A celebration of Fred Brauer's legacy in mathematical biology.

Fred Brauer (1932-2021), one of the pioneers of mathematical population biology, shaped generations of researchers through his lines of research, his books which have become key references in the field, and his mentoring of junior researchers. This dedication reviews some of his work in population harvesting and epidemiological modeling, highlighting how this special collection reflects the impact of his legacy through both his research accomplishments and the formation of new researchers.

Analysis of metapopulation models of the transmission of SARS-CoV-2 in the United States.

During the COVID-19 pandemic, renewal equation estimates of time-varying effective reproduction numbers were useful to policymakers in evaluating the need for and impact of mitigation measures. Our objective here is to illustrate the utility of mechanistic expressions for the basic and effective (or intrinsic and realized) reproduction numbers, [Formula: see text] and related quantities derived from a Susceptible-Exposed-Infectious-Removed (SEIR) model including features of COVID-19 that might affect transmission of SARS-CoV-2, including asymptomatic, pre-symptomatic, and symptomatic infections, with which people may be hospitalized. Expressions from homogeneous host population models can be analyzed to determine the effort needed to reduce [Formula: see text] from [Formula: see text] to 1 and contributions of modeled mitigation measures. Our model is stratified by age, 0-4, 5-9, …, 75+ years, and location, the 50 states plus District of Columbia. Expressions from such heterogeneous host population models include subpopulation reproduction numbers, contributions from the above-mentioned infectious states, metapopulation numbers, subpopulation contributions, and equilibrium prevalence. While the population-immunity at which [Formula: see text] has captured the popular imagination, the metapopulation [Formula: see text] could be attained in an infinite number of ways even if only one intervention (e.g., vaccination) were capable of reducing [Formula: see text] However, gradients of expressions derived from heterogeneous host population models,[Formula: see text] can be evaluated to identify optimal allocations of limited resources among subpopulations. We illustrate the utility of such analytical results by simulating two hypothetical vaccination strategies, one uniform and other indicated by [Formula: see text] as well as the actual program estimated from one of the CDC's nationwide seroprevalence surveys conducted from mid-summer 2020 through the end of 2021.

The physician CEO advantage and hospital performance during the COVID-19 pandemic: capacity utilization and patient satisfaction.

PURPOSE: Prior studies have shown that physician-led hospitals have several advantages over non-physician-led hospitals. This study seeks to test whether these advantages also extend to periods of extreme disruptions such as the COVID-19 pandemic, which affect bed availability and hospital utilization. DESIGN/METHODOLOGY/APPROACH: The authors utilize a bounded Tobit estimation to identify differences in patient satisfaction rates and in-hospital utilization rates of top-rated hospitals in the United States. FINDINGS: Among top-rated US hospitals, those that are physician-led achieve higher patient satisfaction ratings and are more likely to have higher utilization rates. RESEARCH LIMITATIONS/IMPLICATIONS: While the COVID-19 pandemic generated greater demand for inpatient beds, physician-led hospitals improved their hospitals' capacity utilization as compared with those led by non-physician leaders. A longitudinal study to show the change over the years and whether physician Chief Executive Officers (CEOs) are more likely to improve their hospitals' ratings than non-physician CEOs is highly recommended. PRACTICAL IMPLICATIONS: Recruiting and retaining physicians to lead hospitals, especially during disruptions, improve hospital's operating efficiency and enhance patient satisfaction. ORIGINALITY/VALUE: The paper reviews prior research on physician leadership and adds further insights into the crisis leadership literature. The authors provide evidence based on quantitative data analysis that during the COVID-19 pandemic, physician-led top-rated US hospitals experienced an improvement in operating efficiency.

Implications for infectious disease models of heterogeneous mixing on control thresholds.

Mixing among sub-populations, as well as heterogeneity in characteristics affecting their reproduction numbers, must be considered when evaluating public health interventions to prevent or control infectious disease outbreaks. In this overview, we apply a linear algebraic approach to re-derive some well-known results pertaining to preferential within- and proportionate among-group contacts in compartmental models of pathogen transmission. We give results for the meta-population effective reproduction number ([Formula: see text]) assuming different levels of vaccination in the sub-populations. Specifically, we unpack the dependency of [Formula: see text] on the fractions of contacts reserved for individuals within one's own subgroup and, by obtaining implicit expressions for the partial derivatives of [Formula: see text], we show that these increase as this preferential-mixing fraction increases in any sub-population.

