Biology subjects

Lipsitch, M.

Publications and source records attributed to Lipsitch, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Preventing Disease Emergence Following Eradication: Application to Mpox

We use simple mathematical models to explore the factors that influence the evolutionary emergence of mpox to a pathogen capable of sustained human to human transmission that poses a global threat. Smallpox eradication followed by the discontinuation of immunization with vaccinia has led to a decline in the level of population immunity against related poxviruses such as mpox. This decline in immunity results in an increase in both the number of spillovers and the extent of human to human transmission. We find that increases in transmissibility of mpox between humans have a much greater effect on the probability of evolutionary emergence compared with increases in the number of zoonotic spillovers. We suggest that while mpox only needs to have a reproductive number slightly greater than one to become endemic, subsequent adaptation is likely to further increase its transmissibility in the human population. As a consequence a much higher level of vaccination (or other intervention) is needed to control the pathogen after its evolutionary emergence compared with what is needed to prevent it from emerging in the first place.

evolutionary biology↗

bioRxiv2024

Linkage-based ortholog refinement in bacterial pangenomes with CLARC

Bacterial genomes exhibit significant variation in gene content and sequence identity. Pangenome analyses explore this diversity by classifying genes into core and accessory clusters of orthologous groups (COGs). However, strict sequence identity cutoffs can misclassify divergent alleles as different genes, inflating accessory gene counts. CLARC (Connected Linkage and Alignment Redefinition of COGs) [https://github.com/IndraGonz/CLARC] improves pangenome analyses by condensing accessory COGs using functional annotation and linkage information. Through this approach, orthologous groups are consolidated into more practical units of selection. Analyzing 8,000+ Streptococcus pneumoniae genomes, CLARC reduced accessory gene estimates by more than 30% and improved evolutionary predictions based on accessory gene frequencies. By refining COG definitions, CLARC offers critical insights into bacterial evolution, aiding genetic studies across diverse populations.

bioinformatics↗

bioRxiv2020

Negative frequency-dependent selection and asymmetrical transformation stabilise multi-strain bacterial population structures

Streptococcus pneumoniae can be split into multiple strains, each with a characteristic combination of core and accessory genome variation, able to co-circulate and compete within the same hosts. Previous analyses of epidemiological datasets suggested the short-term vaccine-associated dynamics of S. pneumoniae strains may be mediated through multi-locus negative frequency-dependent selection (NFDS), acting to maintain accessory loci at equilibrium frequencies. To test whether this model could explain how such multi-strain populations were generated, it was modified to incorporate recombination. The outputs of simulations featuring symmetrical recombination were compared with genomic data on locus frequencies and distributions between genotypes, pairwise genetic distances and tree shape. These demonstrated NFDS prevented the loss of variation through neutral drift, but generated unstructured populations of diverse isolates. Making recombination asymmetrical, favouring deletion of accessory loci over insertion, alongside multi-locus NFDS significantly improved the fit to genomic data. In a population at equilibrium, structuring into multiple strains was stable due to outbreeding depression, resulting from recombinants with reduced accessory genomes having lower fitness than their parental genotypes. As many bacteria inhibit the integration of insertions into their chromosomes, this combination of asymmetrical recombination and multi-locus NFDS may underlie the co-existence of strains within a single ecological niche.

evolutionary biology↗

bioRxiv2020

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 and ineffective antibiotic use. However, because such assays infer resistance phenotypes based on the presence or absence of known genetic markers, their utility will wane in response to the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance designed to ensure early detection of novel resistance variants, but efficient strategies to do so remain to be defined. Here, we evaluate the efficiency of targeted sampling approaches informed by patient and pathogen characteristics in detecting genetic variants associated with antibiotic resistance or diagnostic escape in Neisseria gonorrhoeae, focusing on this pathogen because of its high burden of disease, the imminent threat of treatment resistance, and the use and ongoing development of genotype-based diagnostics. We show that incorporating patient characteristics, such as demographics, geographic regions, or anatomical sites of isolate collection, into sampling approaches is not a reliable strategy for increasing variant detection efficiency. In contrast, sampling approaches informed by pathogen characteristics, such as genomic diversity and genomic background, are significantly more efficient than random sampling in identifying genetic variants associated with antibiotic resistance and diagnostic escape.

