Mathematical Modeling Framework Research Articles

Modeling ncRNA-Mediated Circuits in Cell Fate Decision: From Systems Biology to Synthetic Biology.

Noncoding RNAs (ncRNAs) play critical roles in essential cell fate decisions. However, the exact molecular mechanisms underlying ncRNA-mediated bistable switches remain elusive and controversial. In recent years, systematic mathematical and quantitative experimental analyses have made significant contributions to elucidating the molecular mechanisms of controlling ncRNA-mediated cell fate decision processes. In this chapter, we review and summarize the general framework of mathematical modeling of ncRNA in a pedagogical way and the application of this general framework to real biological processes. We discuss the emerging properties resulting from the reciprocal regulation between mRNA, miRNA, and competing endogenous mRNA (ceRNA). We also explore the efforts within the synthetic biology approach to understand the fundamental design principles underlying cell fate decisions. Both the positive feedback loops between ncRNAs and transcription factors and the emerging properties from the miRNA-mRNA reciprocal regulation enable bistable switches to direct cell fate decisions.

An enthalpy-based model for the physics of ice-crystal icing

Ice-crystal icing (ICI) in aircraft engines is a major threat to flight safety. Due to the complex thermodynamic and phase-change conditions involved in ICI, rigorous modelling of the accretion process remains limited. The present study proposes a novel modelling approach based on the physically observed mixed-phase nature of the accretion layers. The mathematical model, which is derived from the enthalpy change after accretion (the enthalpy model), is compared with an existing pure-phase layer model (the three-layer model). Scaling laws and asymptotic solutions are developed for both models. The onset of ice accretion, the icing layer thickness and solid ice fraction within the layer are determined by a set of non-dimensional parameters including the Péclet number, the Stefan number, the Biot number, the melt ratio and the evaporative rate. Thresholds for freezing and non-freezing conditions are developed. The asymptotic solutions present good agreement with numerical solutions at low Péclet numbers. Both the asymptotic and numerical solutions show that, when compared with the three-layer model, the enthalpy model presents a thicker icing layer and a thicker water layer above the substrate due to mixed-phased features and modified Stefan conditions. Modelling in terms of the enthalpy poses significant advantages in the development of numerical methods to complex three-dimensional geometrical and flow configurations. These results improve understanding of the accretion process and provide a novel, rigorous mathematical framework for accurate modelling of ICI.

Mathematical modeling framework enhances clinical trial design for maintenance treatment in oncology

Clinical trials are costly and time-intensive endeavors, with a high rate of drug candidate failures. Moreover, the standard approaches often evaluate drugs under a limited number of protocols. In oncology, where multiple treatment protocols can yield divergent outcomes, addressing this issue is crucial. Here, we present a computational framework that simulates clinical trials through a combination of mathematical and statistical models. This approach offers a means to explore diverse treatment protocols efficiently and identify optimal strategies for oncological drug administration. We developed a computational framework with a stochastic mathematical model as its core, capable of simulating virtual clinical trials closely recapitulating the clinical scenarios. Testing our framework on the landmark SOLO-1 clinical trial investigating Poly-ADP-Ribose Polymerase maintenance treatment in high-grade serous ovarian cancer, we demonstrate that managing toxicity through treatment interruptions or dose reductions does not compromise treatment’s clinical benefits. Additionally, we provide evidence suggesting that further reduction of hematological toxicity could significantly improve the clinical outcomes. The value of this computational framework lies in its ability to expedite the exploration of new treatment protocols, delivering critical insights pivotal to shaping the landscape of upcoming clinical trials.

Leveraging mathematical modeling framework to guide regimen strategy for phage therapy

Bacteriophage (phage) cocktail therapy has been relied upon more and more to treat antibiotic-resistant infections. Understanding of the complex kinetics between phages, target bacteria, and the emergence of phage resistance remain hurdles to successful clinical outcomes. Building upon previous mathematical concepts, we develop biologically-motivated nonlinear ordinary differential equation models to explore single, cocktail, and sequential phage treatment modalities. While the optimal pairwise phage treatment strategy was the double simultaneous administration of two highly potent and asymmetrically binding phage strains, it appears unable to prevent the evolution of resistance. This treatment regimen did have a greater lysis efficiency, promoted higher phage population sizes, reduced bacterial density the most, and suppressed the evolution of resistance the longest compared to all other treatments strategies tested. Conversely, the combination of phages with polar potencies allows the more efficiently replicating phages to monopolize susceptible host cells, thereby quickly negating the intended compounding effect of cocktails. Together, we demonstrate that a biologically-motivated modeling-based framework can be leveraged to quantify the effects of each phage’s properties to more precisely predict treatment responses.