Analysis of serological surveys of antibodies to SARS-CoV-2 in the United States to estimate parameters needed for transmission modeling and to evaluate and improve the accuracy of predictions.

Seroprevalence studies can estimate proportions of the population that have been infected or vaccinated, including infections that were not reported because of the lack of symptoms or testing. Based on information from studies in the United States from mid-summer 2020 through the end of 2021, we describe proportions of the population with antibodies to SARS-CoV-2 as functions of age and time. Slices through these surfaces at arbitrary times provide initial and target conditions for simulation modeling. They also provide the information needed to calculate age-specific forces of infection, attack rates, and - together with contact rates - age-specific probabilities of infection on contact between susceptible and infectious people. We modified the familiar Susceptible-Exposed-Infectious-Removed (SEIR) model to include features of the biology of COVID-19 that might affect transmission of SARS-CoV-2 and stratified by age and location. We consulted the primary literature or subject matter experts for contact rates and other parameter values. Using time-varying Oxford COVID-19 Government Response Tracker assessments of US state and DC efforts to mitigate the pandemic and compliance with non-pharmaceutical interventions (NPIs) from a YouGov survey fielded in the US during 2020, we estimate that the efficacy of social-distancing when possible and mask-wearing otherwise at reducing susceptibility or infectiousness was 31% during the fall of 2020. Initialized from seroprevalence among people having commercial laboratory tests for purposes other than SARS-CoV-2 infection assessments on 7 September 2020, our age- and location-stratified SEIR population model reproduces seroprevalence among members of the same population on 25 December 2020 quite well. Introducing vaccination mid-December 2020, first of healthcare and other essential workers, followed by older adults, people who were otherwise immunocompromised, and then progressively younger people, our metapopulation model reproduces seroprevalence among blood donors on 4 April 2021 less well, but we believe that the discrepancy is due to vaccinations being under-reported or blood donors being disproportionately vaccinated, if not both. As experimenting with reliable transmission models is the best way to assess the indirect effects of mitigation measures, we determined the impact of vaccination, conditional on NPIs. Results indicate that, during this period, vaccination substantially reduced infections, hospitalizations and deaths. This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics."

Modeling waning and boosting of COVID-19 in Canada with vaccination.

SARS-CoV-2, the causative agent of COVID-19, has caused devastating health and economic impacts around the globe since its appearance in late 2019. The advent of effective vaccines leads to open questions on how best to vaccinate the population. To address such questions, we developed a model of COVID-19 infection by age that includes the waning and boosting of immunity against SARS-CoV-2 in the context of infection and vaccination. The model also accounts for changes to infectivity of the virus, such as public health mitigation protocols over time, increases in the transmissibility of variants of concern, changes in compliance to mask wearing and social distancing, and changes in testing rates. The model is employed to study public health mitigation and vaccination of the COVID-19 epidemic in Canada, including different vaccination programs (rollout by age), and delays between doses in a two-dose vaccine. We find that the decision to delay the second dose of vaccine is appropriate in the Canadian context. We also find that the benefits of a COVID-19 vaccination program in terms of reductions in infections is increased if vaccination of 15-19 year olds are included in the vaccine rollout.

Optimal allocation of resources to healthcare workers or the general populace: a modelling study.

We consider a model that distinguishes susceptible; infected, but not yet infectious; pre-symptomatic, symptomatic, asymptomatic, and hospitalized infectious; recovered and dead members of two groups: healthcare workers (HCW) and members of the community that they serve. Because of the frequency or duration of their exposures to SARS-CoV-2, a greater fraction of HCW would experience severe COVID-19 symptoms that require medical care, which reduces mortality rates, absent personal protective equipment (PPE). While N95 masks (and, possibly, other scarce medical resources) are available to members of both groups, they do not use them equally well (i.e. efficacy and compliance differ). We investigated the optimal allocation of potentially scarce medical resources between these groups to control the pandemic and reduce overall infections and mortality via derivation and analysis of expressions for the reproduction numbers and final size. We also simulated prevalence and cumulative incidence, quantities relevant to surge capacity and population immunity, respectively. We found that, under realistic conditions, the optimal allocation is virtually or entirely to HCW, but that allocation of surplus masks and other medical resources to members of the general community also reduces infections and deaths.

Assessing the burden of congenital rubella syndrome in China and evaluating mitigation strategies: a metapopulation modelling study.

