Building multiscale models with PhysiBoSS, an agent-based modeling tool.

Multiscale models provide a unique tool for studying complex processes that study events occurring at different scales across space and time. In the context of biological systems, such models can simulate mechanisms happening at the intracellular level such as signaling, and at the extracellular level where cells communicate and coordinate with other cells. They aim to understand the impact of genetic or environmental deregulation observed in complex diseases, describe the interplay between a pathological tissue and the immune system, and suggest strategies to revert the diseased phenotypes. The construction of these multiscale models remains a very complex task, including the choice of the components to consider, the level of details of the processes to simulate, or the fitting of the parameters to the data. One additional difficulty is the expert knowledge needed to program these models in languages such as C++ or Python, which may discourage the participation of non-experts. Simplifying this process through structured description formalisms - coupled with a graphical interface - is crucial in making modeling more accessible to the broader scientific community, as well as streamlining the process for advanced users. This article introduces three examples of multiscale models which rely on the framework PhysiBoSS, an add-on of PhysiCell that includes intracellular descriptions as continuous time Boolean models to the agent-based approach. The article demonstrates how to easily construct such models, relying on PhysiCell Studio, the PhysiCell Graphical User Interface. A step-by-step tutorial is provided as a Supplementary Material and all models are provided at: https://physiboss.github.io/tutorial/.

Use of Individual-Based Mathematical Modelling to Understand More About Antibiotic Resistance Within-Host.

To model complex systems, individual-based models (IBMs), sometimes called "agent-based models" (ABMs), describe a simplification of the system through an adequate representation of the elements. IBMs simulate the actions and interaction of discrete individuals/agents within a system in order to discover the pattern of behavior that comes from these interactions. Examples of individuals/agents in biological systems are individual immune cells and bacteria that act independently with their own unique attributes defined by behavioral rules. In IBMs, each of these agents resides in a spatial environment and interactions are guided by predefined rules. These rules are often simple and can be easily implemented. It is expected that following the interaction guided by these rules we will have a better understanding of agent-agent interaction as well as agent-environment interaction. Stochasticity described by probability distributions must be accounted for. Events that seldom occur such as the accumulation of rare mutations can be easily modeled.Thus, IBMs are able to track the behavior of each individual/agent within the model while also obtaining information on the results of their collective behaviors. The influence of impact of one agent with another can be captured, thus allowing a full representation of both direct and indirect causation on the aggregate results. This means that important new insights can be gained and hypotheses tested.

Agent-based modeling to estimate the impact of lockdown scenarios and events on a pandemic exemplified on SARS-CoV-2.

In actual pandemic situations like COVID-19, it is important to understand the influence of single mitigation measures as well as combinations to create most dynamic impact for lockdown scenarios. Therefore we created an agent-based model (ABM) to simulate the spread of SARS-CoV-2 in an abstract city model with several types of places and agents. In comparison to infection numbers in Germany our ABM could be shown to behave similarly during the first wave. In our model, we implemented the possibility to test the effectiveness of mitigation measures and lockdown scenarios on the course of the pandemic. In this context, we focused on parameters of local events as possible mitigation measures and ran simulations, including varying size, duration, frequency and the proportion of events. The majority of changes to single event parameters, with the exception of frequency, showed only a small influence on the overall course of the pandemic. By applying different lockdown scenarios in our simulations, we could observe drastic changes in the number of infections per day. Depending on the lockdown strategy, we even observed a delayed peak in infection numbers of the second wave. As an advantage of the developed ABM, it is possible to analyze the individual risk of single agents during the pandemic. In contrast to standard or adjusted ODEs, we observed a 21% (with masks) / 48% (without masks) increased risk for single reappearing participants on local events, with a linearly increasing risk based on the length of the events.

Using electric vehicles to enhance power outage resilience - An agent-based modeling approach.

