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At least 19 records

The reproduction number and its probability distribution for stochastic viral dynamics

We consider stochastic models of individual infected cells. The reproduction number, R, is understood as a random variable representing the number of new cells infected by one initial infected cell in an otherwise susceptible (target cell) population. Variability in R results partly from heterogeneity in the viral burst size (the number of viral progeny generated from an infected cell during its lifetime), which depends on the distribution of cellular lifetimes and on the mechanism of virion release. We analyse viral dynamics models with an eclipse phase: the period of time after a cell is infected but before it is capable of releasing virions. The duration of the eclipse, or the subsequent infectious, phase is non-exponential, but composed of stages. We derive the probability distribution of the reproduction number for these viral dynamics models, and show it is a negative binomial distribution in the case of constant viral release from infectious cells, and under the assumption of an excess of target cells. In a deterministic model, the ultimate in-host establishment or extinction of the viral infection depends entirely on whether the mean reproduction number is greater than, or less than, one, respectively. Here, the probability of extinction is determined by the probability distribution of R, not simply its mean value. In particular, we show that in some cases the probability of infection is not an increasing function of the mean reproduction number.

59 BASIC BIOLOGICAL SCIENCES↗

Bayesian Inference of State-Level COVID-19 Basic Reproduction Numbers across the United States

Although many persons in the United States have acquired immunity to COVID-19, either through vaccination or infection with SARS-CoV-2, COVID-19 will pose an ongoing threat to non-immune persons so long as disease transmission continues. We can estimate when sustained disease transmission will end in a population by calculating the population-specific basic reproduction number ℛ0, the expected number of secondary cases generated by an infected person in the absence of any interventions. The value of ℛ0 relates to a herd immunity threshold (HIT), which is given by 1−1/ℛ0. When the immune fraction of a population exceeds this threshold, sustained disease transmission becomes exponentially unlikely (barring mutations allowing SARS-CoV-2 to escape immunity). Here, we report state-level ℛ0 estimates obtained using Bayesian inference. Maximum a posteriori estimates range from 7.1 for New Jersey to 2.3 for Wyoming, indicating that disease transmission varies considerably across states and that reaching herd immunity will be more difficult in some states than others. ℛ0 estimates were obtained from compartmental models via the next-generation matrix approach after each model was parameterized using regional daily confirmed case reports of COVID-19 from 21 January 2020 to 21 June 2020. Our ℛ0 estimates characterize the infectiousness of ancestral strains, but they can be used to determine HITs for a distinct, currently dominant circulating strain, such as SARS-CoV-2 variant Delta (lineage B.1.617.2), if the relative infectiousness of the strain can be ascertained. On the basis of Delta-adjusted HITs, vaccination data, and seroprevalence survey data, we found that no state had achieved herd immunity as of 20 September 2021.

60 APPLIED LIFE SCIENCES↗

Quantifying the basic reproduction number and underestimated fraction of Mpox cases worldwide at the onset of the outbreak

In 2022, there was a global resurgence of mpox, with different clinical-epidemiological features compared with previous outbreaks. Sexual contact was hypothesized as the primary transmission route, and the community of men having sex with men (MSM) was disproportionately affected. Because of the stigma associated with sexually transmitted infections, the real burden of mpox could be masked. We quantified the basic reproduction number (R 0 ) and the underestimated fraction of mpox cases in 16 countries, from the onset of the outbreak until early September 2022, using Bayesian inference and a compartmentalized, risk-structured (high-/low-risk populations) and two-route (sexual/non-sexual transmission) mathematical model. Machine learning (ML) was harnessed to identify underestimation determinants. Estimated R 0 ranged between 1.37 (Canada) and 3.68 (Germany). The underestimation rates for the high- and low-risk populations varied between 25–93% and 65–85%, respectively. The estimated total number of mpox cases, relative to the reported cases, is highest in Colombia (3.60) and lowest in Canada (1.08). In the ML analysis, two clusters of countries could be identified, differing in terms of attitudes towards the 2SLGBTQIAP+ community and the importance of religion. Given the substantial mpox underestimation, surveillance should be enhanced, and country-specific campaigns against the stigmatization of MSM should be organized, leveraging community-based interventions.