genomics↗

bioRxiv2019

Quantifying the surveillance required to sustain genetic marker-based antibiotic resistance diagnostics

Diagnostics that minimize the time to selection of an appropriate antibiotic treatment represent an important strategy in addressing the challenge of antimicrobial resistance (AMR). Among this class of diagnostics, the use of pathogen genotype to predict AMR phenotype has been facilitated by advances in rapid sequencing platforms. A longstanding objection to this approach, however, is that the emergence of novel resistance mechanisms will inevitably lead to a decline in the sensitivity of these diagnostics. Here, we show that while the sensitivities of some genetic markers of resistance remain stably high, sensitivities of other markers rapidly decline, as expected, due to the emergence of novel resistance variants. We then present a simple mathematical framework that defines the sampling and phenotypic testing rates needed for early detection of novel resistance variants and thus demonstrate how surveillance can help maintain the sensitivity and utility of sequence-based AMR diagnostics.\n\nOne sentence summaryTargeted sampling strategies are necessary for early detection of novel resistance mechanisms and sustainability of genotype-based detection of novel resistance mechanisms and sustainability of genotype-based diagnostics.

microbiology↗

bioRxiv2019

Nowcasting by Bayesian Smoothing: A flexible, generalizable model for real-time epidemic tracking

Delays in case reporting are common to disease surveillance systems, making it difficult to track diseases in real-time. \"Nowcast\" approaches attempt to estimate the complete case counts for a given reporting date, using a time series of case reports that is known to be incomplete due to reporting delays. Modeling the reporting delay distribution is a common feature of nowcast approaches. However, many nowcast approaches ignore a crucial feature of infectious disease transmission--that future cases are intrinsically linked to past reported cases--and are optimized to a single application, which may limit generalizability. Here, we present a Bayesian approach, NobBS (Nowcasting by Bayesian Smoothing) capable of producing smooth and accurate nowcasts in multiple disease settings. We test NobBS on dengue in Puerto Rico and influenza-like illness (ILI) in the United States to examine performance and robustness across settings exhibiting a range of common reporting delay characteristics (from stable to time-varying), and compare this approach with a published nowcasting package. We show that introducing a temporal relationship between cases considerably improves performance when the reporting delay distribution is time-varying, and we identify trade-offs in the role of moving windows to accurately capture changes in the delay. We present software implementing this new approach (R package \"NobBS\") for widespread application.\n\nSignificanceAchieving accurate, real-time estimates of disease activity is challenged by delays in case reporting. However, approaches that seek to estimate cases in spite of reporting delays often do not consider the temporal relationship between cases during an outbreak, nor do they identify characteristics of robust approaches that generalize to a wide range of surveillance contexts with very different reporting delays. Here, we present a smooth Bayesian nowcasting approach that produces accurate estimates that capture the time evolution of the epidemic curve and outperform a previous approach in the literature. We assess the performance for two diseases to identify important features of the reporting delay distribution that contribute to the models performance and robustness across surveillance settings.

epidemiology↗

bioRxiv2019

Programmatic goals and spatial epidemiology influence the merit of targeted versus of population-wide interventions for yaws eradication

Infectious disease eradication programs often pursue spatially targeted interventions, but how well they perform might depend on the underlying spatial epidemiology and the specific goal of the program. We use a stochastic compartmental metapopulation model of yaws transmission to investigate how total targeted treatment (TTT) performs compared to mass drug administration (MDA) in different settings. While TTT can efficiently control the prevalence of active yaws disease, we consistently found that multiple rounds of TTT are required to match the impact of 1 round of MDA on the prevalence of latent yaws infection. When complete eradication of yaws is the goal, MDA can achieve the same result as TTT more quickly and probably at lower cost. We found that the performance of TTT is improved when there is little mixing between subpopulations and when there is spatial heterogeneity in transmissibility, but even in these settings, our model suggests that MDA will still outperform TTT.\n\nSignificance StatementYaws is a neglected tropical disease that causes skin lesions. Eradicating yaws is challenging because people can be infected but not show any signs or symptoms for years. Using simulations, we found that targeting antibiotics to people with active yaws and to their neighbors is a good way to combat active yaws, but treating entire populations is a better way to get rid of all infections, including the hidden ones. Also, targeted treatment works better in populations in which people do not move around much and in which how easily the disease is transmitted varies from place to place. Overall, a targeted treatment strategy uses fewer antibiotics but takes longer than mass treatment to achieve results.