BACKGROUND: A rubella vaccine was licensed in China in 1993 and added to the Expanded Programme on Immunization in 2008, but a national cross-sectional serological survey during 2014 indicates that many adolescents remain susceptible. Maternal infections during the first trimester often cause miscarriages, stillbirths, and, among livebirths, congenital rubella syndrome. We aimed to evaluate possible supplemental immunisation activities (SIAs) to accelerate elimination of rubella and congenital rubella syndrome. METHODS: We analysed residual samples from the national serological survey done in 2014, data from monthly rubella surveillance reports from 2005 and 2016, and additional publications through a systematic review. Using an age-structured population model with provincial strata, we calculated the reproduction numbers and evaluated the gradient of the metapopulation effective reproduction number with respect to potential supplemental immunisation rates. We corroborated these analytical results and estimated times-to-elimination by simulating SIAs among adolescents (ages 10-19 years) and young adults (ages 20-29 years) using a model with regional strata. We estimated the incidence of rubella and burden of congenital rubella syndrome by simulating transmission in a relatively small population lacking only spatial structure. FINDINGS: By 2014, childhood immunisation had reduced rubella's reproduction number from 7·6 to 1·2 and SIAs among adolescents were the optimal elimination strategy. We found that less than 10% of rubella infections were reported; that although some women with symptomatic first-trimester infections might have elected to terminate their pregnancies, 700 children could have been born with congenital rubella syndrome during 2014; and that timely SIAs would avert outbreaks that, as susceptible adolescents reached reproductive age, could greatly increase the burden of this syndrome. INTERPRETATION: Our findings suggest that SIAs among adolescents would most effectively reduce congenital rubella syndrome as well as eliminate rubella, owing both to fewer infections in the immunised population and absence of infections that those immunised would otherwise have caused. Metapopulation models with realistic mixing are uniquely capable of assessing such indirect effects. FUNDING: WHO and National Science Foundation.

COVID-19 Seroprevalence in Canada Modelling Waning and Boosting COVID-19 Immunity in Canada a Canadian Immunization Research Network Study.

COVID-19 seroprevalence changes over time, with infection, vaccination, and waning immunity. Seroprevalence estimates are needed to determine when increased COVID-19 vaccination coverage is needed, and when booster doses should be considered, to reduce the spread and disease severity of COVID-19 infection. We use an age-structured model including infection, vaccination and waning immunity to estimate the distribution of immunity to COVID-19 in the Canadian population. This is the first mathematical model to do so. We estimate that 60-80% of the Canadian population has some immunity to COVID-19 by late Summer 2021, depending on specific characteristics of the vaccine and the waning rate of immunity. Models results indicate that increased vaccination uptake in age groups 12-29, and booster doses in age group 50+ are needed to reduce the severity COVID-19 Fall 2021 resurgence.

Staggered release policies for COVID-19 control: Costs and benefits of relaxing restrictions by age and risk.

Lockdown and social distancing restrictions have been widely used as part of policy efforts aimed at controlling the ongoing COVID-19 pandemic. Since these restrictions have a negative impact on the economy, there exists a strong incentive to relax these policies while protecting public health. Using a modified SEIR epidemiological model, this paper explores the costs and benefits associated with the sequential release of specific groups based on age and risk from lockdown and social distancing measures. The results in this paper suggest that properly designed staggered-release policies can do better than simultaneous-release policies in terms of protecting the most vulnerable members of a population, reducing health risks overall, and increasing economic activity.

On the benefits of flattening the curve: A perspective.

The many variations on a graphic illustrating the impact of non-pharmaceutical measures to mitigate pandemic influenza that have appeared in recent news reports about COVID-19 suggest a need to better explain the mechanism by which social distancing reduces the spread of infectious diseases. And some reports understate one benefit of reducing the frequency or proximity of interpersonal encounters, a reduction in the total number of infections. In hopes that understanding will increase compliance, we describe how social distancing (a) reduces the peak incidence of infections, (b) delays the occurrence of this peak, and (c) reduces the total number of infections during epidemics. In view of the extraordinary efforts underway to identify existing medications that are active against SARS-CoV-2 and to develop new antiviral drugs, vaccines and antibody therapies, any of which may have community-level effects, we also describe how pharmaceutical interventions affect transmission.

Modeling the waning and boosting of immunity from infection or vaccination.