Power outages can cause severe disruption to critical infrastructure. With the predicted increase in the electrification of the transport sector, society will become even more vulnerable to the effects of power outages. While increased electric vehicle (EV) adoption will contribute to the electrification process, EVs can also offer capabilities to provide services during an outage. This paper studied the use of a fleet of EVs during the aftermath of a disaster to provide disaster relief by donating power to a shelter, delivering critical supplies and people in need, and providing transport for personnel or performing inspections. While the bulk of the past work has focused on using EVs to increase the resilience of the distribution grid, or individual buildings, to a power outage, this paper was novel in its use of an agent-based model to study EVs that are performing functions to increase the resilience of a community to an outage. The fleet of EVs were provided access to a microgrid with a solar array, one or two EV fast chargers, and three possible sizes of a storage. Useful outputs were produced and studied for such features as daily energy donated to a shelter, daily energy used at the microgrid, and the length of outages that can be supported before the energy is depleted at the microgrid. Results showed that increasing storage size at the microgrid led to substantial increases in the outage length that could be support. Additionally, it was found that focusing a fleet on delivery and transport tasks, as opposed to energy donation, could also increase the length of outages that could be supported.

Dynamic Coalition Formation among IoT Service Providers: A Systematic Exploration of IoT Dynamics Using an Agent-Based Model.

This paper introduces an Agent-Based Model (ABM) designed to investigate the dynamics of the Internet of Things (IoT) ecosystem, focusing on dynamic coalition formation among IoT Service Providers (SPs). Drawing on insights from our previous research in 5G network modeling, the ABM captures intricate interactions among devices, Mobile Network Operators (MNOs), SPs, and customers, offering a comprehensive framework for analyzing the IoT ecosystem's complexities. In particular, to address the emerging challenge of dynamic coalition formation among SPs, we propose a distributed Multi-Agent Dynamic Coalition Formation (MA-DCF) algorithm aimed at enhancing service provision and fostering collaboration. This algorithm optimizes SP coalitions, dynamically adjusting to changing demands over time. Through extensive experimentation, we evaluate the algorithm's performance, demonstrating its superiority in terms of both payoff and stability compared to three classical coalition formation algorithms: static coalition, non-overlapping coalition, and random coalition. This study significantly contributes to a deeper understanding of the IoT ecosystem's dynamics and highlights the potential benefits of dynamic coalition formation among SPs, providing valuable insights and opening future avenues for exploration.

Modeling the Impact of COVID-19 Mitigation Strategies in Pennsylvania, USA.

Purpose. To estimate the impact on mortality of nonpharmaceutical interventions (NPIs) implemented early in the COVID-19 pandemic. Methods. We implemented an agent-based modified SEIR model of COVID-19, calibrated to match death numbers reported in Pennsylvania from January 2020 to April 2021 and including representations of NPIs implemented in Pennsylvania. To investigate the impact of these strategies, we ran the calibrated model with no interventions and with varying combinations, timings, and levels of interventions. Results. The model closely replicated death outcomes data for Pennsylvania. Without NPIs, deaths in the early months of the pandemic were estimated to be much higher (67,718 deaths compared to actual 6,969). Voluntary interventions alone were relatively ineffective at decreasing mortality. Delaying implementation of interventions led to higher deaths (∼9,000 more deaths with just a 1-week delay). School closure was insufficient as a single intervention but was an important part of a combined intervention strategy. Conclusions. NPIs were effective at reducing deaths early in the COVID-19 pandemic. Agent-based models can incorporate substantial detail on infectious disease spread and the impact of mitigations. Policy Implications. The model supports the importance and effectiveness of NPIs to decrease morbidity from respiratory pathogens. This is particularly important for emerging pathogens for which no vaccines or treatments exist, but such strategies are applicable to a variety of respiratory pathogens. Highlights: Nonpharmaceutical interventions were used extensively during the early period of the COVID-19 pandemic, but their use has remained controversial.Agent-based modeling of the impact of these mitigation strategies early in the COVID-19 pandemic supports the effectiveness of nonpharmaceutical interventions at decreasing mortality.Since such interventions are not specific to a particular pathogen, they can be used to protect against any respiratory pathogen, known or emerging. They can be applied rapidly when conditions warrant.

Diffusive lensing as a mechanism of intracellular transport and compartmentalization.

While inhomogeneous diffusivity has been identified as a ubiquitous feature of the cellular interior, its implications for particle mobility and concentration at different length scales remain largely unexplored. In this work, we use agent-based simulations of diffusion to investigate how heterogeneous diffusivity affects the movement and concentration of diffusing particles. We propose that a nonequilibrium mode of membrane-less compartmentalization arising from the convergence of diffusive trajectories into low-diffusive sinks, which we call 'diffusive lensing,' is relevant for living systems. Our work highlights the phenomenon of diffusive lensing as a potentially key driver of mesoscale dynamics in the cytoplasm, with possible far-reaching implications for biochemical processes.