epidemiology↗

bioRxiv2019

Outpatient antibiotic stewardship interventions: geographic scale and associations between antibiotic use and resistance

Antibiotic use is a key driver of antibiotic resistance. Understanding the quantitative association between antibiotic use and resulting resistance is important for predicting future rates of antibiotic resistance and for designing antibiotic stewardship policy. However, the use-resistance association is complicated by "spillover", in which one populations level of antibiotic use affects another populations level of resistance via the transmission of bacteria between those populations. Spillover is known to have effects at the level of families and hospitals, but it is unclear if spillover is relevant at larger scales. We used mathematical modeling and analysis of observational data to address this question. First, we used dynamical models of antibiotic resistance to predict the effects of spillover. Whereas populations completely isolated from one another do not experience any spillover, we found that if even 1% of interactions are between populations, then spillover may have large consequences: the effect of a change in antibiotic use in one population on antibiotic resistance in that population could be reduced by as much as 50%. Then, we quantified spillover in observational antibiotic use and resistance data from US states and European countries for 3 pathogen-antibiotic combinations, finding that increased interactions between populations were associated with smaller differences in antibiotic resistance between those populations. Thus, spillover may have an important impact at the level of states and countries, which has ramifications for predicting the future of antibiotic resistance, designing antibiotic resistance stewardship policy, and interpreting stewardship interventions.

epidemiology↗

bioRxiv2018

Analysis of a meningococcal meningitis outbreak in Niger - potential effectiveness of reactive prophylaxis

BackgroundSeasonal epidemics of bacterial meningitis in the African Meningitis Belt carry a high burden of disease and mortality. Reactive mass vaccination is used as a control measure during epidemics, but the time taken to gain immunity from the vaccine reduces the flexibility and effectiveness of these campaigns. Highly targeted reactive antibiotic prophylaxis could be used to supplement reactive mass vaccination and further reduce the incidence of meningitis, and the potential effectiveness and efficiency of these strategies should be explored.\n\nMethods and FindingsData from an outbreak of meningococcal meningitis in Niger, caused primarily by Neisseria meningitidis serogroup C, is used to estimate clustering of meningitis cases at the household and village level. In addition, reactive antibiotic prophylaxis and reactive vaccination strategies are simulated to estimate their potential effectiveness and efficiency, with a focus on the threshold and spatial unit used to declare an epidemic and initiate the intervention.\n\nThere is village-level clustering of meningitis cases after an epidemic has been declared in a health area. Meningitis risk among household contacts of a meningitis case is no higher than among members of the same village. Village-wide antibiotic prophylaxis can target secondary cases in villages: across of range of parameters pertaining to how the intervention is performed, up to 200/ 672 cases during the season are potentially preventable. On the other hand, household prophylaxis targets very few cases. In general, the village-wide strategy is not very sensitive to the method used to declare an epidemic. Finally, village-wide antibiotic prophylaxis is potentially more efficient than mass vaccination of all individuals at the beginning of the season, and than the equivalent reactive vaccination strategy.\n\nConclusionsVillage-wide antibiotic prophylaxis should be considered and tested further as a response against outbreaks of meningococcal meningitis in the Meningitis Belt, as a supplement to reactive mass vaccination.

epidemiology↗

bioRxiv2018

Outpatient antibiotic prescribing and demographic factors associated with state-level septicemia mortality rates in US adults

