Ethical frameworks should be applied to computational modelling of infectious disease interventions.

This perspective is part of an international effort to improve epidemiological models with the goal of reducing the unintended consequences of infectious disease interventions. The scenarios in which models are applied often involve difficult trade-offs that are well recognised in public health ethics. Unless these trade-offs are explicitly accounted for, models risk overlooking contested ethical choices and values, leading to an increased risk of unintended consequences. We argue that such risks could be reduced if modellers were more aware of ethical frameworks and had the capacity to explicitly account for the relevant values in their models. We propose that public health ethics can provide a conceptual foundation for developing this capacity. After reviewing relevant concepts in public health and clinical ethics, we discuss examples from the COVID-19 pandemic to illustrate the current separation between public health ethics and infectious disease modelling. We conclude by describing practical steps to build the capacity for ethically aware modelling. Developing this capacity constitutes a critical step towards ethical practice in computational modelling of public health interventions, which will require collaboration with experts on public health ethics, decision support, behavioural interventions, and social determinants of health, as well as direct consultation with communities and policy makers.

A model-based assessment of social isolation practices for COVID-19 outbreak response in residential care facilities.

BACKGROUND: Residential aged-care facilities (RACFs, also called long-term care facilities, aged care homes, or nursing homes) have elevated risks of respiratory infection outbreaks and associated disease burden. During the COVID-19 pandemic, social isolation policies were commonly used in these facilities to prevent and mitigate outbreaks. We refer specifically to general isolation policies that were intended to reduce contact between residents, without regard to confirmed infection status. Such policies are controversial because of their association with adverse mental and physical health indicators and there is a lack of modelling that assesses their effectiveness. METHODS: In consultation with the Australian Government Department of Health and Aged Care, we developed an agent-based model of COVID-19 transmission in a structured population, intended to represent the salient characteristics of a residential care environment. Using our model, we generated stochastic ensembles of simulated outbreaks and compared summary statistics of outbreaks simulated under different mitigation conditions. Our study focuses on the marginal impact of general isolation (reducing social contact between residents), regardless of confirmed infection. For a realistic assessment, our model included other generic interventions consistent with the Australian Government's recommendations released during the COVID-19 pandemic: isolation of confirmed resident cases, furlough (mandatory paid leave) of staff members with confirmed infection, and deployment of personal protective equipment (PPE) after outbreak declaration. RESULTS: In the absence of any asymptomatic screening, general isolation of residents to their rooms reduced median cumulative cases by approximately 27%. However, when conducted concurrently with asymptomatic screening and isolation of confirmed cases, general isolation reduced the median number of cumulative infections by only 12% in our simulations. CONCLUSIONS: Under realistic sets of assumptions, our simulations showed that general isolation of residents did not provide substantial benefits beyond those achieved through screening, isolation of confirmed cases, and deployment of PPE. Our results also highlight the importance of effective case isolation, and indicate that asymptomatic screening of residents and staff may be warranted, especially if importation risk from the outside community is high. Our conclusions are sensitive to assumptions about the proportion of total contacts in a facility accounted for by casual interactions between residents.

Rapid prototyping of models for COVID-19 outbreak detection in workplaces.

Early case detection is critical to preventing onward transmission of COVID-19 by enabling prompt isolation of index infections, and identification and quarantining of contacts. Timeliness and completeness of ascertainment depend on the surveillance strategy employed. This paper presents modelling used to inform workplace testing strategies for the Australian government in early 2021. We use rapid prototype modelling to quickly investigate the effectiveness of testing strategies to aid decision making. Models are developed with a focus on providing relevant results to policy makers, and these models are continually updated and improved as new questions are posed. Developed to support the implementation of testing strategies in high risk workplace settings in Australia, our modelling explores the effects of test frequency and sensitivity on outbreak detection. We start with an exponential growth model, which demonstrates how outbreak detection changes depending on growth rate, test frequency and sensitivity. From the exponential model, we learn that low sensitivity tests can produce high probabilities of detection when testing occurs frequently. We then develop a more complex Agent Based Model, which was used to test the robustness of the results from the exponential model, and extend it to include intermittent workplace scheduling. These models help our fundamental understanding of disease detectability through routine surveillance in workplaces and evaluate the impact of testing strategies and workplace characteristics on the effectiveness of surveillance. This analysis highlights the risks of particular work patterns while also identifying key testing strategies to best improve outbreak detection in high risk workplaces.

A framework for considering the utility of models when facing tough decisions in public health: a guideline for policy-makers.

