Person:

Buckee, Caroline

The var gene family of Plasmodium falciparum encodes the immunodominant variant surface antigens PfEMP1. These highly polymorphic proteins are important virulence factors that mediate cytoadhesion to a variety of host tissues, causing sequestration of parasitized red blood cells in vital organs, including the brain or placenta. Acquisition of variant-specific antibodies correlates with protection against severe malarial infections; however, understanding the relationship between gene expression and infection outcome is complicated by the modular genetic architectures of var genes that encode varying numbers of antigenic domains with differential binding specificities. By analyzing the domain architectures of fully sequenced var gene repertoires we reveal a significant, non-random association between the number of domains comprising a var gene and their sequence conservation. As such, var genes can be grouped into those that are short and diverse and genes that are long and conserved, suggesting gene length as an important characteristic in the classification of var genes. We then use an evolutionary framework to demonstrate how the same evolutionary forces acting on the level of an individual gene may have also shaped the parasite's gene repertoire. The observed associations between sequence conservation, gene architecture and repertoire structure can thus be explained by a trade-off between optimizing within-host fitness and minimizing between-host immune selection pressure. Our results demonstrate how simple evolutionary mechanisms can explain var gene structuring on multiple levels and have important implications for understanding the multifaceted epidemiology of P. falciparum malaria.

As many malaria-endemic countries move towards elimination of Plasmodium falciparum, the most virulent human malaria parasite, effective tools for monitoring malaria epidemiology are urgent priorities. P. falciparum population genetic approaches offer promising tools for understanding transmission and spread of the disease, but a high prevalence of multi-clone or polygenomic infections can render estimation of even the most basic parameters, such as allele frequencies, challenging. A previous method, COIL, was developed to estimate complexity of infection (COI) from single nucleotide polymorphism (SNP) data, but relies on monogenomic infections to estimate allele frequencies or requires external allele frequency data which may not available. Estimates limited to monogenomic infections may not be representative, however, and when the average COI is high, they can be difficult or impossible to obtain. Therefore, we developed THE REAL McCOIL, Turning HEterozygous SNP data into Robust Estimates of ALelle frequency, via Markov chain Monte Carlo, and Complexity Of Infection using Likelihood, to incorporate polygenomic samples and simultaneously estimate allele frequency and COI. This approach was tested via simulations then applied to SNP data from cross-sectional surveys performed in three Ugandan sites with varying malaria transmission. We show that THE REAL McCOIL consistently outperforms COIL on simulated data, particularly when most infections are polygenomic. Using field data we show that, unlike with COIL, we can distinguish epidemiologically relevant differences in COI between and within these sites. Surprisingly, for example, we estimated high average COI in a peri-urban subregion with lower transmission intensity, suggesting that many of these cases were imported from surrounding regions with higher transmission intensity. THE REAL McCOIL therefore provides a robust tool for understanding the molecular epidemiology of malaria across transmission settings.

Background: Pakistan currently provides a substantial challenge to global polio eradication, having contributed to 73% of reported poliomyelitis in 2015 and 54% in 2016. A better understanding of the risk factors and movement patterns that contribute to poliovirus transmission across Pakistan would support evidence-based planning for mass vaccination campaigns. Methods and findings We fit mixed-effects logistic regression models to routine surveillance data recording the presence of poliomyelitis associated with wild-type 1 poliovirus in districts of Pakistan over 6-month intervals between 2010 to 2016. To accurately capture the force of infection (FOI) between districts, we compared 6 models of population movement (adjacency, gravity, radiation, radiation based on population density, radiation based on travel times, and mobile-phone based). We used the best-fitting model (based on the Akaike Information Criterion [AIC]) to produce 6-month forecasts of poliomyelitis incidence. The odds of observing poliomyelitis decreased with improved routine or supplementary (campaign) immunisation coverage (multivariable odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.67–0.84; and OR = 0.75, 95% CI 0.66–0.85, respectively, for each 10% increase in coverage) and increased with a higher rate of reporting non-polio acute flaccid paralysis (AFP) (OR = 1.13, 95% CI 1.02–1.26 for a 1-unit increase in non-polio AFP per 100,000 persons aged <15 years). Estimated movement of poliovirus-infected individuals was associated with the incidence of poliomyelitis, with the radiation model of movement providing the best fit to the data. Six-month forecasts of poliomyelitis incidence by district for 2013–2016 showed good predictive ability (area under the curve range: 0.76–0.98). However, although the best-fitting movement model (radiation) was a significant determinant of poliomyelitis incidence, it did not improve the predictive ability of the multivariable model. Overall, in Pakistan the risk of polio cases was predicted to reduce between July–December 2016 and January–June 2017. The accuracy of the model may be limited by the small number of AFP cases in some districts. Conclusions: Spatiotemporal variation in immunization performance and population movement patterns are important determinants of historical poliomyelitis incidence in Pakistan; however, movement dynamics were less influential in predicting future cases, at a time when the polio map is shrinking. Results from the regression models we present are being used to help plan vaccination campaigns and transit vaccination strategies in Pakistan.

