Statistical mechanics and thermodynamics of viral evolution

This paper analyzes a simplified model of viral infection and evolution using the 'grand canonical ensemble' and formalisms from statistical mechanics and thermodynamics to enumerate all possible viruses and to derive thermodynamic variables for the system. We model the infection process as a series of energy barriers determined by the genetic states of the virus and host as a function of immune response and system temperature. We find a phase transition between a positive temperature regime of normal replication and a negative temperature 'disordered' phase of the virus. These phases define different regimes in which different genetic strategies are favored. Perhaps most importantly, it demonstrates that the system has a real thermodynamic temperature. For normal replication, this temperature is linearly related to effective temperature. The strength of immune response rescales temperature but does not change the observed linear relationship. For all temperatures and immunities studied, we find a universal curve relating the order parameter to viral evolvability. Real viruses have finite length RNA segments that encode for proteins which determine their fitness; hence the methods put forth here could be refined to apply to real biological systems, perhaps providing insight into immune escape, the emergence of novel pathogens and other results of viral evolution.Comment: 39 pages (55 pages including supplement), 9 figures, 11 supplemental figure

Variation in dengue virus plaque reduction neutralization testing: systematic review and pooled analysis.

BackgroundThe plaque reduction neutralization test (PRNT) remains the gold standard for the detection of serologic immune responses to dengue virus (DENV). While the basic concept of the PRNT remains constant, this test has evolved in multiple laboratories, introducing variation in materials and methods. Despite the importance of laboratory-to-laboratory comparability in DENV vaccine development, the effects of differing PRNT techniques on assay results, particularly the use of different dengue strains within a serotype, have not been fully characterized.MethodsWe conducted a systematic review and pooled analysis of published literature reporting individual-level PRNT titers to identify factors associated with heterogeneity in PRNT results and compared variation between strains within DENV serotypes and between articles using hierarchical models.ResultsThe literature search and selection criteria identified 8 vaccine trials and 25 natural exposure studies reporting 4,411 titers from 605 individuals using 4 different neutralization percentages, 3 cell lines, 12 virus concentrations and 51 strains. Of 1,057 titers from primary DENV exposure, titers to the exposure serotype were consistently higher than titers to non-exposure serotypes. In contrast, titers from secondary DENV exposures (n = 628) demonstrated high titers to exposure and non-exposure serotypes. Additionally, PRNT titers from different strains within a serotype varied substantially. A pooled analysis of 1,689 titers demonstrated strain choice accounted for 8.04% (90% credible interval [CrI]: 3.05%, 15.7%) of between-titer variation after adjusting for secondary exposure, time since DENV exposure, vaccination and neutralization percentage. Differences between articles (a proxy for inter-laboratory differences) accounted for 50.7% (90% CrI: 30.8%, 71.6%) of between-titer variance.ConclusionsAs promising vaccine candidates arise, the lack of standardized assays among diagnostic and research laboratories make unbiased inferences about vaccine-induced protection difficult. Clearly defined, widely accessible reference reagents, proficiency testing or algorithms to adjust for protocol differences would be a useful first step in improving dengue PRNT comparability and quality assurance

Bacterial infections in neonates following mupirocin-based MRSA decolonization: A multicenter cohort study