The COVID-19 pandemic has brought the combined disciplines of public health, infectious disease and policy modelling squarely into the spotlight. Never before have decisions regarding public health measures and their impacts been such a topic of international deliberation, from the level of individuals and communities through to global leaders. Nor have models-developed at rapid pace and often in the absence of complete information-ever been so central to the decision-making process. However, after nearly 3 years of experience with modelling, policy-makers need to be more confident about which models will be most helpful to support them when taking public health decisions, and modellers need to better understand the factors that will lead to successful model adoption and utilization. We present a three-stage framework for achieving these ends.

Overlapping Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis household transmission and mobile genetic element exchange.

Streptococcus dysgalactiae subspecies equisimilis (SDSE) and Streptococcus pyogenes share skin and throat niches with extensive genomic homology and horizontal gene transfer (HGT) possibly underlying shared disease phenotypes. It is unknown if cross-species transmission interaction occurs. Here, we conduct a genomic analysis of a longitudinal household survey in remote Australian First Nations communities for patterns of cross-species transmission interaction and HGT. Collected from 4547 person-consultations, we analyse 294 SDSE and 315 S. pyogenes genomes. We find SDSE and S. pyogenes transmission intersects extensively among households and show that patterns of co-occurrence and transmission links are consistent with independent transmission without inter-species interference. We identify at least one of three near-identical cross-species mobile genetic elements (MGEs) carrying antimicrobial resistance or streptodornase virulence genes in 55 (19%) SDSE and 23 (7%) S. pyogenes isolates. These findings demonstrate co-circulation of both pathogens and HGT in communities with a high burden of streptococcal disease, supporting a need to integrate SDSE and S. pyogenes surveillance and control efforts.

Correlation of viral loads in disease transmission could affect early estimates of the reproduction number.

Early estimates of the transmission properties of a newly emerged pathogen are critical to an effective public health response, and are often based on limited outbreak data. Here, we use simulations to investigate how correlations between the viral load of cases in transmission chains can affect estimates of these fundamental transmission properties. Our computational model simulates a disease transmission mechanism in which the viral load of the infector at the time of transmission influences the infectiousness of the infectee. These correlations in transmission pairs produce a population-level convergence process during which the distributions of initial viral loads in each subsequent generation converge to a steady state. We find that outbreaks arising from index cases with low initial viral loads give rise to early estimates of transmission properties that could be misleading. These findings demonstrate the potential for transmission mechanisms to affect estimates of the transmission properties of newly emerged viruses in ways that could be operationally significant to a public health response.

Individual variation in vaccine immune response can produce bimodal distributions of protection.

The ability for vaccines to protect against infectious diseases varies among individuals, but computational models employed to inform policy typically do not account for this variation. Here we examine this issue: we implement a model of vaccine efficacy developed in the context of SARS-CoV-2 in order to evaluate the general implications of modelling correlates of protection on the individual level. Due to high levels of variation in immune response, the distributions of individual-level protection emerging from this model tend to be highly dispersed, and are often bimodal. We describe the specification of the model, provide an intuitive parameterisation, and comment on its general robustness. We show that the model can be viewed as an intermediate between the typical approaches that consider the mode of vaccine action to be either "all-or-nothing" or "leaky". Our view based on this analysis is that individual variation in correlates of protection is an important consideration that may be crucial to designing and implementing models for estimating population-level impacts of vaccination programs.

Evaluating the role of asymptomatic throat carriage of Streptococcus pyogenes in impetigo transmission in remote Aboriginal communities in Northern Territory, Australia: a retrospective genomic analysis.

BACKGROUND: Streptococcus pyogenes, or group A Streptococcus (GAS), infections contribute to a high burden of disease in Aboriginal Australians, causing skin infections and immune sequelae such as rheumatic heart disease. Controlling skin infections in these populations has proven difficult, with transmission dynamics being poorly understood. We aimed to identify the relative contributions of impetigo and asymptomatic throat carriage to GAS transmission. METHODS: In this genomic analysis, we retrospectively applied whole genome sequencing to GAS isolates that were collected as part of an impetigo surveillance longitudinal household survey conducted in three remote Aboriginal communities in the Northern Territory of Australia between Aug 6, 2003, and June 22, 2005. We included GAS isolates from all throats and impetigo lesions of people living in two of the previously studied communities. We classified isolates into genomic lineages based on pairwise shared core genomes of more than 99% with five or fewer single nucleotide polymorphisms. We used a household network analysis of epidemiologically and genomically linked lineages to quantify the transmission of GAS within and between households. FINDINGS: We included 320 GAS isolates in our analysis: 203 (63%) from asymptomatic throat swabs and 117 (37%) from impetigo lesions. Among 64 genomic lineages (encompassing 39 emm types) we identified 264 transmission links (involving 93% of isolates), for which the probable source was asymptomatic throat carriage in 166 (63%) and impetigo lesions in 98 (37%). Links originating from impetigo cases were more frequent between households than within households. Households were infected with GAS for a mean of 57 days (SD 39 days), and once cleared, reinfected 62 days (SD 40 days) later. Increased household size and community presence of GAS and scabies were associated with slower clearance of GAS. INTERPRETATION: In communities with high prevalence of endemic GAS-associated skin infection, asymptomatic throat carriage is a GAS reservoir. Public health interventions such as vaccination or community infection control programmes aimed at interrupting transmission of GAS might need to include consideration of asymptomatic throat carriage. FUNDING: Australian National Health and Medical Research Council.