Long-term resilience in wastewater management: Optimizing treated wastewater allocation with a dynamic multi-agent approach.

Water scarcity poses a significant challenge to sustainable development, necessitating innovative approaches to manage limited resources efficiently. Effective water resource management involves not just the conservation and distribution of freshwater supplies but also the strategic reuse of treated wastewater (TWW). This study proposes a novel approach for the optimal allocation of treated wastewater among three key sectors (user agents): agriculture, industry, and urban green space. Recognizing the intricate interplays among these sectors, System Dynamics (SD) and Agent-Based Modeling (ABM) were integrated in a Complex Adaptive System (CAS) to capture the interactions and feedback mechanisms inherent within treated wastewater allocation systems. The Non-dominated Sorting Genetic Algorithm II (NSGA-II) serves as the optimization tool, enabling the identification of optimal allocation strategies across various management scenarios over a 25-year simulation period. Our research navigates the complexities of long-term resource management, accounting for each sector's evolving its objectives and guidelines along the whole system objectives and strategies. The outcomes demonstrate how treated wastewater can be effectively distributed to support economic and social equity -as the system objectives-while supporting agricultural and industrial growth and enhancing efficiency and social well-being -reflecting individual agent objectives-within the CAS framework. The research explores four distinct management scenarios, each prioritizing different sectors to address water resource management challenges. Notably, all four scenarios align with the strategies required by the ruler (government), providing strategic guidance to water resource managers for decision-making. The simulation results reveal a scenario where all sectors' demands are met, with Scenario 4 emerging as the most effective. Scenario 4 aligned with the objectives and guidelines of each sector, demonstrating significant improvements in the CY (Agriculture agent index; increased from 0.2 to 0.68), IGI (Industry agent index; increased from 1 to 1.63), and GAI (Urban Green Space agent index; increased from 1 to 1.23) indices over the 25-year simulation period. By providing a strategic blueprint for policymakers and stakeholders, this study contributes significantly to the discourse on sustainable water resource management, presenting a replicable model for similar contexts globally, where judicious allocation of treated wastewater is paramount for achieving harmony between human activity and ecological preservation.

Agent-based modeling of the COVID-19 pandemic in Florida.

The onset of the COVID-19 pandemic drove a widespread, often uncoordinated effort by research groups to develop mathematical models of SARS-CoV-2 to study its spread and inform control efforts. The urgent demand for insight at the outset of the pandemic meant early models were typically either simple or repurposed from existing research agendas. Our group predominantly uses agent-based models (ABMs) to study fine-scale intervention scenarios. These high-resolution models are large, complex, require extensive empirical data, and are often more detailed than strictly necessary for answering qualitative questions like "Should we lockdown?" During the early stages of an extraordinary infectious disease crisis, particularly before clear empirical evidence is available, simpler models are more appropriate. As more detailed empirical evidence becomes available, however, and policy decisions become more nuanced and complex, fine-scale approaches like ours become more useful. In this manuscript, we discuss how our group navigated this transition as we modeled the pandemic. The role of modelers often included nearly real-time analysis, and the massive undertaking of adapting our tools quickly. We were often playing catch up with a firehose of evidence, while simultaneously struggling to do both academic research and real-time decision support, under conditions conducive to neither. By reflecting on our experiences of responding to the pandemic and what we learned from these challenges, we can better prepare for future demands.

Optimizing Solid Tumor Treatment with Antibody-drug Conjugates Using Agent-Based Modeling: Considering the Role of a Carrier Dose and Payload Class.