60 APPLIED LIFE SCIENCES↗

Cross-scale dynamics and the evolutionary emergence of infectious diseases

When emerging pathogens encounter new host species for which they are poorly adapted, they must evolve to escape extinction. Pathogens experience selection on traits at multiple scales, including replication rates within host individuals and transmissibility between hosts. We analyze a stochastic model linking pathogen growth and competition within individuals to transmission between individuals. Our analysis reveals a new factor, the cross-scale reproductive number of a mutant virion, that quantifies how quickly mutant strains increase in frequency when they initially appear in the infected host population. This cross-scale reproductive number combines with viral mutation rates, single-strain reproductive numbers, and transmission bottleneck width to determine the likelihood of evolutionary emergence, and whether evolution occurs swiftly or gradually within chains of transmission. We find that wider transmission bottlenecks facilitate emergence of pathogens with short-term infections, but hinder emergence of pathogens exhibiting cross-scale selective conflict and long-term infections. Furthermore, our results provide a framework to advance the integration of laboratory, clinical, and field data in the context of evolutionary theory, laying the foundation for a new generation of evidence-based risk assessment of emergence threats.

59 BASIC BIOLOGICAL SCIENCES↗

Nonparametric Inference for the Reproductive Rate in Generalized Compartmental Models

We develop a tractable nonparametric model for the time-varying reproductive rate of infectious diseases that combines the structure of a deterministic compartmental model and a stochastic model for incidence data. We use Bayesian inference to estimate, with uncertainty, the reproductive rate of the Coronavirus 2019 outbreak in the U.S. states of California, Florida, Michigan, New Mexico, New York, and Texas from January 2020 to March 2022. Employing the inferred reproductive rates, we estimate the posterior distribution of the time-varying reproduction numbers for each state. Compering the time-varying reproduction numbers across the states, we identify some epidemic waves, potentially driven from changes in human behavior and virus mutations.

97 MATHEMATICS AND COMPUTING↗

A ``Tail" of Two Cities: Fatality-based Modeling of COVID-19 Evolution in New York City and Cook County, IL

I describe $SIR$ modeling of the COVID-19 pandemic in two U.S. urban environments, New York City (NYC) and Cook County, IL, from onset through the month of June, 2020. Since testing was not widespread early in the pandemic in the U.S., I do not use data on confirmed cases and rely solely on public fatality data to estimate model parameters. Fits to the first 20 days of data determine a degenerate combination of the basic reproduction number, $R_0$, and the mean time to removal from the infectious population, $\gamma^{-1}$, with $\gamma (R_0-1) = 0.25 (0.21)$ inverse days for NYC (Cook County). Equivalently, the initial doubling time was $t_d = 2.8 (3.4)$ days for NYC (Cook). The early fatality data suggest that both locations had infections in early February. I model the mitigation measures implemented in mid-March in both locations (distancing, quarantine, isolation, etc) via a time-dependent reproduction number $R_t$ that declines monotonically from $R_0$ to a sma ller asymptotic value, with a parameterized functional form. The timing (mid-March) and duration (several days) of the transitions in $R_t$ appear well determined by the data. However, the fatality data determine only a degenerate combination of the parameters $R_0$, the percentage reduction in social contact due to mitigation measures, $X$, and the infection fatality rate (IFR), $f$. With flat priors, based on simulations the NYC model parameters have 95.45\% credible intervals of $R_0 = 3.0-5.4$, $X= 80-99.9\%$ and $f=2-6\%$, with $5-13\%$ of the population asymptotically infected. A strong external prior indicating a lower value of $f$ or of $\gamma^{-1}$ would imply lower values of $R_0$ and $X$ and higher percentage infection of the population. For Cook County, the evolution was qualitatively different: after mitigation measures were implemented, the daily fatality counts reached a plateau for about a month before tailing off. This is consistent with an $SIR$ model that exhibits ``critical slowing-down", in which $R_t$ plateaus ! at a value just above unity. For Cook County, the 95.45\% credible intervals for the model parameters are much broader and shifted downward, $R_0=1.4-4.7$, $X=26-54\%$, and $f=0.1-0.6\%$ with $15-88\%$ of the population asymptotically infected. Despite the apparently lower efficacy of its social contact reduction measures, Cook County has had significantly fewer fatalities per population than NYC, $D_\infty/N=100$ vs. 270 per 100,000. In the model, this is attributed to the lower inferred IFR for Cook; an external prior pointing to similar values of the IFR for the two locations would instead chalk up the difference in $D/N$ to differences in the relative growth rate of the disease. I derive a model-dependent threshold, $X^{crit}_e$, for `safe' re-opening, that is, for easing of contact reduction that would not trigger a second wave; for NYC, the models predict that increasing social contact by more than 20\% from post-mitigation levels will lead to renewed spread, while for Cook County the threshold value is very uncertain, given the parameter degeneracies. The timing of 2nd-wave growth will depend on the amplitude of contact increase relative to $X^{crit}_e$ and on the asymptotic growth rate, and the impact in terms of fatalities will depend on the parameter $f$.