Background: The spread of Coronavirus Disease 2019 (COVID-19) across the United States confirms that not all Americans are equally at risk of infection, severe disease, or mortality. A range of intersecting biological, demographic, and socioeconomic factors are likely to determine an individual’s susceptibility to COVID-19. These factors vary significantly across counties in the United States, and often reflect the structural inequities in our society. Recognizing this vast inter-county variation in risks will be critical to mounting an adequate response strategy.

Methods and Findings: Using publicly available county-specific data we identified key biological, demographic, and socioeconomic factors influencing susceptibility to COVID-19, guided by international experiences and consideration of epidemiological parameters of importance. We created bivariate county-level maps to summarize examples of key relationships across these categories, grouping age and poverty; comorbidities and lack of health insurance; proximity, density and bed capacity; and race and ethnicity, and premature death. We have also made available an interactive online tool that allows public health officials to query risk factors most relevant to their local context.

Our data demonstrate significant inter-county variation in key epidemiological risk factors, with a clustering of counties in certain states, which will result in an increased demand on their public health system. While the East and West coast cities are particularly vulnerable owing to their densities (and travel routes), a large number of counties in the Southeastern states have a high proportion of at-risk populations, with high levels of poverty, comorbidities, and premature death at baseline, and low levels of health insurance coverage.

The list of variables we have examined is by no means comprehensive, and several of them are interrelated and magnify underlying vulnerabilities. The online tool allows readers to explore additional combinations of risk factors, set categorical thresholds for each covariate, and filter counties above different population thresholds.

Conclusion: COVID-19 responses and decision making in the United States remain decentralized. Both the federal and state governments will benefit from recognizing high intra-state, inter-county variation in population risks and response capacity. Many of the factors that are likely to exacerbate the burden of COVID-19 and the demand on healthcare systems are the compounded result of long-standing structural inequalities in US society. Strategies to protect those in the most vulnerable counties will require urgent measures to better support communities’ attempts at social distancing and to accelerate cooperation across jurisdictions to supply personnel and equipment to counties that will experience high demand.

Cases from the ongoing outbreak of atypical pneumonia caused by the 2019 novel coronavirus (2019-nCoV) exported from mainland China can lead to self-sustained outbreaks in other populations. Internationally imported cases are currently being reported in several different locations. Early detection of imported cases is critical for containment of the virus. Based on air travel volume estimates from Wuhan to international destinations and using a generalized linear regression model we identify locations which may potentially have undetected internationally imported cases.

As of mid-August 2020, more than 170 000 U.S. residents have died of coronavirus disease 2019 (COVID-19); however, the true number of deaths resulting from COVID-19, both directly and indirectly, is likely to be much higher. The proper attribution of deaths to this pandemic has a range of societal, legal, mortuary, and public health consequences. This article discusses the current difficulties of disaster death attribution and describes the strengths and limitations of relying on death counts from death certificates, estimations of indirect deaths, and estimations of excess mortality. Improving the tabulation of direct and indirect deaths on death certificates will require concerted efforts and consensus across medical institutions and public health agencies. In addition, actionable estimates of excess mortality will require timely access to standardized and structured vital registry data, which should be shared directly at the state level to ensure rapid response for local governments. Correct attribution of direct and indirect deaths and estimation of excess mortality are complementary goals that are critical to our understanding of the pandemic and its effect on human life.

The current coronavirus disease 2019 (COVID-19) pandemic has impacted dense urban populations particularly hard. Here, we provide an in-depth characterization of disease incidence and mortality patterns, and their dependence on demographic and socioeconomic strata in Santiago, a highly segregated city and the capital of Chile. We find that among all age groups, there is a strong association between socioeconomic status and both mortality –measured either by direct COVID-19 attributed deaths or excess deaths– and public health capacity. Specifically, we show that behavioral factors like human mobility, as well as health system factors such as testing volumes, testing delays, and test positivity rates are associated with disease outcomes. These robust patterns suggest multiple possibly interacting pathways that can explain the observed disease burden and mortality differentials: (i) in lower socioeconomic status municipalities, human mobility was not reduced as much as in more affluent municipalities; (ii) testing volumes in these locations were insufficient early in the pandemic and public health interventions were applied too late to be effective; (iii) test positivity and testing delays were much higher in less affluent municipalities, indicating an impaired capacity of the health-care system to contain the spread of the epidemic; and (iv) infection fatality rates appear much higher in the lower end of the socioeconomic spectrum. Together, these findings highlight the exacerbated consequences of health-care inequalities in a large city of the developing world, and provide practical methodological approaches useful for characterizing COVID-19 burden and mortality in other segregated urban centers.