The effects of local homogeneity assumptions in metapopulation models of infectious disease.

Computational models of infectious disease can be broadly categorized into two types: individual-based (agent-based) or compartmental models. While there are clear conceptual distinctions between these methodologies, a fair comparison of the approaches is difficult to achieve. Here, we carry out such a comparison by building a set of compartmental metapopulation models from an agent-based representation of a real population. By adjusting the compartmental model to approximately match the dynamics of the agent-based model, we identify two key qualitative properties of the individual-based dynamics which are lost upon aggregation into metapopulations. These are (i) the local depletion of susceptibility to infection and (ii) decoupling of different regional groups due to correlation between commuting behaviours and contact rates. The first of these effects is a general consequence of aggregating small, closely connected groups (i.e. families) into larger homogeneous metapopulations. The second can be interpreted as a consequence of aggregating two distinct types of individuals: school children, who travel short distances but have many potentially infectious contacts, and adults, who travel further but tend to have fewer contacts capable of transmitting infection. Our results could be generalized to other types of correlations between the characteristics of individuals and the behaviours that distinguish them.

Simulating Transmission Scenarios of the Delta Variant of SARS-CoV-2 in Australia.

An outbreak of the Delta (B.1.617.2) variant of SARS-CoV-2 that began around mid-June 2021 in Sydney, Australia, quickly developed into a nation-wide epidemic. The ongoing epidemic is of major concern as the Delta variant is more infectious than previous variants that circulated in Australia in 2020. Using a re-calibrated agent-based model, we explored a feasible range of non-pharmaceutical interventions, including case isolation, home quarantine, school closures, and stay-at-home restrictions (i.e., "social distancing.") Our modelling indicated that the levels of reduced interactions in workplaces and across communities attained in Sydney and other parts of the nation were inadequate for controlling the outbreak. A counter-factual analysis suggested that if 70% of the population followed tight stay-at-home restrictions, then at least 45 days would have been needed for new daily cases to fall from their peak to below ten per day. Our model predicted that, under a progressive vaccination rollout, if 40-50% of the Australian population follow stay-at-home restrictions, the incidence will peak by mid-October 2021: the peak in incidence across the nation was indeed observed in mid-October. We also quantified an expected burden on the healthcare system and potential fatalities across Australia.

COVID-19 in low-tolerance border quarantine systems: Impact of the Delta variant of SARS-CoV-2.

In controlling transmission of coronavirus disease 2019 (COVID-19), the effectiveness of border quarantine strategies is a key concern for jurisdictions in which the local prevalence of disease and immunity is low. In settings like this such as China, Australia, and New Zealand, rare outbreak events can lead to escalating epidemics and trigger the imposition of large-scale lockdown policies. Here, we develop and apply an individual-based model of COVID-19 to simulate case importation from managed quarantine under various vaccination scenarios. We then use the output of the individual-based model as input to a branching process model to assess community transmission risk. For parameters corresponding to the Delta variant, our results demonstrate that vaccination effectively counteracts the pathogen's increased infectiousness. To prevent outbreaks, heightened vaccination in border quarantine systems must be combined with mass vaccination. The ultimate success of these programs will depend sensitively on the efficacy of vaccines against viral transmission.

How will mass-vaccination change COVID-19 lockdown requirements in Australia?

