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Background In response to the ongoing COVID-19 pandemic, several countries adopted measures of social distancing to a different degree. For many countries, after successfully curbing the initial wave, lockdown measures were gradually lifted. In Belgium, such relief started on May 4th with phase 1, followed by several subsequent phases over the next few weeks. Methods We analysed the expected impact of relaxing stringent lockdown measures taken according to the phased Belgian exit strategy. We developed a stochastic, data-informed, meta-population model that accounts for mixing and mobility of the age-structured population of Belgium. The model is calibrated to daily hospitalization data and is able to reproduce the outbreak at the national level. We consider different scenarios for relieving the lockdown, quantified in terms of relative reductions in pre-pandemic social mixing and mobility. We validate our assumptions by making comparisons with social contact data collected during and after the lockdown. Results Our model is able to successfully describe the initial wave of COVID-19 in Belgium and identifies interactions during leisure/other activities as pivotal in the exit strategy. Indeed, we find a smaller impact of school re-openings as compared to restarting leisure activities and re-openings of work places. We also assess the impact of case isolation of new (suspected) infections, and find that it allows re-establishing relatively more social interactions while still ensuring epidemic control. Scenarios predicting a second wave of hospitalizations were not observed, suggesting that the per-contact probability of infection has changed with respect to the pre-lockdown period. Conclusions Contacts during leisure activities are found to be most influential, followed by professional contacts and school contacts, respectively, for an impending second wave of COVID-19. Regular re-assessment of social contacts in the population is therefore crucial to adjust to evolving behavioral changes that can affect epidemic diffusion. This work received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (PC and NH, grant number 682540 – TransMID project, PL, NH, PB grant number 101003688 – EpiPose project). SA and NH gratefully acknowledge support from the Fonds voor Wetenschappelijk Onderzoek (FWO) (RESTORE project – G0G2920N). LW received funding from the Research Foundation Flanders (1234620N). PL received funding from the Research Foundation Flanders (post-doctoral grant 1242021N). The resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the Research Foundation – Flanders (FWO) and the Flemish Government. We thank several researchers from the SIMID COVID-19 consortium from the University of Antwerp and Hasselt University for numerous constructive discussions and meetings. We thank Giulia Pullano, Laura Di Domenico and Vittoria Colizza for useful discussions. The authors are also very grateful for access to the data from the Belgian Scientific Institute for Public Health, Sciensano.

Funding Information: The research conducted by D.M.H. and N.H. in this study was funded by the Fonds Wetenschappelijk Onder-zoek—Vlaanderen (Research Foundation—Flanders; FWO, http://www.fwo.be/en/) (Grant Agreements G0E8416N and G0B2317N). The research done by J.D.S. and A.M.V. in this study has been supported in part by Grants G.0692.14 and G0B2317N, funded by the FWO, Belgium. P.J.K.L. was supported By a PhD Grant of the FWO (1S31916N), and is currently funded via a post-doctoral fellowship (1242021N) of the FWO. WD was supported by a postdoctoral fellowship from FWO (12L5816N). Research done by V.M. in this study has been completed as part of the ELTE Thematic Excellence Programme 2020 supported by the National Research, Development and Innovation Office (TKP2020-IKA-05). The authors gratefully acknowledge support from the FWO Scientific Research Community on Network Statistics for Sexually Transmitted Diseases Epidemiology. The computational resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the Research Foundation—Flanders (FWO) and the Flemish Government—department EWI. Publisher Copyright: © 2021, The Author(s). Model comparisons have been widely used to guide intervention strategies to control infectious diseases. Agreement between different models is crucial for providing robust evidence for policy-makers because differences in model properties can influence their predictions. In this study, we compared models implemented by two individual-based model simulators for HIV epidemiology in a heterosexual population with Herpes simplex virus type-2 (HSV-2). For each model simulator, we constructed four models, starting from a simplified basic model and stepwise including more model complexity. For the resulting eight models, the predictions of the impact of behavioural interventions on the HIV epidemic in Yaoundé-Cameroon were compared. The results show that differences in model assumptions and model complexity can influence the size of the predicted impact of the intervention, as well as the predicted qualitative behaviour of the HIV epidemic after the intervention. These differences in predictions of an intervention were also observed for two models that agreed in their predictions of the HIV epidemic in the absence of that intervention. Without additional data, it is impossible to determine which of these two models is the most reliable. These findings highlight the importance of making more data available for the calibration and validation of epidemiological models. publishersversion published