INTRODUCTION: Antibody-drug conjugates (ADCs) show significant clinical efficacy in the treatment of solid tumors, but a major limitation to their success is poor intratumoral distribution. Adding a carrier dose improves both distribution and overall drug efficacy of ADCs, but the optimal carrier dose has not been outlined for different payload classes. OBJECTIVE: In this work, we study two carrier dose regimens: 1) matching payload potency to cellular delivery but potentially not reaching cells farther away from blood vessels, or 2) dosing to tumor saturation but risking a reduction in cell killing from a lower amount of payload delivered per cell. METHODS: We use a validated computational model to test four different payloads conjugated to trastuzumab to determine the optimal carrier dose as a function of target expression, ADC dose, and payload potency. RESULTS: We find that dosing to tumor saturation is more efficacious than matching payload potency to cellular delivery for all payloads because the increase in the number of cells targeted by the ADC outweighs the loss in cell killing on targeted cells. An important exception exists if the carrier dose reduces the payload uptake per cell to the point where all cell killing is lost. Likewise, receptor downregulation can mitigate the benefits of a carrier dose. CONCLUSIONS: Because tumor saturation and in vitro potency can be measured early in ADC design, these results provide insight into maximizing ADC efficacy and demonstrate the benefits of using simulation to guide ADC design.

Model-driven decision support: A community-based meta-implementation strategy to predict population impact.

PURPOSE: Standard tools for public health decision making such as data dashboards, trial repositories, and intervention briefs may be necessary but insufficient for guiding community leaders in optimizing local public health strategy. Predictive modeling decision support tools may be the missing link that allows community level decision makers to confidently direct funding and other resources to interventions and implementation strategies that will improve upon the status quo. METHODS: We describe a community-based model-driven decision support (MDDS) approach that requires community engagement, local data, and predictive modeling tools (agent-based modeling in our case studies) to improve decision-making on implementing strategies to address complex public health problems such as overdose deaths. We refer to our approach as a meta-implementation strategy as it provides guidance to a community on what intervention combinations and their required implementation strategies are needed to achieve desired outcomes. We use standard implementation measures including the Stages of Implementation Completion to assess adoption of this meta-implementation approach. RESULTS: Using two case studies, we illustrate how MDDS can be used to support decision making related to HIV prevention and reductions in overdose deaths at the city and county level. Even when community acceptance seems high, data acquisition and diffuse responsibility for implementing specific strategies recommended by modeling are barriers to adoption. CONCLUSIONS: MDDS has the capacity to improve community decision makers use of scientific knowledge by providing projections of the impact of intervention strategies under various scenarios. Further research is necessary to assess its effectiveness and the best strategies to implement it.

Growth-induced collective bending and kinetic trapping of cytoskeletal filaments.

Growth and turnover of actin filaments play a crucial role in the construction and maintenance of actin networks within cells. Actin filament growth occurs within limited space and finite subunit resources in the actin cortex. To understand how filament growth shapes the emergent architecture of actin networks, we developed a minimal agent-based model coupling filament mechanics and growth in a limiting subunit pool. We find that rapid filament growth induces kinetic trapping of highly bent actin filaments. Such collective bending patterns are long-lived, organized around nematic defects, and arise from competition between filament polymerization and bending elasticity. The stability of nematic defects and the extent of kinetic trapping are amplified by an increase in the abundance of the actin pool and by crosslinking the network. These findings suggest that kinetic trapping is a robust consequence of growth in crowded environments, providing a route to program shape memory in actin networks.

Agent-based approaches for biological modeling in oncology: A literature review.

CONTEXT: Computational modeling involves the use of computer simulations and models to study and understand real-world phenomena. Its application is particularly relevant in the study of potential interactions between biological elements. It is a promising approach to understand complex biological processes and predict their behavior under various conditions. METHODOLOGY: This paper is a review of the recent literature on computational modeling of biological systems. Our study focuses on the field of oncology and the use of artificial intelligence (AI) and, in particular, agent-based modeling (ABM), between 2010 and May 2023. RESULTS: Most of the articles studied focus on improving the diagnosis and understanding the behaviors of biological entities, with metaheuristic algorithms being the models most used. Several challenges are highlighted regarding increasing and structuring knowledge about biological systems, developing holistic models that capture multiple scales and levels of organization, reproducing emergent behaviors of biological systems, validating models with experimental data, improving computational performance of models and algorithms, and ensuring privacy and personal data protection are discussed.

Approximate inference for longitudinal mechanistic HIV contact network.