Immunity following natural infection or immunization may wane, increasing susceptibility to infection with time since infection or vaccination. Symptoms, and concomitantly infectiousness, depend on residual immunity. We quantify these phenomena in a model population composed of individuals whose susceptibility, infectiousness, and symptoms all vary with immune status. We also model age, which affects contact, vaccination and possibly waning rates. The resurgences of pertussis that have been observed wherever effective vaccination programs have reduced typical disease among young children follow from these processes. As one example, we compare simulations with the experience of Sweden following resumption of pertussis vaccination after the hiatus from 1979 to 1996, reproducing the observations leading health authorities to introduce booster doses among school-aged children and adolescents in 2007 and 2014, respectively. Because pertussis comprises a spectrum of symptoms, only the most severe of which are medically attended, accurate models are needed to design optimal vaccination programs where surveillance is less effective.

Influence of demographically-realistic mortality schedules on vaccination strategies in age-structured models.

Because demographic realism complicates analysis, mathematical modelers either ignore demography or make simplifying assumptions (e.g., births and deaths equal). But human populations differ demographically, perhaps most notably in their mortality schedules. We developed an age-stratified population model with births, deaths, aging and mixing between age groups. The model includes types I and II mortality as special cases. We used the gradient approach (Feng et al., 2015, 2017) to explore the impact of mortality patterns on optimal strategies for mitigating vaccine-preventable diseases such as measles and rubella, which the international community has targeted for eradication. Identification of optimal vaccine allocations to reduce the effective reproduction number Rv under various scenarios is presented. Numerical simulations of the model with various types of mortality are carried out to ascertain the long-term effects of vaccination on disease incidence. We conclude that both optimal vaccination strategies and long-term effects of vaccination may depend on demographic assumptions.

Modeling the population impacts of avian malaria on Hawaiian honeycreepers: Bifurcation analysis and implications for conservation.

Avian malaria is a mosquito-borne parasitic disease of birds caused by protists of the genera Plasmodium, most notably Plasmodium relictum. This disease has been identified as a primary cause of the drastic decline and extinctions of birds, in particular Hawaiian honeycreepers (Drepanidinae), where rates of mortality may exceed 90%. We formulate an epizootiological model of the transmission dynamics of avian malaria between populations of bird hosts and mosquito vectors using a system of compartmental ordinary differential equations. We derive the basic reproduction number as well as criteria for the existence and local stability of disease-free and enzootic equilibria. These results provide useful information for evaluating management strategies. A local sensitivity analysis of certain model invariants to uncertain parameter values is performed to ascertain which biological factors have the largest impact on ecological outcomes and, in particular, long-term bird population densities. We discuss and compare the effectiveness of two disease control and conservation strategies: captive propagation of honeycreepers and larval mosquito habitat reduction. We provide examples of combinations of these strategies that either are predicted to eliminate enzootic avian malaria or to increase predicted bird density above a given ecologically meaningful threshold.

Evaluating vaccination policies to accelerate measles elimination in China: a meta-population modelling study.

BACKGROUND: Measles is among the most highly infectious human diseases. By virtue of increasingly effective childhood vaccination, together with targeted supplemental immunization activities (SIAs), health authorities in the People's Republic of China have reduced measles' reproduction number from about 18 to 2.3. Despite substantial residual susceptibility among young adults, more in some locales than others, sustained routine childhood immunization likely would eliminate measles eventually. To support global eradication efforts, as well as expedite morbidity and mortality reductions in China, we evaluated alternative SIAs via mechanistic mathematical modelling. METHODS: Our model Chinese population is stratified by immune status (susceptible to measles infection; infected, but not yet infectious; infectious; and recovered or immunized), age (0, 1-4, 5-9, …, 65+ years) and location (31 provinces). Contacts between sub-populations are either empirical or a mixture of preferential and proportionate with respect to age and decline exponentially with distance between locations at age-dependent rates. We estimated initial conditions and most parameters from recent cross-sectional serological surveys, disease surveillance and demographic observations. Then we calculated the reproduction numbers and gradient of the effective number with respect to age- and location-specific immunization rates. We corroborated these analytical results by simulating adolescent and young adult SIAs using a version of our model in which the age-specific contact rates vary seasonally. RESULTS: Whereas the gradient indicates that vaccinating young adults generally is the optimal strategy, simulations indicate that a catch-up campaign among susceptible adolescent schoolchildren would accelerate elimination, with timing dependent on uptake. CONCLUSIONS: These results are largely due to indirect effects (i.e. fewer infections than immunized people might otherwise cause), which meta-population models with realistic mixing are uniquely capable of reproducing accurately.