Outbreaks of SARS-CoV-2 are threatening the health care systems of several countries around the world. The initial control of SARS-CoV-2 epidemics relied on non-pharmaceutical interventions, such as social distancing, teleworking, mouth masks and contact tracing. However, as pre-symptomatic transmission remains an important driver of the epidemic, contact tracing efforts struggle to fully control SARS-CoV-2 epidemics. Therefore, in this work, we investigate to what extent the use of universal testing, i.e., an approach in which we screen the entire population, can be utilized to mitigate this epidemic. To this end, we rely on PCR test pooling of individuals that belong to the same households, to allow for a universal testing procedure that is feasible with the limited testing capacity. We evaluate two isolation strategies: on the one hand pool isolation, where we isolate all individuals that belong to a positive PCR test pool, and on the other hand individual isolation, where we determine which of the individuals that belong to the positive PCR pool are positive, through an additional testing step. We evaluate this universal testing approach in the STRIDE individual-based epidemiological model in the context of the Belgian COVID-19 epidemic. As the organisation of universal testing will be challenging, we discuss the different aspects related to sample extraction and PCR testing, to demonstrate the feasibility of universal testing when a decentralized testing approach is used. We show through simulation, that weekly universal testing is able to control the epidemic, even when many of the contact reductions are relieved. Finally, our model shows that the use of universal testing in combination with stringent contact reductions could be considered as a strategy to eradicate the virus., Author summary As pre-symptomatic transmission is an important driver of COVID-19 epidemics (i.e., the virus is transmitted before the infected individual is aware of its infection), contact tracing efforts struggle to fully control SARS-CoV-2 epidemics. For this reason, the use of universal testing, where each individual of the community is tested on a regular basis, has been suggested. However, the large amount of PCR tests that is required to facilitate this approach, remains an important impediment. Therefore, we propose a new universal testing procedure that is feasible with the current testing capacity, where we rely on PCR test pooling of individuals that belong to the same households. We evaluate this universal testing procedure in a fine-grained epidemiological model (i.e., an individual-based model) that covers the Belgian population. Through this evaluation, we assess the procedure’s performance to keep the epidemic under control, while allowing for various contact reductions. We assess the robustness of the model, by analysing different levels of community compliance, and we show that weekly universal testing could prove a successful strategy to control SARS-CoV-2 outbreaks.

The SARS-CoV-2 pathogen is currently spreading worldwide and its propensity for presymptomatic and asymptomatic transmission makes it difficult to control. The control measures adopted in several countries aim at isolating individuals once diagnosed, limiting their social interactions and consequently their transmission probability. These interventions, which have a strong impact on the disease dynamics, can affect the inference of the epidemiological quantities. We first present a theoretical explanation of the effect caused by non-pharmaceutical intervention measures on the mean serial and generation intervals. Then, in a simulation study, we vary the assumed efficacy of control measures and quantify the effect on the mean and variance of realized generation and serial intervals. The simulation results show that the realized serial and generation intervals both depend on control measures and their values contract according to the efficacy of the intervention strategies. Interestingly, the mean serial interval differs from the mean generation interval. The deviation between these two values depends on two factors. First, the number of undiagnosed infectious individuals. Second, the relationship between infectiousness, symptom onset and timing of isolation. Similarly, the standard deviations of realized serial and generation intervals do not coincide, with the former shorter than the latter on average. The findings of this study are directly relevant to estimates performed for the current COVID-19 pandemic. In particular, the effective reproduction number is often inferred using both daily incidence data and the generation interval. Failing to account for either contraction or mis-specification by using the serial interval could lead to biased estimates of the effective reproduction number. Consequently, this might affect the choices made by decision makers when deciding which control measures to apply based on the value of the quantity thereof., Author summary The generation and serial intervals are epidemiological quantities used to describe and predict an ongoing epidemic outbreak. These quantities are related to the contact pattern of individuals, since infection events can take place if infectious and susceptible individuals have a contact. Therefore, intervention measures that reduce the interactions between members of the population are expected to affect both the realized generation and serial intervals. For the current COVID-19 pandemic unprecedented interventions have been adopted worldwide, e.g. strict lockdown, isolation and quarantine, which influence the realized value of generation and serial intervals. The extent of the effect thereof depends on the efficacy of the control measure in place, on the relationship between symptom onset and infectiousness and on the proportion of infectious individuals that can be detected. To get more insight on this, we present an investigation that highlights the effect of quarantine and isolation on realized generation and serial intervals. In particular, we show that not only their variances but also their mean values can differ, suggesting that the use of the mean serial interval as a proxy for the mean generation time can lead to biased estimates of epidemiological quantities.