OBJECTIVETo characterize the risk of infection after MRSA decolonization with intranasal mupirocin.DESIGNMulticenter, retrospective cohort study.SETTINGTertiary care neonatal intensive care units (NICUs) from 3 urban hospitals in the United States ranging in size from 45 to 100 beds.METHODSMRSA-colonized neonates were identified from NICU admissions occurring from January 2007 to December 2014, during which a targeted decolonization strategy was used for MRSA control. In 2 time-to-event analyses, MRSA-colonized neonates were observed from the date of the first MRSA-positive surveillance screen until (1) the first occurrence of novel gram-positive cocci in sterile culture or discharge or (2) the first occurrence of novel gram-negative bacilli in sterile culture or discharge. Mupirocin exposure was treated as time varying.RESULTSA total of 522 MRSA-colonized neonates were identified from 16,144 neonates admitted to site NICUs. Of the MRSA-colonized neonates, 384 (74%) received mupirocin. Average time from positive culture to mupirocin treatment was 3.5 days (standard deviation, 7.2 days). The adjusted hazard of gram-positive cocci infection was 64% lower among mupirocin-exposed versus mupirocin-unexposed neonates (hazard ratio, 0.36; 95% confidence interval [CI], 0.17–0.76), whereas the adjusted hazard ratio of gram-negative bacilli infection comparing mupirocin-exposed and -unexposed neonates was 1.05 (95% CI, 0.42–2.62).CONCLUSIONSIn this multicentered cohort of MRSA-colonized neonates, mupirocin-based decolonization treatment appeared to decrease the risk of infection with select gram-positive organisms as intended, and the treatment was not significantly associated with risk of subsequent infections with organisms not covered by mupirocin’s spectrum of activity.Infect Control Hosp Epidemiol2017;38:930–936</jats:sec

Impact on Epidemic Measles of Vaccination Campaigns Triggered by Disease Outbreaks or Serosurveys: A Modeling Study.

BACKGROUND: Routine vaccination supplemented by planned campaigns occurring at 2-5 y intervals is the core of current measles control and elimination efforts. Yet, large, unexpected outbreaks still occur, even when control measures appear effective. Supplementing these activities with mass vaccination campaigns triggered when low levels of measles immunity are observed in a sample of the population (i.e., serosurveys) or incident measles cases occur may provide a way to limit the size of outbreaks. METHODS AND FINDINGS: Measles incidence was simulated using stochastic age-structured epidemic models in settings conducive to high or low measles incidence, roughly reflecting demographic contexts and measles vaccination coverage of four heterogeneous countries: Nepal, Niger, Yemen, and Zambia. Uncertainty in underlying vaccination rates was modeled. Scenarios with case- or serosurvey-triggered campaigns reaching 20% of the susceptible population were compared to scenarios without triggered campaigns. The best performing of the tested case-triggered campaigns prevent an average of 28,613 (95% CI 25,722-31,505) cases over 15 y in our highest incidence setting and 599 (95% CI 464-735) cases in the lowest incidence setting. Serosurvey-triggered campaigns can prevent 89,173 (95% CI, 86,768-91,577) and 744 (612-876) cases, respectively, but are triggered yearly in high-incidence settings. Triggered campaigns reduce the highest cumulative incidence seen in simulations by up to 80%. While the scenarios considered in this strategic modeling exercise are reflective of real populations, the exact quantitative interpretation of the results is limited by the simplifications in country structure, vaccination policy, and surveillance system performance. Careful investigation into the cost-effectiveness in different contexts would be essential before moving forward with implementation. CONCLUSIONS: Serologically triggered campaigns could help prevent severe epidemics in the face of epidemiological and vaccination uncertainty. Hence, small-scale serology may serve as the basis for effective adaptive public health strategies, although, in high-incidence settings, case-triggered approaches are likely more efficient

High Hepatitis E Seroprevalence Among Displaced Persons in South Sudan.

AbstractLarge protracted outbreaks of hepatitis E virus (HEV) have been documented in displaced populations in Africa over the past decade though data are limited outside these exceptional settings. Serological studies can provide insights useful for improving surveillance and disease control. We conducted an age-stratified serological survey using samples previously collected for another research study from 206 residents of an internally displaced person camp in Juba, South Sudan. We tested serum for anti-HEV antibodies (IgM and IgG) and estimated the prevalence of recent and historical exposure to the virus. Using data on individuals' serostatus, camp arrival date, and state of origin, we used catalytic transmission models to estimate the relative risk of HEV infection in the camp compared with that in the participants' home states. The age-adjusted seroprevalence of anti-HEV IgG was 71% (95% confidence interval = 63-78), and 4% had evidence of recent exposure (IgM). We estimated HEV exposure rates to be more than 2-fold (hazard ratio = 2.3, 95% credible interval = 0.3-5.8) higher in the camp than in the participants' home states, although this difference was not statistically significant. HEV transmission may be higher than previously appreciated, even in the absence of reported cases. Improved surveillance in similar settings is needed to understand the burden of disease and minimize epidemic impact through early detection and response