Assessing the effects of modeling the spectrum of clinical symptoms on the dynamics and control of Ebola.

Mathematical modelers have attempted to capture the dynamics of Ebola transmission and to evaluate the effectiveness of control measures, as well as to make predictions about ongoing outbreaks. Many of their models consider only infections with typical symptoms, but Ebola presents clinically in a more complicated way. Even the most common symptom, fever, is not experienced by 13% of patients. This suggests that infected individuals could be asymptomatic or have moderately symptomatic infections as reported during previous Ebola outbreaks. To account crudely for the spectrum of clinical symptoms that characterizes Ebola infection, we developed a model including moderate and severe symptoms. Our model captures the dynamics of the recent outbreak of Ebola in Liberia. Our estimate of the basic reproduction number is 1.83 (CI: 1.72, 1.86), consistent with the WHO response team's estimate using early outbreak case data. We also estimate the effectiveness of interventions using observations before and after their introduction. As the final epidemic size is linked to the timing of interventions in an exponential fashion, a simple empirical formula is provided to guide policy-making. It suggests that early implementation could significantly decrease final size. We also compare our model to one with typical symptoms by excluding moderate ones. The model with only typical symptoms overestimates the basic reproduction number and effectiveness of control measures, and exaggerates changes in peak size attributable to the timing of interventions. In addition, uncertainty about how moderate symptoms affect the basic reproduction number is considered, and PRCC (Partial rank correlation coefficient) is used to analyze the global sensitivity of relevant parameters. Possible control strategies are evaluated through numerical simulations and sensitivity analysis, indicating that simultaneously strengthening contact-tracing and effectiveness of isolation in hospital would be most effective. In this study, we show that asymptomatic Ebola infections may have implications for policy-making.

Influence of non-homogeneous mixing on final epidemic size in a meta-population model.

In meta-population models for infectious diseases, the basic reproduction number R0 can be as much as 70% larger in the case of preferential mixing than that in homogeneous mixing [J.W. Glasser, Z. Feng, S.B. Omer, P.J. Smith, and L.E. Rodewald, The effect of heterogeneity in uptake of the measles, mumps, and rubella vaccine on the potential for outbreaks of measles: A modelling study, Lancet ID 16 (2016), pp. 599-605. doi: 10.1016/S1473-3099(16)00004-9 ]. This suggests that realistic mixing can be an important factor to consider in order for the models to provide a reliable assessment of intervention strategies. The influence of mixing is more significant when the population is highly heterogeneous. In this paper, another quantity, the final epidemic size ( F ) of an outbreak, is considered to examine the influence of mixing and population heterogeneity. Final size relation is derived for a meta-population model accounting for a general mixing. The results show that F can be influenced by the pattern of mixing in a significant way. Another interesting finding is that, heterogeneity in various sub-population characteristics may have the opposite effect on R0 and F .

ESTIMATING AGE-SPECIFIC HAZARD RATES OF INFECTION FROM CROSS-SECTIONAL OBSERVATIONS.

Mathematical models of pathogen transmission in age-structured host populations, can be used to design or evaluate vaccination programs. For reliable results, their forces or hazard rates of infection (FOI) must be formulated correctly and the requisite contact rates and probabilities of infection on contact estimated from suitable observations. Elsewhere, we have described methods for calculating the probabilities of infection on contact from the contact rates and FOI. Here, we present methods for estimating the FOI from cross-sectional serological surveys or disease surveillance in populations with or without concurrent vaccination. We consider both continuous and discrete age, and present estimates of the FOI for vaccine-preventable diseases that confer temporary or permanent immunity.

Los modelos matemáticos de transmisión de patógenos en poblaciones de huéspedes estructuradas por edad pueden usarse para diseñar o evaluar programas de vacunación. Para obtener resultados confiables, sus fuerzas o tasas de riesgo de infección (FOI) deben formularse correctamente y las tasas de contacto requeridas y las probabilidades de infección en contacto deben estimarse a partir de observaciones adecuadas. En otros lugares, hemos descrito métodos para calcular las probabilidades de infección por contacto a partir de las tasas de contacto y FOI. Aquí, presentamos métodos para estimar el FOI a partir de encuestas serológicas transversales o vigilancia de enfermedades en poblaciones con o sin vacunación concurrente. Consideramos tanto la edad continua como la discreta, y presentamos estimaciones del FOI para enfermedades prevenibles por vacunación que confieren inmunidad temporal o permanente.