In interactive multi-objective reinforcement learning (MORL), an agent has to simultaneously learn about the environment and the preferences of the user, in order to quickly zoom in on those decisions that are likely to be preferred by the user. In this paper we study interactive MORL in the context of multi-objective multi-armed bandits. Contrary to earlier approaches to interactive MORL that force the utility of the user to be expressed as a weighted sum of the values for each objective, we do not make such stringent a priori assumptions. Specifically, we not only allow non-linear preferences, but also obviate the need to specify the exact model class in the utility function must fall. To achieve this, we propose a new approach called Gaussian-process Utility Thompson Sampling (GUTS). GUTS employs parameterless Bayesian learning to allow any type of utility function, exploits monotonicity information, and limits the number of queries posed to the user by ensuring that questions are statistically significant. We show empirically that GUTS can learn non-linear preferences, and that the regret and number of queries posed to the user are highly sub-linear in the number of arm pulls. (A preliminary version of this work was presented at the ALA workshop in 2018 [20]).

Epidemics of infectious diseases are an important threat to public health and global economies. Yet, the development of prevention strategies remains a challenging process, as epidemics are non-linear and complex processes. For this reason, we investigate a deep reinforcement learning approach to automatically learn prevention strategies in the context of pandemic influenza. Firstly, we construct a new epidemiological meta-population model, with 379 patches (one for each administrative district in Great Britain), that adequately captures the infection process of pandemic influenza. Our model balances complexity and computational efficiency such that the use of reinforcement learning techniques becomes attainable. Secondly, we set up a ground truth such that we can evaluate the performance of the 'Proximal Policy Optimization' algorithm to learn in a single district of this epidemiological model. Finally, we consider a large-scale problem, by conducting an experiment where we aim to learn a joint policy to control the districts in a community of 11 tightly coupled districts, for which no ground truth can be established. This experiment shows that deep reinforcement learning can be used to learn mitigation policies in complex epidemiological models with a large state space. Moreover, through this experiment, we demonstrate that there can be an advantage to consider collaboration between districts when designing prevention strategies.

Multi-agent coordination is prevalent in many real-world applications. However, such coordination is challenging due to its combinatorial nature. An important observation in this regard is that agents in the real world often only directly affect a limited set of neighbouring agents. Leveraging such loose couplings among agents is key to making coordination in multi-agent systems feasible. In this work, we focus on learning to coordinate. Specifically, we consider the multi-agent multi-armed bandit framework, in which fully cooperative loosely-coupled agents must learn to coordinate their decisions to optimize a common objective. We propose multi-agent Thompson sampling (MATS), a new Bayesian exploration-exploitation algorithm that leverages loose couplings. We provide a regret bound that is sublinear in time and low-order polynomial in the highest number of actions of a single agent for sparse coordination graphs. Additionally, we empirically show that MATS outperforms the state-of-the-art algorithm, MAUCE, on two synthetic benchmarks, and a novel benchmark with Poisson distributions. An example of a loosely-coupled multi-agent system is a wind farm. Coordination within the wind farm is necessary to maximize power production. As upstream wind turbines only affect nearby downstream turbines, we can use MATS to efficiently learn the optimal control mechanism for the farm. To demonstrate the benefits of our method toward applications we apply MATS to a realistic wind farm control task. In this task, wind turbines must coordinate their alignments with respect to the incoming wind vector in order to optimize power production. Our results show that MATS improves significantly upon state-of-the-art coordination methods in terms of performance, demonstrating the value of using MATS in practical applications with sparse neighbourhood structures., SCOPUS: ar.j, info:eu-repo/semantics/published