Frieman, Joshua↗

COVID-19 dynamics across the US: A deep learning study of human mobility and social behavior

This paper presents a deep learning framework for epidemiology system identification from noisy and sparse observations with quantified uncertainty. The proposed approach employs an ensemble of deep neural networks to infer the time-dependent reproduction number of an infectious disease by formulating a tensor-based multi-step loss function that allows us to efficiently calibrate the model on multiple observed trajectories. The method is applied to a mobility and social behavior-based SEIR model of COVID-19 spread. The model is trained on Google and Unacast mobility data spanning a period of 66 days, and is able to yield accurate future forecasts of COVID-19 spread in 203 US counties within a time-window of 15 days. Interestingly, a sensitivity analysis that assesses the importance of different mobility and social behavior parameters reveals that attendance of close places, including workplaces, residential, and retail and recreational locations, has the largest impact on the effective reproduction number. Furthermore, the model enables us to rapidly probe and quantify the effects of government interventions, such as lock-down and re-opening strategies. Taken together, the proposed framework provides a robust workflow for data-driven epidemiology model discovery under uncertainty and produces probabilistic forecasts for the evolution of a pandemic that can judiciously provide information for policy and decision making. All codes and data accompanying this manuscript are available at https://github.com/PredictiveIntelligenceLab/DeepCOVID19.

60 APPLIED LIFE SCIENCES↗

Adaptive changes in sexual behavior in the high–risk population in response to human monkeypox transmission in Canada can help control the outbreak: Insights from a two–group, two–route epidemic model

Monkeypox, a zoonotic disease, is emerging as a potential sexually transmitted infection/disease, with underlying transmission mechanisms still unclear. We devised a risk-structured, compartmental model, incorporating sexual behavior dynamics. We compared different strategies targeting the high-risk population: a scenario of control policies geared toward the use of condoms and/or sexual abstinence (robust control strategy) with risk compensation behavior change, and a scenario of control strategies with behavior change in response to the doubling rate (adaptive control strategy). Monkeypox's basic reproduction number is 1.464, 0.0066, and 1.461 in the high-risk, low-risk, and total populations, respectively, with the high-risk group being the major driver of monkeypox spread. Policies imposing condom use or sexual abstinence need to achieve a 35% minimum compliance rate to stop further transmission, while a combination of both can curb the spread with 10% compliance to abstinence and 25% to condom use. With risk compensation, the only option is to impose sexual abstinence by at least 35%. Adaptive control is more effective than robust control where the daily sexual contact number is reduced proportionally and remains constant thereafter, shortening the time to epidemic peak, lowering its size, facilitating disease attenuation, and playing a key role in controlling the current outbreak.

60 APPLIED LIFE SCIENCES↗

Within-Host Phenotypic Evolution and the Population-Level Control of Chronic Viral Infections by Treatment and Prophylaxis

Chronic viral infections can persist for decades spanning thousands of viral generations, leading to a highly diverse population of viruses with its own complex evolutionary history. We propose an expandable mathematical framework for understanding how the emergence of genetic and phenotypic diversity affects the population-level control of those infections by both non-curative treatment and chemo-prophylactic measures. Our frameworks allows both neutral and phenotypic evolution, and we consider the specific evolution of contagiousness, resistance to therapy, and efficacy of prophylaxis. We compute both the controlled and uncontrolled, population-level basic reproduction number accounting for the within-host evolutionary process where new phenotypes emerge and are lost in infected persons, which we also extend to include both treatment and prophylactic control efforts. We used these results to discuss the conditions under which the relative efficacy of prophylactic versus therapeutic methods of control are superior. Finally, we give expressions for the endemic equilibrium of these models for certain constrained versions of the within-host evolutionary model providing a potential method for estimating within-host evolutionary parameters from population-level genetic sequence data.

sensitivity analysis↗

Staged progression epidemic models for the transmission of invasive nontyphoidal Salmonella (iNTS) with treatment