BackgroundRates of septicemia/sepsis mortality and hospitalization in the US have risen significantly during the recent years, and antibiotic use may contribute to those rates through various mechanisms.\n\nMethodsWe used multivariable linear regression to relate state-specific rates of outpatient prescribing overall for fluoroquinolones, penicillins, macrolides, and cephalosporins between 2013-2014 to state-specific rates of septicemia mortality (ICD-10 codes A40-41 present as either the underlying or contributing causes of death) in each of the following age groups of adults: (18-49y, 50-64y, 65-74y, 75-84y, 85+y) between 2013-2014, adjusting for median household income, average annual temperature, age-specific percentages of state residents who (i) lived below the poverty level, (ii) were African American, (iii) lacked health insurance (in non-elderly age groups), and random effects associated with the different US Health and Human Services (HHS) regions.\n\nResultsRates of penicillin prescribing were positively associated with septicemia mortality rates in the analyses for persons aged 65-74y, 75-84y and over 85y. Rates of cephalosporin prescribing were positively associated with septicemia mortality rates in the analyses for persons aged 18-49y and 65-74y. Rates of fluoroquinolone prescribing were positively associated with septicemia mortality rates in the analyses for persons aged 18-49y. Percent African Americans in a given age group was positively associated with septicemia mortality rates in the analyses for age groups over 65y, and 18-49y. Percent of residents in a given age group living below the poverty level was positively associated with septicemia mortality rates in the analysis for persons aged 65-74y.\n\nConclusionsOur results suggest that rates of penicillin prescribing are associated with rates of septicemia mortality in older US adults, while rates of cephalosporin prescribing are associated with rates of septicemia mortality in persons aged 18-49y and 65-74y, and rates of fluoroquinolone prescribing are associated with rates of septicemia mortality in persons aged 18-49y. Further studies are needed to better understand the potential effect of antibiotic replacement in the treatment of different syndromes, such as replacement of fluoroquinolones by other antibiotics, possibly penicillins and cephalosporins following the recent US FDA guidelines on restriction of fluoroquinolone use, on the rates of sepsis mortality.

epidemiology↗

bioRxiv2018

The distribution of antibiotic use and its association with antibiotic resistance

Antibiotic use is a primary driver of antibiotic resistance. However, antibiotic use can be distributed in different ways in a population, and the association between the distribution of use and antibiotic resistance has not been explored. Here we tested the hypothesis that repeated use of antibiotics has a stronger association with population-wide antibiotic resistance than broadly- distributed, low-intensity use. First, we characterized the distribution of outpatient antibiotic use across US states, finding that antibiotic use is uneven and that repeated use of antibiotics makes up a minority of antibiotic use. Second, we compared antibiotic use with resistance for 72 pathogen-antibiotic combinations across states. Finally, having partitioned total use into extensive and intensive margins, we found that intense use had a weaker association with resistance than extensive use. If the use-resistance relationship is causal, these results suggest that reducing total use and selection intensity will require reducing broadly-distributed, low- intensity use.

epidemiology↗

bioRxiv2018

Outpatient prescribing of four major antibiotic classes and prevalence of antimicrobial resistance in US adults

BackgroundThere is limited information on the relation between antibiotic use and antibiotic resistance in the US.\n\nMethodsWe used multivariable logistic regression to relate state-specific rates of outpatient prescribing overall for fluoroquinolones, penicillins, macrolides, and cephalosporins between 2011-2014 to state-specific prevalence of resistance for select combinations of antibiotics/bacteria among catheter-associated urinary tract infections (CAUTIs) in the CDC Patient Safety Atlas data between 2011-2014 for adults aged 65+y and 19-64y, adjusting for potential confounders.\n\nResultsRates of fluoroquinolone prescribing were positively associated with prevalence of fluoroquinolone resistance in Escherichia coli and Pseudomonas aeruginosa (both age groups), resistance to extended-spectrum (ES) cephalosporins in E. coli (aged 19-64y), and resistance to methicillin in Staphylococcus aureus (aged 19-64y). Rates of penicillin prescribing were positively associated with prevalence of resistance to fluoroquinolones in E. coli (aged 65+) and P. aeruginosa (both age groups), and resistance to ES cephalosporins in Klebsiella spp. (both age groups). Rates of cephalosporin prescribing were negatively associated with prevalence of resistance to fluoroquinolones in E. coli and resistance to ES cephalosporins in Klebsiella spp. (both age groups). Average annual temperature was positively associated with prevalence of resistance to ES cephalosporins in E. coli and P. aeruginosa, and resistance to fluoroquinolones in E. coli.\n\nConclusionsOur results suggest that prescribing of fluoroquinolones and penicillins to US adults is associated with prevalence of antibiotic resistance, including ESBLs and MRSA. Further work is needed to understand the potential benefit of replacing fluoroquinolones and penicillins by other antibiotics for reducing prevalence of antibiotic resistance.