BackgroundThe rising COVID-19 pandemic caused many governments to impose policies restricting social interactions. These policies have slowed down the spread of the SARS-CoV-2 virus to the extent that restrictions can be gradually lifted. Models can be useful to assess the consequences of deconfinement strategies with respect to business, school and leisure activities.MethodsWe adapted the individual-based model “STRIDE” to simulate interactions between the 11 million inhabitants of Belgium at the levels of households, workplaces, schools and communities. We calibrated our model to observed hospital incidence and seroprevalence data. STRIDE can explore contact tracing options and account for repetitive leisure contacts in extended household settings (so called “household bubbles”) with varying levels of connectivity.FindingsHousehold bubbles have the potential to reduce the number of COVID-19 hospital admissions by up to 90%. The effectiveness of contact tracing depends on its timing, as it becomes futile more than 4 days after the index case developed symptoms. Assuming that children have a lower level of susceptibility and lower probability to experience symptomatic SARS-CoV-2 infection, (partial) school closure options have relatively little impact on COVID-19 burden.InterpretationNot only the absolute number and intensity of physical contacts drive the transmission dynamics and COVID-19 burden, also their repetitiveness is influential. Contact tracing seems essential for a controlled and persistent release of lockdown measures, but requires timely compliance to testing, reporting and self-isolation. Rapid tracing and testing, and communication ensuring continued involvement of the population are therefore essential.

Background: Current outbreaks of COVID-19 are threatening the health care systems of several countries around the world. Control measures, based on isolation, contact tracing, and quarantine, can decrease and delay the burden of the ongoing epidemic. With respect to the ongoing COVID-19 epidemic, recent modeling work shows that these interventions may be inadequate to control local outbreaks, even when perfect isolation is assumed. The effect of infectiousness prior to symptom onset combined with asymptomatic infectees further complicates the use of contact tracing. We aim to study whether antivirals, which decrease the viral load and reduce infectiousness, could be integrated into control measures in order to augment the feasibility of controlling the epidemic. Methods: Using a simulation-based model of viral transmission, we tested the efficacy of different intervention measures to control local COVID-19 outbreaks. For individuals that were identified through contact tracing, we evaluate two procedures: monitoring individuals for symptoms onset and testing of individuals. Additionally, we investigate the implementation of an antiviral compound combined with the contact tracing process. Results: For an infectious disease in which asymptomatic and presymptomatic infections are plausible, an intervention measure based on contact tracing performs better when combined with testing instead of monitoring, provided that the test is able to detect infections during the incubation period. Antiviral drugs, in combination with contact tracing, quarantine, and isolation, result in a significant decrease of the final size and the peak incidence, and increase the probability that the outbreak will fade out. Conclusion: In all tested scenarios, the model highlights the benefits of control measures based on the testing of traced individuals. In addition, the administration of an antiviral drug, together with quarantine, isolation, and contact tracing, is shown to decrease the spread of the epidemic. This control measure could be an effective strategy to control local and re-emerging outbreaks of COVID-19. This work is funded by the EpiPose project from the European Union's SC1-PHE-CORONAVIRUS-2020 programme, project number 101003688, by the European Union's Horizon 2020 research and innovation programme (grant agreement 682540-TransMID), the European Union's Horizon 2020 research and innovation program under grant agreement no. 101003627 (SCORE project), and the Stichting Antoine Faes. A.T. acknowledges support from the special research fund of the University of Antwerp. P.L. was supported by funding from the Flemish Government under the "Onderzoeksprogramma Artificiele Intelligentie (AI) Vlaanderen" programme. Hens, N (corresponding author), Univ Antwerp, Ctr Hlth Econ Res & Modelling Infect Dis, Antwerp, Belgium; Hasselt Univ, Interuniv Inst Biostatist & Stat Bioinformat, Data Sci Inst, Hasselt, Belgium. niel.hens@uhasselt.be