We develop and analyze a stage-progression compartmental model to study the emerging invasive nontyphoidal Salmonella (iNTS) epidemic in sub-Saharan Africa. iNTS bloodstream infections are often fatal, and the diverse and non-specific clinical features of iNTS make it difficult to diagnose. We focus our study on identifying approaches that can reduce the incidence of new infections. In sub-Saharan Africa, transmission and mortality are correlated with the ongoing HIV epidemic and severe malnutrition. We use our model to quantify the impact that increasing antiretroviral therapy (ART) for HIV infected adults and reducing malnutrition in children would have on mortality from iNTS in the population. We consider immunocompromised subpopulations in the region with major risk factors for mortality, such as malaria and malnutrition among children and HIV infection and ART coverage in both children and adults. We parameterize the progression rates between infection stages using the branching probabilities and estimated time spent at each stage. We interpret the basic reproduction number R 0 as the total contribution from an infinite infection loop produced by the asymptomatic carriers in the infection chain. The results indicate that the asymptomatic HIV+ adults without ART serve as the driving force of infection for the iNTS epidemic. We conclude that the worst disease outcome is among the pediatric population, which has the highest infection rates and death counts. Our sensitivity analysis indicates that the most effective strategies to reduce iNTS mortality in the studied population are to improve the ART coverage among high-risk HIV+ adults and reduce malnutrition among children.

59 BASIC BIOLOGICAL SCIENCES↗

Differential contagiousness of respiratory disease across the United States

The initial contagiousness of a communicable disease within a given population is quantified by the basic reproduction number, $R_0$. This number depends on both pathogen and population properties. On the basis of compartmental models that reproduce Coronavirus Disease 2019 (COVID-19) surveillance data, we used Bayesian inference and the next-generation matrix approach to estimate region-specific $R_0$ values for 280 of 384 metropolitan statistical areas (MSAs) in the United States (US), which account for 95% of the US population living in urban areas and 82% of the total population. We focused on MSA populations after finding that these populations were more uniformly impacted by COVID-19 than state populations. Our maximum a posteriori (MAP) estimates for $R_0$ range from 1.9 to 7.7 and quantify the relative susceptibilities of regional populations to spread of respiratory diseases.

60 APPLIED LIFE SCIENCES↗

High Rate of Non-Human Feeding by Aedes aegypti Reduces Zika Virus Transmission in South Texas

Mosquito-borne viruses are emerging or re-emerging globally, afflicting millions of people around the world. Aedes aegypti, the yellow fever mosquito, is the principal vector of dengue, Zika, and chikungunya viruses, and has well-established populations across tropical and subtropical urban areas of the Americas, including the southern United States. While intense arboviral epidemics have occurred in Mexico and further south in the Americas, local transmission in the United States has been minimal. Here, we study Ae. aegypti and Culex quinquefasciatus host feeding patterns and vertebrate host communities in residential environments of South Texas to identify host-utilization relative to availability. Only 31% of Ae. aegypti blood meals were derived from humans, while 50% were from dogs and 19% from other wild and domestic animals. In Cx. quinquefasciatus, 67% of blood meals were derived from chicken, 22% came from dogs, 9% from various wild avian species, and 2% from other mammals including one human, one cat, and one pig. We developed a model for the reproductive number, R0, for Zika virus (ZIKV) in South Texas relative to northern Mexico using human disease data from Tamaulipas, Mexico. We show that ZIKV R0 in South Texas communities could be greater than one if the risk of human exposure to Ae. aegypti bites in these communities is at least 60% that of Northern Mexico communities. The high utilization of non-human vertebrates and low risk of human exposure in South Texas diminishes the outbreak potential for human-amplified urban arboviruses transmitted by Ae. aegypti.

59 BASIC BIOLOGICAL SCIENCES↗

High Contagiousness and Rapid Spread of Severe Acute Respiratory Syndrome Coronavirus 2

Severe acute respiratory syndrome coronavirus 2 is the causative agent of the ongoing coronavirus disease pandemic. Initial estimates of the early dynamics of the outbreak in Wuhan, China, suggested a doubling time of the number of infected persons of 6–7 days and a basic reproductive number (R 0 ) of 2.2–2.7. We collected extensive individual case reports across China and estimated key epidemiologic parameters, including the incubation period (4.2 days). We then designed 2 mathematical modeling approaches to infer the outbreak dynamics in Wuhan by using high-resolution domestic travel and infection data. Results show that the doubling time early in the epidemic in Wuhan was 2.3–3.3 days. Assuming a serial interval of 6–9 days, we calculated a median R0 value of 5.7 (95% CI 3.8–8.9). Here, we further show that active surveillance, contact tracing, quarantine, and early strong social distancing efforts are needed to stop transmission of the virus.