The IDSpatialStats R Package: Quantifying Spatial Dependence of Infectious Disease Spread

Spatial statistics for infectious diseases are important because the spatial and temporal scale over which transmission operates determine the dynamics of disease spread. Many methods for quantifying the distribution and clustering of spatial point patterns have been developed (e.g. K-function and pair correlation function) and are routinely applied to infectious disease case occurrence data. However, these methods do not explicitly account for overlapping chains of transmission and require knowledge of the underlying population distribution, which can be limiting when analyzing epidemic case occurrence data. Therefore, we developed two novel spatial statistics that account for these effects to estimate: 1) the mean of the spatial transmission kernel, and 2) the τ-statistic, a measure of global clustering based on pathogen subtype. We briefly introduce these statistics and show how to implement them using the IDSpatialStats R package

Measuring Spatial Dependence for Infectious Disease Epidemiology.

Global spatial clustering is the tendency of points, here cases of infectious disease, to occur closer together than expected by chance. The extent of global clustering can provide a window into the spatial scale of disease transmission, thereby providing insights into the mechanism of spread, and informing optimal surveillance and control. Here the authors present an interpretable measure of spatial clustering, τ, which can be understood as a measure of relative risk. When biological or temporal information can be used to identify sets of potentially linked and likely unlinked cases, this measure can be estimated without knowledge of the underlying population distribution. The greater our ability to distinguish closely related (i.e., separated by few generations of transmission) from more distantly related cases, the more closely τ will track the true scale of transmission. The authors illustrate this approach using examples from the analyses of HIV, dengue and measles, and provide an R package implementing the methods described. The statistic presented, and measures of global clustering in general, can be powerful tools for analysis of spatially resolved data on infectious diseases

The impact of the demographic transition on dengue in Thailand: Insights from a statistical analysis and mathematical modeling

Background: An increase in the average age of dengue hemorrhagic fever (DHF) cases has been reported in Thailand. The cause of this increase is not known. Possible explanations include a reduction in transmission due to declining mosquito populations, declining contact between human and mosquito, and changes in reporting. We propose that a demographic shift toward lower birth and death rates has reduced dengue transmission and lengthened the interval between large epidemics. Methods and Findings: Using data from each of the 72 provinces of Thailand, we looked for associations between force of infection (a measure of hazard, defined as the rate per capita at which susceptible individuals become infected) and demographic and climactic variables. We estimated the force of infection from the age distribution of cases from 1985 to 2005. We find that the force of infection has declined by 2% each year since a peak in the late 1970s and early 1980s. Contrary to recent findings suggesting that the incidence of DHF has increased in Thailand, we find a small but statistically significant decline in DHF incidence since 1985 in a majority of provinces. The strongest predictor of the change in force of infection and the mean force of infection is the median age of the population. Using mathematical simulations of dengue transmission we show that a reduced birth rate and a shift in the population's age structure can explain the shift in the age distribution of cases, reduction of the force of infection, and increase in the periodicity of multiannual oscillations of DHF incidence in the absence of other changes. Conclusions: Lower birth and death rates decrease the flow of susceptible individuals into the population and increase the longevity of immune individuals. The increase in the proportion of the population that is immune increases the likelihood that an infectious mosquito will feed on an immune individual, reducing the force of infection. Though the force of infection has decreased by half, we find that the critical vaccination fraction has not changed significantly, declining from an average of 85% to 80%. Clinical guidelines should consider the impact of continued increases in the age of dengue cases in Thailand. Countries in the region lagging behind Thailand in the demographic transition may experience the same increase as their population ages. The impact of demographic changes on the force of infection has been hypothesized for other diseases, but, to our knowledge, this is the first observation of this phenomenon

Propensity score estimation: neural networks, support vector machines, decision trees (CART), and meta-classifiers as alternatives to logistic regression

Propensity scores for the analysis of observational data are typically estimated using logistic regression. Our objective in this Review was to assess machine learning alternatives to logistic regression which may accomplish the same goals but with fewer assumptions or greater accuracy