Evaluating vaccine allocation strategies using simulation-assisted causal modelling (preprint)

Early on during a pandemic, vaccine availability is limited, requiring prioritisation of different population groups. Evaluating vaccine allocation is therefore a crucial element of pandemics response. In the present work, we develop a model to retrospectively evaluate age-dependent counterfactual vaccine allocation strategies against the COVID-19 pandemic. To estimate the effect of allocation on the expected severe-case incidence, we employ a simulation-assisted causal modelling approach which combines a compartmental infection-dynamics simulation, a coarse-grained, data-driven causal model and literature estimates for immunity waning. We compare Israel's implemented vaccine allocation strategy in 2021 to counterfactual strategies such as no prioritisation, prioritisation of younger age groups or a strict risk-ranked approach; we find that Israel's implemented strategy was indeed highly effective. We also study the marginal impact of increasing vaccine uptake for a given age group and find that increasing vaccinations in the elderly is most effective at preventing severe cases, whereas additional vaccinations for middle-aged groups reduce infections most effectively. Due to its modular structure, our model can easily be adapted to study future pandemics. We demonstrate this flexibility by investigating vaccine allocation strategies for a pandemic with characteristics of the Spanish Flu. Our approach thus helps evaluate vaccination strategies under the complex interplay of core epidemic factors, including age-dependent risk profiles, immunity waning, vaccine availability and spreading rates.

Pyfectious: An individual-level simulator to discover optimal containment polices for epidemic diseases (preprint)

Simulating the spread of infectious diseases in human communities is critical for predicting the trajectory of an epidemic and verifying various policies to control the devastating impacts of the outbreak. Many existing simulators are based on compartment models that divide people into a few subsets and simulate the dynamics among those subsets using hypothesized differential equations. However, these models lack the requisite granularity to study the effect of intelligent policies that influence every individual in a particular way. In this work, we introduce a simulator software capable of modeling a population structure and controlling the disease's propagation at an individualistic level. In order to estimate the confidence of the conclusions drawn from the simulator, we employ a comprehensive probabilistic approach where the entire population is constructed as a hierarchical random variable. This approach makes the inferred conclusions more robust against sampling artifacts and gives confidence bounds for decisions based on the simulation results. To showcase potential applications, the simulator parameters are set based on the formal statistics of the COVID-19 pandemic, and the outcome of a wide range of control measures is investigated. Furthermore, the simulator is used as the environment of a reinforcement learning problem to find the optimal policies to control the pandemic. The obtained experimental results indicate the simulator's adaptability and capacity in making sound predictions and a successful policy derivation example based on real-world data. As an exemplary application, our results show that the proposed policy discovery method can lead to control measures that produce significantly fewer infected individuals in the population and protect the health system against saturation.

Listening to Bluetooth Beacons for Epidemic Risk Mitigation (preprint)

During the ongoing COVID-19 pandemic, there have been burgeoning efforts to develop and deploy digital contact tracing systems to expedite contact tracing and risk notification. Unfortunately, the success of these systems has been limited, partly owing to poor interoperability with manual contact tracing, low adoption rates, and a societally sensitive trade-off between utility and privacy. In this work, we introduce a new privacy-preserving and inclusive system for epidemic risk assessment and notification that aims to address the above limitations. Rather than capturing pairwise encounters between user devices as done by existing systems, our system captures encounters between user devices and beacons placed in strategic locations where infection clusters may originate. Epidemiological simulations using an agent-based model demonstrate several beneficial properties of our system. By achieving bidirectional interoperability with manual contact tracing, our system may help reduce the effective reproduction number already at adoption levels of 10%. The use of location and environmental information provided by beacons allows our system to achieve significantly higher sensitivity and specificity than existing systems and thus may improve the efficacy of contact tracing under limited isolation and testing resources. Moreover, to achieve high utility, it is sufficient to deploy beacons in a small fraction of strategic locations. Finally, our simulations also show that existing systems could inherit these beneficial properties if they integrated the beacons used by our system.

Assaying Large-scale Testing Models to Interpret COVID-19 Case Numbers (preprint)

Large-scale testing is considered key to assess the state of the current COVID-19 pandemic. Yet, the link between the reported case numbers and the true state of the pandemic remains elusive. We develop mathematical models based on competing hypotheses regarding this link, thereby providing different prevalence estimates based on case numbers, and validate them by predicting SARS-CoV-2-attributed death rate trajectories. Assuming that individuals were tested based solely on a predefined risk of being infectious implies the absolute case numbers reflect the prevalence, but turned out to be a poor predictor, consistently overestimating growth rates at the beginning of two COVID-19 epidemic waves. In contrast, assuming that testing capacity is fully exploited performs better. This leads to using the percent-positive rate as a more robust indicator of epidemic dynamics, however we find it is subject to a saturation phenomenon that needs to be accounted for as the number of tests becomes larger.