Network models are increasingly used to study infectious disease spread. Exponential Random Graph models have a history in this area, with scalable inference methods now available. An alternative approach uses mechanistic network models. Mechanistic network models directly capture individual behaviors, making them suitable for studying sexually transmitted diseases. Combining mechanistic models with Approximate Bayesian Computation allows flexible modeling using domain-specific interaction rules among agents, avoiding network model oversimplifications. These models are ideal for longitudinal settings as they explicitly incorporate network evolution over time. We implemented a discrete-time version of a previously published continuous-time model of evolving contact networks for men who have sex with men and proposed an ABC-based approximate inference scheme for it. As expected, we found that a two-wave longitudinal study design improves the accuracy of inference compared to a cross-sectional design. However, the gains in precision in collecting data twice, up to 18%, depend on the spacing of the two waves and are sensitive to the choice of summary statistics. In addition to methodological developments, our results inform the design of future longitudinal network studies in sexually transmitted diseases, specifically in terms of what data to collect from participants and when to do so.

Utilizing Agent-Based Modeling for Optimization of Wayfinding in Hospital: A Case Study.

OBJECTIVES: This research aims to propose a novel methodology for analyzing and optimizing wayfinding in complex environments by examining their spatial configurations. BACKGROUND: Wayfinding difficulties often lead to disorientation and hinder users' ability to locate destinations. Although architectural design can aid in simplifying user access, existing approaches lack a specific focus on wayfinding optimization despite its significant impact on users' navigational abilities. METHODS: In this study, an agent-based model was employed to assess the efficacy of wayfinding in a multistory hospital. Subsequently, the layouts were optimized, leading to the creation of a new space distribution diagram. The simulation was then repeated to examine the potential improvement in wayfinding. Data collection encompassed user types, workflow scenarios, population distribution, and user speed. RESULTS: Comparative analysis of the agent-based simulation findings before and after layout optimization revealed a decrease in total distance and time spent on the modified floor plans for all users when compared to the existing layout. This suggests that the optimized layout holds significant potential for enhancing wayfinding performance. Given the positive outcomes observed for users, this approach is particularly well suited for preliminary design stages of complex environments, where designations among user groups are less crucial or flexibility is desired. Additional advantages include the ability to generate a comprehensive simulation of users' daily workflow, which is integrated into the optimization process and considers specific requirements regarding spatial adjacency.

Towards early diagnosis of Alzheimer's disease: advances in immune-related blood biomarkers and computational approaches.

Alzheimer's disease has an increasing prevalence in the population world-wide, yet current diagnostic methods based on recommended biomarkers are only available in specialized clinics. Due to these circumstances, Alzheimer's disease is usually diagnosed late, which contrasts with the currently available treatment options that are only effective for patients at an early stage. Blood-based biomarkers could fill in the gap of easily accessible and low-cost methods for early diagnosis of the disease. In particular, immune-based blood-biomarkers might be a promising option, given the recently discovered cross-talk of immune cells of the central nervous system with those in the peripheral immune system. Here, we give a background on recent advances in research on brain-immune system cross-talk in Alzheimer's disease and review machine learning approaches, which can combine multiple biomarkers with further information (e.g. age, sex, APOE genotype) into predictive models supporting an earlier diagnosis. In addition, mechanistic modeling approaches, such as agent-based modeling open the possibility to model and analyze cell dynamics over time. This review aims to provide an overview of the current state of immune-system related blood-based biomarkers and their potential for the early diagnosis of Alzheimer's disease.

Impact of Tissue Damage and Hemodynamics on Restenosis Following Percutaneous Transluminal Angioplasty: A Patient-Specific Multiscale Model.

Multiscale agent-based modeling frameworks have recently emerged as promising mechanobiological models to capture the interplay between biomechanical forces, cellular behavior, and molecular pathways underlying restenosis following percutaneous transluminal angioplasty (PTA). However, their applications are mainly limited to idealized scenarios. Herein, a multiscale agent-based modeling framework for investigating restenosis following PTA in a patient-specific superficial femoral artery (SFA) is proposed. The framework replicates the 2-month arterial wall remodeling in response to the PTA-induced injury and altered hemodynamics, by combining three modules: (i) the PTA module, consisting in a finite element structural mechanics simulation of PTA, featuring anisotropic hyperelastic material models coupled with a damage formulation for fibrous soft tissue and the element deletion strategy, providing the arterial wall damage and post-intervention configuration, (ii) the hemodynamics module, quantifying the post-intervention hemodynamics through computational fluid dynamics simulations, and (iii) the tissue remodeling module, based on an agent-based model of cellular dynamics. Two scenarios were explored, considering balloon expansion diameters of 5.2 and 6.2 mm. The framework captured PTA-induced arterial tissue lacerations and the post-PTA arterial wall remodeling. This remodeling process involved rapid cellular migration to the PTA-damaged regions, exacerbated cell proliferation and extracellular matrix production, resulting in lumen area reduction up to 1-month follow-up. After this initial reduction, the growth stabilized, due to the resolution of the inflammatory state and changes in hemodynamics. The similarity of the obtained results to clinical observations in treated SFAs suggests the potential of the framework for capturing patient-specific mechanobiological events occurring after PTA intervention.