Individual quarantine and active monitoring of contacts are core disease control strategies, particularly for emerging infectious diseases such as Coronavirus Disease 2019 (COVID-19). To estimate the comparative efficacy of these interventions to control COVID-19, we fit a stochastic branching model, comparing two sets of reported parameters for the dynamics of the disease. Our results suggest that individual quarantine may contain an outbreak of COVID-19 with a short serial interval (4.8 days) only in settings with high intervention performance where at least three-quarters of infected contacts are individually quarantined. However, in settings where this performance is unrealistically high and the outbreak of COVID-19 continues to grow, so too will the burden of the number of contacts traced for active monitoring or quarantine. In such circumstances where resources are prioritized for scalable interventions such as social distancing, we show active monitoring or individual quarantine of high-risk contacts can contribute synergistically to social distancing. To the extent that interventions based on contact tracing can be implemented, therefore, they can help mitigate the spread of COVID-19. Our model highlights the urgent need for more data on the serial interval and the extent of presymptomatic transmission in order to make data-driven policy decisions regarding the cost-benefit comparisons of individual quarantine vs. active monitoring of contacts.

BACKGROUND Quantifying the effect of natural disasters on society is critical for recovery of public health services and infrastructure. The death toll can be difficult to assess in the aftermath of a major disaster. In September 2017, Hurricane Maria caused massive infrastructural damage to Puerto Rico, but its effect on mortality remains contentious. The official death count is 64.

METHODS Using a representative, stratified sample, we surveyed 3299 randomly chosen households across Puerto Rico to produce an independent estimate of all-cause mortality after the hurricane. Respondents were asked about displacement, infrastructure loss, and causes of death. We calculated excess deaths by comparing our estimated post-hurricane mortality rate with official rates for the same period in 2016.

RESULTS From the survey data, we estimated a mortality rate of 14.3 deaths (95% confidence interval [CI], 9.8 to 18.9) per 1000 persons from September 20 through December 31, 2017. This rate yielded a total of 4645 excess deaths during this period (95% CI, 793 to 8498), equivalent to a 62% increase in the mortality rate as compared with the same period in 2016. However, this number is likely to be an underestimate because of survivor bias. The mortality rate remained high through the end of December 2017, and one third of the deaths were attributed to delayed or interrupted health care. Hurricane-related migration was substantial.

CONCLUSIONS This household-based survey suggests that the number of excess deaths related to Hurricane Maria in Puerto Rico is more than 70 times the official estimate. (Funded by the Harvard T.H. Chan School of Public Health and others.)

With the rapidly increasing abundance and accessibility of genomic data, there is a growing interest in using population genetic approaches to characterize fine-scale dispersal of organisms, providing insight into biological processes across a broad range of fields including ecology, evolution and epidemiology. For sexually recombining haploid organisms such as the human malaria parasite P. falciparum, however, there have been no systematic assessments of the type of data and methods required to resolve fine scale connectivity. This analytical gap hinders the use of genomics for understanding local transmission patterns, a crucial goal for policy makers charged with eliminating this important human pathogen. Here we use data collected from four clinics with a catchment area spanning approximately 120 km of the Thai-Myanmar border to compare the ability of divergence (FST) and relatedness based on identity by descent (IBD) to resolve spatial connectivity between malaria parasites collected from proximal clinics. We found no relationship between inter-clinic distance and FST, likely due to sampling of highly related parasites within clinics, but a significant decline in IBD-based relatedness with increasing inter-clinic distance. This association was contingent upon the data set type and size. We estimated that approximately 147 single-infection whole genome sequenced parasite samples or 222 single-infection parasite samples genotyped at 93 single nucleotide polymorphisms (SNPs) were sufficient to recover a robust spatial trend estimate at this scale. In summary, surveillance efforts cannot rely on classical measures of genetic divergence to measure P. falciparum transmission on a local scale. Given adequate sampling, IBD-based relatedness provides a useful alternative, and robust trends can be obtained from parasite samples genotyped at approximately 100 SNPs.