Background To prevent future outbreaks of COVID-19, Australia is pursuing a mass-vaccination approach in which a targeted group of the population comprising healthcare workers, aged-care residents and other individuals at increased risk of exposure will receive a highly effective priority vaccine. The rest of the population will instead have access to a less effective vaccine. Methods We apply a large-scale agent-based model of COVID-19 in Australia to investigate the possible implications of this hybrid approach to mass-vaccination. The model is calibrated to recent epidemiological and demographic data available in Australia, and accounts for several components of vaccine efficacy. Findings Within a feasible range of vaccine efficacy values, our model supports the assertion that complete herd immunity due to vaccination is not likely in the Australian context. For realistic scenarios in which herd immunity is not achieved, we simulate the effects of mass-vaccination on epidemic growth rate, and investigate the requirements of lockdown measures applied to curb subsequent outbreaks. In our simulations, Australia's vaccination strategy can feasibly reduce required lockdown intensity and initial epidemic growth rate by 43% and 52%, respectively. The severity of epidemics, as measured by the peak number of daily new cases, decreases by up to two orders of magnitude under plausible mass-vaccination and lockdown strategies. Interpretation The study presents a strong argument for a large-scale vaccination campaign in Australia, which would substantially reduce both the intensity of future outbreaks and the stringency of non-pharmaceutical interventions required for their suppression. Funding Australian Research Council; National Health and Medical Research Council.

Mapping home internet activity during COVID-19 lockdown to identify occupation related inequalities.

During the COVID-19 pandemic, evidence has accumulated that movement restrictions enacted to combat virus spread produce disparate consequences along socioeconomic lines. We investigate the hypothesis that people engaged in financially secure employment are better able to adhere to mobility restrictions, due to occupational factors that link the capacity for flexible work arrangements to income security. We use high-resolution spatial data on household internet traffic as a surrogate for adaptation to home-based work, together with the geographical clustering of occupation types, to investigate the relationship between occupational factors and increased internet traffic during work hours under lockdown in two Australian cities. By testing our hypothesis based on the observed trends, and exploring demographic factors associated with divergences from our hypothesis, we are left with a picture of unequal impact dominated by two major influences: the types of occupations in which people are engaged, and the composition of households and families. During lockdown, increased internet traffic was correlated with income security and, when school activity was conducted remotely, to the proportion of families with children. Our findings suggest that response planning and provision of social and economic support for residents within lockdown areas should explicitly account for income security and household structure. Overall, the results we present contribute to the emerging picture of the impacts of COVID-19 on human behaviour, and will help policy makers to understand the balance between public health and social impact in making decisions about mitigation policies.

Risk mapping for COVID-19 outbreaks in Australia using mobility data.

COVID-19 is highly transmissible and containing outbreaks requires a rapid and effective response. Because infection may be spread by people who are pre-symptomatic or asymptomatic, substantial undetected transmission is likely to occur before clinical cases are diagnosed. Thus, when outbreaks occur there is a need to anticipate which populations and locations are at heightened risk of exposure. In this work, we evaluate the utility of aggregate human mobility data for estimating the geographical distribution of transmission risk. We present a simple procedure for producing spatial transmission risk assessments from near-real-time population mobility data. We validate our estimates against three well-documented COVID-19 outbreaks in Australia. Two of these were well-defined transmission clusters and one was a community transmission scenario. Our results indicate that mobility data can be a good predictor of geographical patterns of exposure risk from transmission centres, particularly in outbreaks involving workplaces or other environments associated with habitual travel patterns. For community transmission scenarios, our results demonstrate that mobility data add the most value to risk predictions when case counts are low and spatially clustered. Our method could assist health systems in the allocation of testing resources, and potentially guide the implementation of geographically targeted restrictions on movement and social interaction.

Interfering with influenza: nonlinear coupling of reactive and static mitigation strategies.

When new, highly infectious strains of influenza emerge, global pandemics can occur before an effective vaccine is developed. Without a strain-specific vaccine, pandemics can only be mitigated by employing combinations of low-efficacy pre-pandemic vaccines and reactive response measures that are carried out as the pandemic unfolds. Unfortunately, the application of reactive interventions can lead to unintended consequences that may exacerbate unpredictable spreading dynamics and cause more drawn-out epidemics. Here, we employ a detailed model of pandemic influenza in Australia to simulate the combination of pre-pandemic vaccination and reactive antiviral prophylaxis. This study focuses on population-level coupling effects between the respective methods, and the associated spatio-temporal fluctuations in pandemic dynamics produced by reactive strategies. Our results show that combining strategies can produce either mutual improvement of performance or interference that reduces the effectiveness of each strategy when they are used together. We demonstrate that these coupling effects between intervention strategies are extremely sensitive to delay times, compliance rates and the type of contact targeting used to administer prophylaxis.

Modelling transmission and control of the COVID-19 pandemic in Australia.