PanCast: Listening to Bluetooth Beacons for Epidemic Risk Mitigation (preprint)

During the ongoing COVID-19 pandemic, there have been burgeoning efforts to develop and deploy smartphone apps to expedite contact tracing and risk notification. Most of these apps track pairwise encounters between individuals via Bluetooth and then use these tracked encounters to identify and notify those who might have been in proximity of a contagious individual. Unfortunately, these apps have not yet proven sufficiently effective, partly owing to low adoption rates, but also due to the difficult tradeoff between utility and privacy and the fact that, in COVID-19, most individuals do not infect anyone but a few superspreaders infect many in superspreading events. In this paper, we proposePanCast, a privacy-preserving and inclusive system for epidemic risk assessment and notification that scales gracefully with adoption rates, utilizes location and environmental information to increase utility without tracking its users, and can be used to identify superspreading events. To this end, rather than capturing pairwise encounters between smartphones, our system utilizes Bluetooth encounters between beacons placed in strategic locations where superspreading events are most likely to occur and inexpensive, zero-maintenance, small devices that users can attach to their keyring. PanCast allows healthy individuals to use the system in a purely passive "radio" mode, and can assist and benefit from other digital and manual contact tracing systems. Finally, PanCast can be gracefully dismantled at the end of the pandemic, minimizing abuse from any malevolent government or entity.

COVI-AgentSim: an Agent-based Model for Evaluating Methods of Digital Contact Tracing (preprint)

The rapid global spread of COVID-19 has led to an unprecedented demand for effective methods to mitigate the spread of the disease, and various digital contact tracing (DCT) methods have emerged as a component of the solution. In order to make informed public health choices, there is a need for tools which allow evaluation and comparison of DCT methods. We introduce an agent-based compartmental simulator we call COVI-AgentSim, integrating detailed consideration of virology, disease progression, social contact networks, and mobility patterns, based on parameters derived from empirical research. We verify by comparing to real data that COVI-AgentSim is able to reproduce realistic COVID-19 spread dynamics, and perform a sensitivity analysis to verify that the relative performance of contact tracing methods are consistent across a range of settings. We use COVI-AgentSim to perform cost-benefit analyses comparing no DCT to: 1) standard binary contact tracing (BCT) that assigns binary recommendations based on binary test results; and 2) a rule-based method for feature-based contact tracing (FCT) that assigns a graded level of recommendation based on diverse individual features. We find all DCT methods consistently reduce the spread of the disease, and that the advantage of FCT over BCT is maintained over a wide range of adoption rates. Feature-based methods of contact tracing avert more disability-adjusted life years (DALYs) per socioeconomic cost (measured by productive hours lost). Our results suggest any DCT method can help save lives, support re-opening of economies, and prevent second-wave outbreaks, and that FCT methods are a promising direction for enriching BCT using self-reported symptoms, yielding earlier warning signals and a significantly reduced spread of the virus per socioeconomic cost.

Predicting Infectiousness for Proactive Contact Tracing (preprint)

The COVID-19 pandemic has spread rapidly worldwide, overwhelming manual contact tracing in many countries and resulting in widespread lockdowns for emergency containment. Large-scale digital contact tracing (DCT) has emerged as a potential solution to resume economic and social activity while minimizing spread of the virus. Various DCT methods have been proposed, each making trade-offs between privacy, mobility restrictions, and public health. The most common approach, binary contact tracing (BCT), models infection as a binary event, informed only by an individual's test results, with corresponding binary recommendations that either all or none of the individual's contacts quarantine. BCT ignores the inherent uncertainty in contacts and the infection process, which could be used to tailor messaging to high-risk individuals, and prompt proactive testing or earlier warnings. It also does not make use of observations such as symptoms or pre-existing medical conditions, which could be used to make more accurate infectiousness predictions. In this paper, we use a recently-proposed COVID-19 epidemiological simulator to develop and test methods that can be deployed to a smartphone to locally and proactively predict an individual's infectiousness (risk of infecting others) based on their contact history and other information, while respecting strong privacy constraints. Predictions are used to provide personalized recommendations to the individual via an app, as well as to send anonymized messages to the individual's contacts, who use this information to better predict their own infectiousness, an approach we call proactive contact tracing (PCT). We find a deep-learning based PCT method which improves over BCT for equivalent average mobility, suggesting PCT could help in safe re-opening and second-wave prevention.

Real-time Prediction of COVID-19 related Mortality using Electronic Health Records (preprint)

Coronavirus Disease 2019 (COVID-19) is an emerging respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with rapid human-to-human transmission and a high case fatality rate particularly in older patients. Due to the exponential growth of infections, many healthcare systems across the world are under pressure to care for increasing amounts of at-risk patients. Given the high number of infected patients, identifying patients with the highest mortality risk early is critical to enable effective intervention and optimal prioritisation of care. Here, we present the COVID-19 Early Warning System (CovEWS), a clinical risk scoring system for assessing COVID-19 related mortality risk. CovEWS provides continuous real-time risk scores for individual patients with clinically meaningful predictive performance up to 192 hours (8 days) in advance, and is automatically derived from patients' electronic health records (EHRs) using machine learning. We trained and evaluated CovEWS using de-identified data from a cohort of 66430 COVID-19 positive patients seen at over 69 healthcare institutions in the United States (US), Australia, Malaysia and India amounting to an aggregated total of over 2863 years of patient observation time. On an external test cohort of 5005 patients, CovEWS predicts COVID-19 related mortality from $78.8\%$ ($95\%$ confidence interval [CI]: $76.0$, $84.7\%$) to $69.4\%$ ($95\%$ CI: $57.6, 75.2\%$) specificity at a sensitivity greater than $95\%$ between respectively 1 and 192 hours prior to observed mortality events - significantly outperforming existing generic and COVID-19 specific clinical risk scores. CovEWS could enable clinicians to intervene at an earlier stage, and may therefore help in preventing or mitigating COVID-19 related mortality.