Integrating multiplexed imaging and multiscale modeling identifies tumor phenotype conversion as a critical component of therapeutic T cell efficacy.

Cancer progression is a complex process involving interactions that unfold across molecular, cellular, and tissue scales. These multiscale interactions have been difficult to measure and to simulate. Here, we integrated CODEX multiplexed tissue imaging with multiscale modeling software to model key action points that influence the outcome of T cell therapies with cancer. The initial phenotype of therapeutic T cells influences the ability of T cells to convert tumor cells to an inflammatory, anti-proliferative phenotype. This T cell phenotype could be preserved by structural reprogramming to facilitate continual tumor phenotype conversion and killing. One takeaway is that controlling the rate of cancer phenotype conversion is critical for control of tumor growth. The results suggest new design criteria and patient selection metrics for T cell therapies, call for a rethinking of T cell therapeutic implementation, and provide a foundation for synergistically integrating multiplexed imaging data with multiscale modeling of the cancer-immune interface. A record of this paper's transparent peer review process is included in the supplemental information.

Protective effects of antibiotic resistant bacteria on susceptibles in biofilm: Influential factors, mechanism, and modeling.

In environmental biofilms, antibiotic-resistant bacteria facilitate the persistence of susceptible counterparts under antibiotic stresses, contributing to increased community-level resistance. However, there is a lack of quantitative understanding of this protective effect and its influential factors, hindering accurate risk assessment of biofilm resistance in diverse environment. This study isolated an opportunistic Escherichia coli pathogen from soil, and engineered it with plasmids conferring antibiotic resistance. Protective effects of the ampicillin resistant strain (AmpR) on their susceptible counterparts (AmpS) were observed in ampicillin-stress colony biofilms. The concentration of ampicillin delineated protective effects into 3 zones: continuous protection (<1 MIC of AmpS), initial AmpS/R dependent (1-8 MIC of AmpS), and ineffective (>8 MIC of AmpS). Intriguingly, Zone 2 exhibited a surprising "less is more" phenomenon tuned by the initial AmpS/R ratio, where biofilm with an initially lower AmpR (1:50 vs 50:1) harbored 30-90 % more AmpR after 24 h growth under antibiotic stress. Compared to AmpS, AmpR displayed superiority in adhesion, antibiotic degradation, motility, and quorum sensing, allowing them to preferentially colonize biofilm edge and areas with higher ampicillin. An agent-based model incorporating protective effects successfully simulated tempo-spatial dynamics of AmpR and AmpS influenced by antibiotic stress and initial AmpS/R. This study provides a holistic view on the pervasive but poorly understood protective effects in biofilm, enabling development of better risk assessment and precisely targeted control strategies of biofilm resistance in diverse environment.

Agent-based modeling in cancer biomedicine: applications and tools for calibration and validation.

Computational models are not just appealing because they can simulate and predict the development of biological phenomena across multiple spatial and temporal scales, but also because they can integrate information from well-established in vitro and in vivo models and test new hypotheses in cancer biomedicine. Agent-based models and simulations are especially interesting candidates among computational modeling procedures in cancer research due to the capability to, for instance, recapitulate the dynamics of neoplasia and tumor - host interactions. Yet, the absence of methods to validate the consistency of the results across scales can hinder adoption by turning fine-tuned models into black boxes. This review compiles relevant literature that explores strategies to leverage high-fidelity simulations of multi-scale, or multi-level, cancer models with a focus on verification approached as simulation calibration. We consolidate our review with an outline of modern approaches for agent-based models' validation and provide an ambitious outlook toward rigorous and reliable calibration.