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel virus of the family Coronaviridae. The virus causesthe infectious disease COVID-19. The biology of coronaviruses has been studied for many years. However, bioinformaticstools designed explicitly for SARS-CoV-2 have only recently been developed as a rapid reaction to the need for fast detection,understanding and treatment of COVID-19. To control the ongoing COVID-19 pandemic, it is of utmost importance to getinsight into the evolution and pathogenesis of the virus. In this review, we cover bioinformatics workflows and tools for theroutine detection of SARS-CoV-2 infection, the reliable analysis of sequencing data, the tracking of the COVID-19 pandemicand evaluation of containment measures, the study of coronavirus evolution, the discovery of potential drug targets anddevelopment of therapeutic strategies. For each tool, we briefly describe its use case and how it advances researchspecifically for SARS-CoV-2. Fil: Hufsky, Franziska. Friedrich Schiller University Jena; Alemania Fil: Lamkiewicz, Kevin. Friedrich Schiller University Jena; Alemania Fil: Almeida, Alexandre. the Wellcome Sanger Institute; Reino Unido Fil: Aouacheria, Abdel. Centre National de la Recherche Scientifique; Francia Fil: Arighi, Cecilia. Biocuration and Literature Access at PIR; Estados Unidos Fil: Bateman, Alex. European Bioinformatics Institute. Head of Protein Sequence Resources; Reino Unido Fil: Baumbach, Jan. Universitat Technical Zu Munich; Alemania Fil: Beerenwinkel, Niko. Universitat Technical Zu Munich; Alemania Fil: Brandt, Christian. Jena University Hospital; Alemania Fil: Cacciabue, Marco Polo Domingo. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación En Ciencias Veterinarias y Agronómicas. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Agrobiotecnología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Chuguransky, Sara Rocío. European Bioinformatics Institute; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Drechsel, Oliver. Robert Koch-Institute; Alemania Fil: Finn, Robert D.. Biocurator for Pfam and InterPro databases; Reino Unido Fil: Fritz, Adrian. Helmholtz Centre for Infection Research; Alemania Fil: Fuchs, Stephan. Robert Koch-Institute; Alemania Fil: Hattab, Georges. University Marburg; Alemania Fil: Hauschild, Anne Christin. University Marburg; Alemania Fil: Heider, Dominik. University Marburg; Alemania Fil: Hoffmann, Marie. Freie Universität Berlin; Alemania Fil: Hölzer, Martin. Friedrich Schiller University Jena; Alemania Fil: Hoops, Stefan. University of Virginia; Estados Unidos Fil: Kaderali, Lars. University Medicine Greifswald; Alemania Fil: Kalvari, Ioanna. European Bioinformatics Institute; Reino Unido Fil: von Kleist, Max. Robert Koch-Institute; Alemania Fil: Kmiecinski, Renó. Robert Koch-Institute; Alemania Fil: Kühnert, Denise. Max Planck Institute for the Science of Human History; Alemania Fil: Lasso, Gorka. Albert Einstein College of Medicine; Estados Unidos Fil: Libin, Pieter. Hasselt University; Bélgica Fil: List, Markus. Universitat Technical Zu Munich; Alemania Fil: Löchel, Hannah F.. University Marburg; Alemania