epidemiology↗

bioRxiv2018

Resistance diagnostics as a public health tool to combat antibiotic resistance: A model-based evaluation

Rapid point-of-care resistance diagnostics (POC-RD) are thought to be a key tool in the fight against antibiotic resistance. By tailoring drug choice to infection genotype, doctors can improve treatment efficacy while limiting costs of inappropriate antibiotic prescription. Here we combine epidemiological theory and data to assess the potential of POC-RD innovations in a public health context, as a means to limit or even reverse selection for antibiotic resistance. POC-RD can be used to impose a non-biological fitness cost on resistant strains, by triggering targeted interventions that reduce their opportunities for transmission. We assess this diagnostic-imposed fitness cost in the context of a spectrum of bacterial population biologies and POC-RD conditional strategies, and find that the expected impact varies from selection against resistance for obligate pathogens to marginal public health improvements for opportunistic pathogens with high bystander antibiotic exposure during asymptomatic carriage (e.g. the pneumococcus). We close by generalizing the notion of RD-informed strategies to incorporate both POC and carriage surveillance information, and illustrate that coupling transmission control interventions to the discovery of resistant strains in carriage can potentially select against resistance in a broad range of opportunistic pathogens.

epidemiology↗

bioRxiv2018

Prediction of post-vaccine population structure of Streptococcus pneumoniae using accessory gene frequencies

Predicting how pathogen populations will change over time is challenging. Such has been the case with Streptococcus pneumoniae, an important human pathogen, and the pneumococcal conjugate vaccines (PCVs), which target only a fraction of the strains in the population. Here, we use the frequencies of accessory genes to predict changes in the pneumococcal population after vaccination, hypothesizing that these frequencies reflect negative frequency-dependent selection (NFDS) on the gene products. We find that the standardized predicted fitness of a strain estimated by an NFDS-based model at the time the vaccine is introduced enables to predict whether the strain increases or decreases in prevalence following vaccination. Further, we are able to forecast the equilibrium post-vaccine population composition and assess the invasion capacity of emerging lineages. Overall, we provide a method for predicting the impact of an intervention on pneumococcal populations with potential application to other bacterial pathogens in which NFDS is a driving force.

evolutionary biology↗

bioRxiv2018

On the role of different age groups during pertussis epidemics in California, 2010 and 2014

BackgroundThere is limited information on the roles of different age groups in propagating pertussis outbreaks, and the temporal changes in those roles since the introduction of acellular pertussis vaccines.\n\nMethodsThe relative roles of different age groups in propagating the 2010 and the 2014 pertussis epidemics in California were evaluated using the RR statistic that measures the change in the groups proportion among all detected cases before-vs.-after the epidemic peak.\n\nResultsFor the 2010-11 epidemic, evidence for a predominant transmission age group was weak, with the largest RR estimates being 1.26(95%CI (1.08,1.46)) (aged 11-13y); 1.19(1.01,1.4) (aged 9-10y); 1.17(0.86,1.59) (aged 14-15y); 1.12(0.86,1.46) (aged 16-19y); and 1.1(0.89,1.36) (aged 7-8y). The 2014 epidemic showed a strong signal of the role of older adolescents, with the highest RR estimate being in those aged 14-15y (RR=1.83(1.61,2.07)), followed by adolescents aged 16-19y (RR=1.41(1.24,1.61)) and 11-13y (RR=1.26(1.12,1.41)), with lower RR estimates in other age groups.\n\nConclusionsAs the time following introduction of acellular pertussis vaccines in California progressed, older adolescents played an increasing role in transmission during the major pertussis outbreaks. Booster pertussis vaccination for older adolescents with vaccines effective against pertussis transmission should be considered with the aim of mitigating future pertussis epidemics in the community.

epidemiology↗

bioRxiv2018

Levels of prescribing for four major antibiotic classes and rates of septicemia hospitalization in different US states

