84 research outputs found
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Epidemiologic data and pathogen genome sequences: a powerful synergy for public health
Epidemiologists aim to inform the design of public health interventions with evidence on the evolution, emergence and spread of infectious diseases. Sequencing of pathogen genomes, together with date, location, clinical manifestation and other relevant data about sample origins, can contribute to describing nearly every aspect of transmission dynamics, including local transmission and global spread. The analyses of these data have implications for all levels of clinical and public health practice, from institutional infection control to policies for surveillance, prevention and treatment. This review highlights the range of epidemiological questions that can be addressed from the combination of genome sequence and traditional ‘line lists’ (tables of epidemiological data where each line includes demographic and clinical features of infected individuals). We identify opportunities for these data to inform interventions that reduce disease incidence and prevalence. By considering current limitations of, and challenges to, interpreting these data, we aim to outline a research agenda to accelerate the genomics-driven transformation in public health microbiology
Discovering recent selection forces shaping the evolution of dengue viruses based on polymorphism data across geographic scales
Incomplete selection makes it challenging to infer selection on genes at short time scales, especially for microorganisms, due to stronger linkage between loci. However, in many cases, the selective force changes with environment, time, or other factors, and it is of great interest to understand selective forces at this level to answer relevant biological questions. We developed a new method that uses the change in d(N)/d(S), instead of the absolute value of d(N)/d(S), to infer the dominating selective force based on sequence data across geographical scales. If a gene was under positive selection, d(N)/d(S) was expected to increase through time, whereas if a gene was under negative selection, d(N)/d(S) was expected to decrease through time. Assuming that the migration rate decreased and the divergence time between samples increased from between-continent, within-continent different-country, to within-country level, d(N)/d(S) of a gene dominated by positive selection was expected to increase with increasing geographical scales, and the opposite trend was expected in the case of negative selection. Motivated by the McDonald-Kreitman (MK) test, we developed a pairwise MK test to assess the statistical significance of detected trends in d(N)/d(S). Application of the method to a global sample of dengue virus genomes identified multiple significant signatures of selection in both the structural and non-structural proteins. Because this method does not require allele frequency estimates and uses synonymous mutations for comparison, it is less prone to sampling error, providing a way to infer selection forces within species using publicly available genomic data from locations over broad geographical scales.Peer reviewe
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Modeling the impact of racial and ethnic disparities on COVID-19 epidemic dynamics.
BACKGROUND: The impact of variable infection risk by race and ethnicity on the dynamics of SARS-CoV-2 spread is largely unknown. METHODS: Here, we fit structured compartmental models to seroprevalence data from New York State and analyze how herd immunity thresholds (HITs), final sizes, and epidemic risk change across groups. RESULTS: A simple model where interactions occur proportionally to contact rates reduced the HIT, but more realistic models of preferential mixing within groups increased the threshold toward the value observed in homogeneous populations. Across all models, the burden of infection fell disproportionately on minority populations: in a model fit to Long Island serosurvey and census data, 81% of Hispanics or Latinos were infected when the HIT was reached compared to 34% of non-Hispanic whites. CONCLUSIONS: Our findings, which are meant to be illustrative and not best estimates, demonstrate how racial and ethnic disparities can impact epidemic trajectories and result in unequal distributions of SARS-CoV-2 infection. FUNDING: K.C.M. was supported by National Science Foundation GRFP grant DGE1745303. Y.H.G. and M.L. were funded by the Morris-Singer Foundation. M.L. was supported by SeroNet cooperative agreement U01 CA261277
Estimating the fitness cost and benefit of antimicrobial resistance from pathogen genomic data
Increasing levels of antibiotic resistance in many bacterial pathogen populations are a major threat to public health. Resistance to an antibiotic provides a fitness benefit when the bacteria are exposed to this antibiotic, but resistance also often comes at a cost to the resistant pathogen relative to susceptible counterparts. We lack a good understanding of these benefits and costs of resistance for many bacterial pathogens and antibiotics, but estimating them could lead to better use of antibiotics in a way that reduces or prevents the spread of resistance. Here, we propose a new model for the joint epidemiology of susceptible and resistant variants, which includes explicit parameters for the cost and benefit of resistance. We show how Bayesian inference can be performed under this model using phylogenetic data from susceptible and resistant lineages and that by combining data from both we are able to disentangle and estimate the resistance cost and benefit parameters separately. We applied our inferential methodology to several simulated datasets to demonstrate good scalability and accuracy. We analysed a dataset of Neisseria gonorrhoeae genomes collected between 2000 and 2013 in the USA. We found that two unrelated lineages resistant to fluoroquinolones shared similar epidemic dynamics and resistance parameters. Fluoroquinolones were abandoned for the treatment of gonorrhoea due to increasing levels of resistance, but our results suggest that they could be used to treat a minority of around 10% of cases without causing resistance to grow again
Fine-Scale Haplotype Structure Reveals Strong Signatures of Positive Selection in a Recombining Bacterial Pathogen
Identifying genetic variation in bacteria that has been shaped by ecological differences remains an important challenge. For recombining bacteria, the sign and strength of linkage provide a unique lens into ongoing selection. We show that derived allelesPeer reviewe
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Optimizing prevalence estimates for a novel pathogen by reducing uncertainty in test characteristics
Emergence of a novel pathogen drives the urgent need for diagnostic tests that can aid in defining disease prevalence. The limitations associated with rapid development and deployment of these tests result in a dilemma: In efforts to optimize prevalence estimates, would tests be better used in the lab to reduce uncertainty in test characteristics or to increase sample size in field studies? Here, we provide a framework to address this question through a joint Bayesian model that simultaneously analyzes lab validation and field survey data, and we define the impact of test allocation on inferences of sensitivity, specificity, and prevalence. In many scenarios, prevalence estimates can be most improved by apportioning additional effort towards validation rather than to the field. The joint model provides superior estimation of prevalence, sensitivity, and specificity, compared with typical analyses that model lab and field data separately, and it can be used to inform sample allocation when testing is limited.