There is a continuing debate on relative benefits of various mitigation and suppression strategies aimed to control the spread of COVID-19. Here we report the results of agent-based modelling using a fine-grained computational simulation of the ongoing COVID-19 pandemic in Australia. This model is calibrated to match key characteristics of COVID-19 transmission. An important calibration outcome is the age-dependent fraction of symptomatic cases, with this fraction for children found to be one-fifth of such fraction for adults. We apply the model to compare several intervention strategies, including restrictions on international air travel, case isolation, home quarantine, social distancing with varying levels of compliance, and school closures. School closures are not found to bring decisive benefits unless coupled with high level of social distancing compliance. We report several trade-offs, and an important transition across the levels of social distancing compliance, in the range between 70% and 80% levels, with compliance at the 90% level found to control the disease within 13-14 weeks, when coupled with effective case isolation and international travel restrictions.

Creating a surrogate commuter network from Australian Bureau of Statistics census data.

Between the 2011 and 2016 national censuses, the Australian Bureau of Statistics changed its anonymity policy compliance system for the distribution of census data. The new method has resulted in dramatic inconsistencies when comparing low-resolution data to aggregated high-resolution data. Hence, aggregated totals do not match true totals, and the mismatch gets worse as the data resolution gets finer. Here, we address several aspects of this inconsistency with respect to the 2016 usual-residence to place-of-work travel data. We introduce a re-sampling system that rectifies many of the artifacts introduced by the new ABS protocol, ensuring a higher level of consistency across partition sizes. We offer a surrogate high-resolution 2016 commuter dataset that reduces the difference between the aggregated and true commuter totals from ~34% to only ~7%, which is on the order of the discrepancy across partition resolutions in data from earlier years.

Urbanization affects peak timing, prevalence, and bimodality of influenza pandemics in Australia: Results of a census-calibrated model.

We examine salient trends of influenza pandemics in Australia, a rapidly urbanizing nation. To do so, we implement state-of-the-art influenza transmission and progression models within a large-scale stochastic computer simulation, generated using comprehensive Australian census datasets from 2006, 2011, and 2016. Our results offer a simulation-based investigation of a population's sensitivity to pandemics across multiple historical time points and highlight three notable trends in pandemic patterns over the years: increased peak prevalence, faster spreading rates, and decreasing spatiotemporal bimodality. We attribute these pandemic trends to increases in two key quantities indicative of urbanization: the population fraction residing in major cities and international air traffic. In addition, we identify features of the pandemic's geographic spread that we attribute to changes in the commuter mobility network. The generic nature of our model and the ubiquity of urbanization trends around the world make it likely for our results to be applicable in other rapidly urbanizing nations.

The demise of Angkor: Systemic vulnerability of urban infrastructure to climatic variations.

Complex infrastructural networks provide critical services to cities but can be vulnerable to external stresses, including climatic variability. This vulnerability has also challenged past urban settlements, but its role in cases of historic urban demise has not been precisely documented. We transform archeological data from the medieval Cambodian city of Angkor into a numerical model that allows us to quantify topological damage to critical urban infrastructure resulting from climatic variability. Our model reveals unstable behavior in which extensive and cascading damage to infrastructure occurs in response to flooding within Angkor's urban water management system. The likelihood and extent of the cascading failure abruptly grow with the magnitude of flooding relative to normal flows in the system. Our results support the hypothesis that systemic infrastructural vulnerability, coupled with abrupt climatic variation, contributed to the demise of the city. The factors behind Angkor's demise are analogous to challenges faced by modern urban communities struggling with complex critical infrastructure.

Emergent pattern formation in an interstitial biofilm.

Collective behavior of bacterial colonies plays critical roles in adaptability, survivability, biofilm expansion and infection. We employ an individual-based model of an interstitial biofilm to study emergent pattern formation based on the assumptions that rod-shaped bacteria furrow through a viscous environment and excrete extracellular polymeric substances which bias their rate of motion. Because the bacteria furrow through their environment, the substratum stiffness is a key control parameter behind the formation of distinct morphological patterns. By systematically varying this property (which we quantify with a stiffness coefficient γ), we show that subtle changes in the substratum stiffness can give rise to a stable state characterized by a high degree of local order and long-range pattern formation. The ordered state exhibits characteristics typically associated with bacterial fitness advantages, even though it is induced by changes in environmental conditions rather than changes in biological parameters. Our findings are applicable to a broad range of biofilms and provide insights into the relationship between bacterial movement and their environment, and basic mechanisms behind self-organization of biophysical systems.