60 APPLIED LIFE SCIENCES↗

Extrapair offspring of the blue-footed booby show no sign of higher fitness in the first 10 years of life

According to the good genes and genetic compatibility hypotheses, females of socially monogamous species obtain genetic benefits for their offspring by performing extrapair copulations with males of higher quality than their social mates or males with whom they are more genetically compatible. If extrapair offspring do receive genetic benefits in the form of advantageous alleles or more compatible allele combinations, they should outperform their within-pair half-siblings' survival and/or reproductive output. Here, in this study, we followed 52 extrapair and 737 within-pair blue-footed booby, Sula nebouxii, offspring during their first 10 years of life (excluding the embryonic period and the first 10 days after hatching) to assess whether they differed in fledging probability, fledgling body condition, recruitment probability, age at first reproduction, number of breeding events or accumulated breeding success. Extrapair and within-pair offspring did not differ in any of these proxies of fitness. Furthermore, we found that extrapair offspring were equally likely to occur in any hatching position. However, differences in fledgling production over the lifetime could not be ruled out, and because only within-pair production of eggs and fledglings was tallied, the possibility remains that extrapair offspring could produce more extrapair offspring later in life than do within-pair offspring. Furthermore, the possibility of context-dependent genetic benefits occurring only under stressful conditions cannot be discounted because our sample of offspring was obtained in a single exceptionally favourable reproductive season.

59 BASIC BIOLOGICAL SCIENCES↗

The role of geographical spreaders in infectious pattern formation and front propagation speeds

The pattern formation and spatial spread of infectious populations are investigated using a kernel-based Susceptible–Infectious–Recovered (SIR) model applicable across a wide range of basic reproduction numbers R O . The goal is to examine the role of geographical spreaders on transient spatial pattern formation of infectious populations and the associated maximum invasive front speeds c max . In the simulations conducted here, geographical spreaders are defined as a portion of the infected population Φ experiencing high mobility between identical communities. The spatial organization of the infected population and c max are determined when the infections are randomly initiated in space within multiple communities. For small but finite , scaling analysis and numerical simulations in 1-dimension suggest that when the spreading kernel is Gaussian-shaped, where is the inverse of the infectious duration. This finding for agrees with a diffusion-based representation of mobility in 1-D. Numerical simulations in 2-D across wide-ranging suggest that , the variance of the spatial kernel describing mobility of long-distance geographical spreaders across communities, determines the spatial organization of infections across communities. When (long-distance mobility, where is the minimum spatial extent defining adjacent communities), the infectious population will experience a transient but spatially coherent pattern with a wavelength that can be derived from the spreading kernel properties. Moreover, the 2-D simulations for the bounded kernel suggest that attainment of is also dictated by but the magnitude is not sensitive to unlike diffusion-based models.

60 APPLIED LIFE SCIENCES↗

Model-based evaluation of school- and non-school-related measures to control the COVID-19 pandemic

The role of school-based contacts in the epidemiology of SARS-CoV-2 is incompletely understood. We use an age-structured transmission model fitted to age-specific seroprevalence and hospital admission data to assess the effects of school-based measures at different time points during the COVID-19 pandemic in the Netherlands. Our analyses suggest that the impact of measures reducing school-based contacts depends on the remaining opportunities to reduce non-school-based contacts. If opportunities to reduce the effective reproduction number (R e ) with non-school-based measures are exhausted or undesired and R e is still close to 1, the additional benefit of school-based measures may be considerable, particularly among older school children. As two examples, we demonstrate that keeping schools closed after the summer holidays in 2020, in the absence of other measures, would not have prevented the second pandemic wave in autumn 2020 but closing schools in November 2020 could have reduced R e below 1, with unchanged non-school-based contacts.

60 APPLIED LIFE SCIENCES↗

Effect of specific non-pharmaceutical intervention policies on SARS-CoV-2 transmission in the counties of the United States

Non-pharmaceutical interventions (NPIs) remain the only widely available tool for controlling the ongoing SARS-CoV-2 pandemic. We estimated weekly values of the effective basic reproductive number (R eff ) using a mechanistic metapopulation model and associated these with county-level characteristics and NPIs in the United States (US). Interventions that included school and leisure activities closure and nursing home visiting bans were all associated with a median R eff below 1 when combined with either stay at home orders (median R eff 0.97, 95% confidence interval (CI) 0.58–1.39) or face masks (median R eff 0.97, 95% CI 0.58–1.39). While direct causal effects of interventions remain unclear, our results suggest that relaxation of some NPIs will need to be counterbalanced by continuation and/or implementation of others.

60 APPLIED LIFE SCIENCES↗