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The Population Dynamics of Antibiotic Resistance in Staphylococcus aureus in Boston: A Return to Antibiotic Susceptibility
Abstract Background: Methicillin resistant Staphylococcus aureus (MRSA) has been declining over the past decade, but changes in S. aureus overall and the implications for trends in antibiotic resistance remain unclear. We determine whether the decline in rates of infection by MRSA has been accompanied by changes in rates of infection by methicillin susceptible, penicillin resistant S. aureus (MSSA) and penicillin susceptible S. aureus (PSSA). We test if these dynamics are associated with specific genetic lineages and evaluate gains and losses of resistance at the strain level. Methods: We conducted a 15 year retrospective observational study at two tertiary care institutions in Boston, MA of 31,589 adult inpatients with S. aureus infections. Surveillance swabs and duplicate specimens were excluded. We also sequenced a sample of contemporary isolates (n = 180) obtained between January 2016 and July 2016. We determined changes in the annual rates of infection per 1,000 inpatient admissions by S. aureus subtype and in the annual mean antibiotic resistance by subtype. We performed phylogenetic analysis to generate a population structure and infer gain and loss of the genetic determinants of resistance. Results: Of the 43,954 S. aureus infections over the study period, 21,779 were MRSA, 17,565 MSSA and 4,610 PSSA. After multivariate adjustment, annual rates of infection by S. aureus declined from to 2014 by 2.9% (95% confidence interval (CI), 1.6%–4.3%), attributable to an annual decline in MRSA of 9.1% (95% CI, 6.3%–11.9%) and in MSSA by 2.2% (95% CI, 0.4%–4.0%). PSSA increased over this time period by 4.6% (95% CI, 3.0%–6.3%) annually. Resistance in S. aureus decreased from 2000 to 2014 by 0.86 antibiotics (95% CI, 0.81–0.91). By phylogenetic inference, 5/35 MSSA and 2/20 PSSA isolates in the common MRSA lineages ST5/USA100 and ST8/USA300 arose from the loss of genes conferring resistance. Conclusion: At two large tertiary care centers in Boston, S. aureus infections have decreased in rate and have become more susceptible to antibiotics, with a rise in PSSA making penicillin an increasingly viable and important treatment option. Disclosures All authors: No reported disclosures
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Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants.
Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate antibiotic use. However, because such assays infer resistance based on known genetic markers, their utility will wane with the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance to ensure early detection of novel resistance variants, but efficient strategies to do so remain undefined. We evaluate the efficiency of targeted sampling approaches informed by patient and pathogen characteristics in detecting antibiotic resistance and diagnostic escape variants in Neisseria gonorrhoeae, a pathogen associated with a high burden of disease and antibiotic resistance and the development of genotype-based diagnostics. We show that patient characteristic-informed sampling is not a reliable strategy for efficient variant detection. In contrast, sampling informed by pathogen characteristics, such as genomic diversity and genomic background, is significantly more efficient than random sampling in identifying genetic variants associated with resistance and diagnostic escape
Viral Kinetics of Sequential SARS-CoV-2 Infections
The impact of a prior SARS-CoV-2 infection on the progression of subsequent infections has been unclear. Using a convenience sample of 94,812 longitudinal RT-qPCR measurements from anterior nares and oropharyngeal swabs, we identified 71 individuals with two well-sampled SARS-CoV-2 infections between March 11th, 2020, and July 28th, 2022. We compared the SARS-CoV-2 viral kinetics of first vs. second infections in this group, adjusting for viral variant, vaccination status, and age. Relative to first infections, second infections usually featured a faster clearance time. Furthermore, a person\u27s relative (rank-order) viral clearance time, compared to others infected with the same variant, was roughly conserved across first and second infections, so that individuals who had a relatively fast clearance time in their first infection also tended to have a relatively fast clearance time in their second infection (Spearman correlation coefficient: 0.30, 95% credible interval (0.12, 0.46)). These findings provide evidence that, like vaccination, immunity from a prior SARS-CoV-2 infection shortens the duration of subsequent acute SARS-CoV-2 infections principally by reducing viral clearance time. Additionally, there appears to be an inherent element of the immune response, or some other host factor, that shapes a person\u27s relative ability to clear SARS-CoV-2 infection that persists across sequential infections
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