BackgroundTreatment for all recommendations has allowed access to antiretroviral (ARV) treatment to an increasing number of patients. This minimizes transmission of infection but can potentiate the risk for development of transmitted drug resistance (TDR) and acquired drug resistance (ADR).ObjectiveTo study the trends of TDR and ADR in patients followed in Portuguese hospitals between 2001 and 2017.Method11911 patients of the Portuguese REGA database were included. TDR was defined as the presence of one or more surveillance drug resistance mutations according to the WHO surveillance list. Phenotypic resistance to ARV was evaluated with Standford HIVdb v7.0. Patterns of TDR, ADR and prevalence of mutations over time were analysed with logistic regression.ResultsThe prevalence of TDR increased from 7.9% in 2003 to 13.1% in 2017 (pfor-trendfor-trend=0.002) and 2.9% to 8.9% (pfor-trendfor-trend=0.985). Paradoxically, the prevalence of ADR declined from 86.6% in 2001 to 51.0% in 2017 (pfor-trendfor-trendConclusionsWhile ADR is declining since 2001, TDR has been increasing, reaching a value of 13.1% by the end of 2017. It is urgent to develop public health programs to monitor levels and patterns of TDR in newly diagnosed patients.

Migration is associated with HIV-1 vulnerability. Objectives: To identify long-term trends in HIV-1 molecular epidemiology and antiretroviral drug resistance (ARV) among migrants followed up in Portugal Methods: 5177 patients were included between 2001 and 2017. Rega, Scuel, Comet, and jPHMM algorithms were used for subtyping. Transmitted drug resistance (TDR) and Acquired drug resistance (ADR) were defined as the presence of surveillance drug resistance mutations (SDRMs) and as mutations of the IAS-USA 2015 algorithm, respectively. Statistical analyses were performed. Results: HIV-1 subtypes infecting migrants were consistent with the ones prevailing in their countries of origin. Over time, overall TDR significantly increased and specifically for Non-nucleoside reverse transcriptase inhibitor (NNRTIs) andNucleoside reverse transcriptase inhibitor (NRTIs). TDR was higher in patients from Mozambique. Country of origin Mozambique and subtype B were independently associated with TDR. Overall, ADR significantly decreased over time and specifically for NRTIs and Protease Inhibitors (PIs). Age, subtype B, and viral load were independently associated with ADR. Conclusions: HIV-1 molecular epidemiology in migrants suggests high levels of connectivity with their country of origin. The increasing levels of TDR in migrants could indicate an increase also in their countries of origin, where more efficient surveillance should occur., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction: Treatment for All recommendations have allowed access to antiretroviral (ARV) treatment for an increasing number of patients. This minimizes the transmission of infection but can potentiate the risk of transmitted (TDR) and acquired drug resistance (ADR). Objective: To study the trends of TDR and ADR in patients followed up in Portuguese hospitals between 2001 and 2017. Methods: In total, 11,911 patients of the Portuguese REGA database were included. TDR was defined as the presence of one or more surveillance drug resistance mutation according to the WHO surveillance list. Genotypic resistance to ARV was evaluated with Stanford HIVdb v7.0. Patterns of TDR, ADR and the prevalence of mutations over time were analyzed using logistic regression. Results and Discussion: The prevalence of TDR increased from 7.9% in 2003 to 13.1% in 2017 (p &lt, 0.001). This was due to a significant increase in both resistance to nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleotide reverse transcriptase inhibitors (NNRTIs), from 5.6% to 6.7% (p = 0.002) and 2.9% to 8.9% (p &lt, 0.001), respectively. TDR was associated with infection with subtype B, and with lower viral load levels (p &lt, 0.05). The prevalence of ADR declined from 86.6% in 2001 to 51.0% in 2017 (p &lt, 0.001), caused by decreasing drug resistance to all antiretroviral (ARV) classes (p &lt, 0.001). Conclusions: While ADR has been decreasing since 2001, TDR has been increasing, reaching a value of 13.1% by the end of 2017. It is urgently necessary to develop public health programs to monitor the levels and patterns of TDR in newly diagnosed patients.