resemble the true links and nonlinks more closely and estimated modified ORs with this approach. We compared these two sets of ORs with the true ORs for transmission. Finally, we applied this method to TB data in Hamburg, Germany, and Massachusetts, USA, to find pair-level covariates associated with transmission. RESULTS: Using simulations, we found that associations between covariates and genetic relatedness had the same relative magnitudes and directions as the true associations with transmission, but biased absolute magnitudes. Modifying the genetic links and nonlinks reduced the bias and increased the confidence interval widths, more accurately capturing error. In Hamburg and Massachusetts, pairs were more likely to be probable transmission links if they lived in closer proximity, had a shorter time between observations, or had shared ethnicity, social risk factors, drug resistance, or genotypes. CONCLUSIONS: We developed a method to improve the use of genetic relatedness as a proxy for transmission, and aid in understanding TB transmission dynamics in low-burden settings.

Leveraging Pathogen Sequence and Contact Tracing Data to Enhance Vaccine Trials in Emerging Epidemics.

INTRODUCTION: Advance planning of vaccine trials conducted during outbreaks increases our ability to rapidly define the efficacy and potential impact of a vaccine. Vaccine efficacy against infectiousness (VEI) is an important measure for understanding a vaccine's full impact, yet it is currently not identifiable in many trial designs because it requires knowledge of infectors' vaccination status. Recent advances in genomics have improved our ability to reconstruct transmission networks. We aim to assess if augmenting trials with pathogen sequence and contact tracing data can permit them to estimate VEI. METHODS: We develop a transmission model with a vaccine trial in an outbreak setting, incorporate pathogen sequence data and contact tracing data, and assign probabilities to likely infectors. We then propose and evaluate the performance of an estimator of VEI. RESULTS: We find that under perfect knowledge of infector-infectee pairs, we are able to accurately estimate VEI. Use of sequence data results in imperfect reconstruction of transmission networks, biasing estimates of VEI towards the null, with approaches using deep sequence data performing better than approaches using consensus sequence data. Inclusion of contact tracing data reduces the bias. CONCLUSION: Pathogen genomics enhance identifiability of VEI, but imperfect transmission network reconstruction biases estimate toward the null and limits our ability to detect VEI. Given the consistent direction of the bias, estimates obtained from trials using these methods will provide lower bounds on the true VEI. A combination of sequence and epidemiologic data results in the most accurate estimates, underscoring the importance of contact tracing.

Decentralized Care for Rifampin-Resistant Tuberculosis, Western Cape, South Africa.

In 2011, South Africa implemented a policy to decentralize treatment for rifampin-resistant tuberculosis (TB) to reduce durations of hospitalization and enable local treatment. We assessed policy implementation in Western Cape Province, where services expanded from 6 specialized TB hospitals to 406 facilities, by analyzing National Health Laboratory Service data on TB during 2012-2015. We calculated the percentage of patients who visited a TB hospital <1 year after rifampin-resistant TB diagnosis, the median duration of their hospitalizations, and the total distance between facilities visited. We assessed temporal changes with linear regression and stratified results by location. Of 2,878 patients, 65% were from Cape Town. In Cape Town, 29% visited a TB hospital; elsewhere, 68% visited a TB hospital. We found that hospitalizations and travel distances were shorter in Cape Town than in the surrounding areas.

HIT-COVID, a global database tracking public health interventions to COVID-19.

The COVID-19 pandemic has sparked unprecedented public health and social measures (PHSM) by national and local governments, including border restrictions, school closures, mandatory facemask use and stay at home orders. Quantifying the effectiveness of these interventions in reducing disease transmission is key to rational policy making in response to the current and future pandemics. In order to estimate the effectiveness of these interventions, detailed descriptions of their timelines, scale and scope are needed. The Health Intervention Tracking for COVID-19 (HIT-COVID) is a curated and standardized global database that catalogues the implementation and relaxation of COVID-19 related PHSM. With a team of over 200 volunteer contributors, we assembled policy timelines for a range of key PHSM aimed at reducing COVID-19 risk for the national and first administrative levels (e.g. provinces and states) globally, including details such as the degree of implementation and targeted populations. We continue to maintain and adapt this database to the changing COVID-19 landscape so it can serve as a resource for researchers and policymakers alike.

Estimating the relative probability of direct transmission between infectious disease patients.

BACKGROUND: Estimating infectious disease parameters such as the serial interval (time between symptom onset in primary and secondary cases) and reproductive number (average number of secondary cases produced by a primary case) are important in understanding infectious disease dynamics. Many estimation methods require linking cases by direct transmission, a difficult task for most diseases. METHODS: Using a subset of cases with detailed genetic and/or contact investigation data to develop a training set of probable transmission events, we build a model to estimate the relative transmission probability for all case-pairs from demographic, spatial and clinical data. Our method is based on naive Bayes, a machine learning classification algorithm which uses the observed frequencies in the training dataset to estimate the probability that a pair is linked given a set of covariates. RESULTS: In simulations, we find that the probabilities estimated using genetic distance between cases to define training transmission events are able to distinguish between truly linked and unlinked pairs with high accuracy (area under the receiver operating curve value of 95%). Additionally, only a subset of the cases, 10-50% depending on sample size, need to have detailed genetic data for our method to perform well. We show how these probabilities can be used to estimate the average effective reproductive number and apply our method to a tuberculosis outbreak in Hamburg, Germany. CONCLUSIONS: Our method is a novel way to infer transmission dynamics in any dataset when only a subset of cases has rich contact investigation and/or genetic data.