BackgroundRates of sepsis/septicemia hospitalization in the US have risen significantly during recent years, and antibiotic resistance and use may contribute to those rates through various mechanisms.\n\nMethodsWe used multivariable linear regression to relate state-specific rates of outpatient prescribing overall for fluoroquinolones, penicillins, macrolides, and cephalosporins between 2011-2012 to state-specific rates of hospitalization with septicemia (ICD-9 codes 038.xx present anywhere on discharge diagnosis) in each of the following age groups of adults: (18-49y, 50-64y, 65-74y, 75-84y, 85+y) reported to the Healthcare Cost and Utilization Project (HCUP) between 2011-2012, adjusting for additional covariates, and random effects associated with the ten US Health and Human Services (HHS) regions.\n\nResultsRates of penicillin prescribing were positively associated with septicemia hospitalization rates in the analyses for persons aged 50-64y, 65-74y, and 74-84y. Percent African Americans in a given age group was positively associated with septicemia hospitalization rates in the analyses for persons aged 75-84y and over 85y. Average minimal daily temperature was positively associated with septicemia hospitalization rates in the analyses for persons aged 18-49y, 50-64y, 75-84y and over 85y.\n\nConclusionsOur results suggest positive associations between the rates of prescribing for penicillins and the rates of sepsis hospitalization in US adults aged 50-84y. Further studies are needed to understand the potential effect of antibiotic replacement in the treatment of various syndromes, such as replacement of fluoroquinolones by other antibiotics, possibly penicillins following the recent US FDA guidelines on restriction of fluoroquinolone use, on the rates of sepsis hospitalization.

epidemiology↗

bioRxiv2018

Antimicrobial resistance prevalence and rates of hospitalization with septicemia in the diagnosis in adults in different US states

ObjectivesRates of hospitalization with sepsis/septicemia and associated mortality in the US have risen significantly during the last two decades. Antibiotic resistance may contribute to the rates of sepsis-related outcomes through lack of clearance of bacterial infections following antibiotic treatment during different stages of infection. However, there is limited information about the relation between prevalence of resistance to various antibiotics in different bacteria and rates of sepsis-related outcomes. MethodsFor different age groups of adults (18-49y,50-64y,65-74y,75-84y,85+y) and combinations of antibiotics/bacteria, we evaluated associations between state-specific prevalence (percentage) of resistant samples for a given combination of antibiotics/bacteria among catheter-associated urinary tract infections in the CDC Antibiotic Resistance Patient Safety Atlas data between 2011-2014 and rates of hospitalization with septicemia (ICD-9 codes 038.xx present on the discharge diagnosis) reported to the Healthcare Cost and Utilization Project (HCUP), as well as rates of mortality with sepsis (ICD-10 codes A40-41.xx present on death certificate). ResultsAmong the different combinations of antibiotics/bacteria, prevalence of resistance to fluoroquinolones in E. coli had the strongest association with septicemia hospitalization rates for individuals aged over 50y, and with sepsis mortality rates for individuals aged 18-84y. A number of positive correlations between prevalence of resistance for different combinations of antibiotics/bacteria and septicemia hospitalization/sepsis mortality rates in adults were also found. ConclusionsOur findings, as well as our related work on the relation between antibiotic use and sepsis rates support the association between resistance to/use of certain antibiotics and rates of sepsis-related outcomes, suggesting the potential utility of antibiotic replacement.

epidemiology↗

bioRxiv2018

Herd Immunity Alters the Conditions for Performing Dose Schedule Comparisons: An Individual-based Model of Pneumococcal Carriage

BACKGROUND BACKGROUND METHODS RESULTS DISCUSSION CONCLUSIONS LIST OF ABBREVIATIONS Ethics approval and consent... Consent for publication Availability of data and... Competing interests Funding Authors' contributions DECLARATIONS REFERENCES Mass vaccination of infants and toddlers with pneumococcal conjugate vaccines (PCVs) has led to large declines in pneumococcal disease in countries around the world [1]. These vaccines currently contain 10 or 13 different capsular polysaccharides from Streptococcus pneumoniae, each conjugated to a protein carrier. In S. pneumoniae, the chemical structure of the capsular polys ...

epidemiology↗