Causal analysis of Covid-19 spread in Germany (preprint)

In this work, we study the causal relations among German regions in terms of the spread of Covid-19 since the beginning of the pandemic, taking into account the restriction policies that were applied by the different federal states. We propose and prove a new theorem for a causal feature selection method for time series data, robust to latent confounders, which we subsequently apply on Covid-19 case numbers. We present findings about the spread of the virus in Germany and the causal impact of restriction measures, discussing the role of various policies in containing the spread. Since our results are based on rather limited target time series (only the numbers of reported cases), care should be exercised in interpreting them. However, it is encouraging that already such limited data seems to contain causal signals. This suggests that as more data becomes available, our causal approach may contribute towards meaningful causal analysis of political interventions on the development of Covid-19, and thus also towards the development of rational and data-driven methodologies for choosing interventions.

Bloom Origami Assays: Practical Group Testing (preprint)

We study the problem usually referred to as group testing in the context of COVID-19. Given n samples collected from patients, how should we select and test mixtures of samples to maximize information and minimize the number of tests? Group testing is a well-studied problem with several appealing solutions, but recent biological studies impose practical constraints for COVID-19 that are incompatible with traditional methods. Furthermore, existing methods use unnecessarily restrictive solutions, which were devised for settings with more memory and compute constraints than the problem at hand. This results in poor utility. In the new setting, we obtain strong solutions for small values of n using evolutionary strategies. We then develop a new method combining Bloom filters with belief propagation to scale to larger values of n (more than 100) with good empirical results. We also present a more accurate decoding algorithm that is tailored for specific COVID-19 settings. This work demonstrates the practical gap between dedicated algorithms and well-known generic solutions. Our efforts results in a new and practical multiplex method yielding strong empirical performance without mixing more than a chosen number of patients into the same probe. Finally, we briefly discuss adaptive methods, casting them into the framework of adaptive sub-modularity.

Simpson's paradox in Covid-19 case fatality rates: a mediation analysis of age-related causal effects (preprint)

We point out an instantiation of Simpson's paradox in Covid-19 case fatality rates (CFRs): comparing data of 44,672 cases from China with early reports from Italy (9th March), we find that CFRs are lower in Italy for every age group, but higher overall. This phenomenon is explained by a stark difference in case demographic between the two countries. Using this as a motivating example, we introduce basic concepts from mediation analysis and show how these can be used to quantify different direct and indirect effects when assuming a coarse-grained causal graph involving country, age, and mortality. As a case study, we then investigate total, direct, and indirect (age-mediated) causal effects between different countries and at different points in time. This allows us to separate age-related effects from others unrelated to age, and thus facilitates a more transparent comparison of CFRs across countries throughout the evolution of the Covid-19 pandemic.

Crackovid: Optimizing Group Testing (preprint)

We study the problem usually referred to as group testing in the context of COVID-19. Given $n$ samples taken from patients, how should we select mixtures of samples to be tested, so as to maximize information and minimize the number of tests? We consider both adaptive and non-adaptive strategies, and take a Bayesian approach with a prior both for infection of patients and test errors. We start by proposing a mathematically principled objective, grounded in information theory. We then optimize non-adaptive optimization strategies using genetic algorithms, and leverage the mathematical framework of adaptive sub-modularity to obtain theoretical guarantees for the greedy-adaptive method.

Quantifying the Effects of Contact Tracing, Testing, and Containment Measures in the Presence of Infection Hotspots (preprint)

Multiple lines of evidence at the individual and population level strongly suggest that infection hotspots, or superspreading events, where a single individual infects many others, play a key role in the transmission dynamics of COVID-19. However, most of the existing epidemiological models either assume or result in a Poisson distribution of the number of infections caused by a single infectious individual, often called secondary infections. As a result, these models overlook the observed overdispersion in the number of secondary infections and are unable to accurately characterize infection hotspots. In this work, we aim to fill this gap by introducing a temporal point process framework that explicitly represents sites where infection hotspots may occur. Under our model, overdispersion on the number of secondary infections emerges naturally. Moreover, using an efficient sampling algorithm, we demonstrate how to apply Bayesian optimization with longitudinal case data to estimate the transmission rate of infectious individuals at sites they visit and in their households, as well as the mobility reduction due to social distancing. Simulations using fine-grained demographic data and site locations from several cities and regions demonstrate that our framework faithfully characterizes the observed longitudinal trend of COVID-19 cases. In addition, the simulations show that our model can be used to estimate the effect of testing, contact tracing, and containment at an unprecedented spatiotemporal resolution, and reveal that these measures do not decrease overdispersion in the number of secondary infections.