Cellular diffusion processes in singularly perturbed domains

There are many processes in cell biology that can be modeled in terms of particles diffusing in a two-dimensional (2D) or three-dimensional (3D) bounded domain Ω⊂Rd\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varOmega \\subset {\\mathbb {R}}^d$$\\end{document} containing a set of small subdomains or interior compartments Uj\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\mathcal {U}}_j$$\\end{document}, j=1,…,N\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$j=1,\\ldots ,N$$\\end{document} (singularly-perturbed diffusion problems). The domain Ω\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varOmega $$\\end{document} could represent the cell membrane, the cell cytoplasm, the cell nucleus or the extracellular volume, while an individual compartment could represent a synapse, a membrane protein cluster, a biological condensate, or a quorum sensing bacterial cell. In this review we use a combination of matched asymptotic analysis and Green’s function methods to solve a general type of singular boundary value problems (BVP) in 2D and 3D, in which an inhomogeneous Robin condition is imposed on each interior boundary ∂Uj\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\partial {\\mathcal {U}}_j$$\\end{document}. This allows us to incorporate a variety of previous studies of singularly perturbed diffusion problems into a single mathematical modeling framework. We mainly focus on steady-state solutions and the approach to steady-state, but also highlight some of the current challenges in dealing with time-dependent solutions and randomly switching processes.

Mathematical modelling of a flexible steering robot for vehicle trajectory control

Abstract This paper presents a mathematical modelling framework for a novel design of a steering robot to control vehicle trajectory. A systematic approach is adopted to capture the dynamics of a belt transmission mechanical system of the robot. The steering robot is powered by a Brushless Direct Current (BLDC) servo motor which employs a Field Oriented Current (FOC) control for motor position control. The system’s accuracy is demonstrated through simulations conducted using MATLAB SIMULINK, showcasing its capability to effectively track the reference steering angle.

Проблемы поиска и преследования беспилотных летательных аппаратов с использованием теоретико-игрового подхода

Currently, the application of mathematical modeling theory is widely used in various fields and, among other things, can be used to prevent illegal actions. This study examines scenarios involving a single pursuer tracking a single evader, as well as situations involving multiple pursuers pursuing multiple evaders. The authors formulate this problem as a search and pursuit problem for four-rotor unmanned aerial vehicles (UAVs) or quadcopters. The solution to the problem is based on game theory, as it provides a mathematical framework for modeling and studying strategic interactions involving multiple decision makers. The authors consider a game where the set of strategies of the runner is the set of possible combinations of speeds and directions of his movement, and the set of strategies of the pursuer is the set of all possible permutations of the elements of his speeds. The matrix of the resulting game consists of elements that are the time of capture. A mathematical problem on the optimal assignments of searching and pursuing unmanned aerial vehicles is formulated and solved. Purpose: optimizing the effectiveness of strategies for detecting and capturing four-rotor unmanned aerial vehicles (quadcopters). Methods: methods of mathematical modeling, game theory apparatus, Hungarian method of solving the problem of assignments, decision theory, the principle of dynamic programming, the Maple package for solving examples were used. Results: In order to fulfill the conditions for solving the problem of optimal assignments, it is necessary and sufficient that it is balanced. This assignment problem can be balanced by entering the required number of fictitious boats or escaping boats. After that, it is possible to formulate and solve the dual problem of optimal appointments. The resulting game can be solved by any method of solving matrix games. In this way, it is possible to determine the policy of harassment and search between drones. Practical importance: All escaped quadcopter UAVs can be chased and successfully intercepted using the developed models. Examples of the study of mathematical models using the Maple software package are given.

TIP: A trust inference and propagation model in multi-human multi-robot teams

Trust is a crucial factor for effective human–robot teaming. Existing literature on trust modeling predominantly focuses on dyadic human-autonomy teams where one human agent interacts with one robot. There is little, if not no, research on trust modeling in teams consisting of multiple human and robotic agents. To fill this important research gap, we present the Trust Inference and Propagation (TIP) model to model and estimate human trust in multi-human multi-robot teams. In a multi-human multi-robot team, we postulate that there exist two types of experiences that a human agent has with a robot: direct and indirect experiences. The TIP model presents a novel mathematical framework that explicitly accounts for both types of experiences. To evaluate the model, we conducted a human-subject experiment with 15 pairs of participants (N=30\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$N=30$$\\end{document}). Each pair performed a search and detection task with two drones. Results show that our TIP model successfully captured the underlying trust dynamics and significantly outperformed a baseline model. To the best of our knowledge, the TIP model is the first mathematical framework for computational trust modeling in multi-human multi-robot teams.

Data-driven corporate growth: A dynamic financial modelling framework for strategic agility

This research aimed to develop a Dynamic Financial Growth Model (DFGM) to enhance corporate growth by promoting strategic agility through data-driven decision-making. The main objective was to optimize corporate value by integrating real-time data, dynamic decision-making, risk management, and scenario analysis. The research employed a mathematical modelling framework that combined predictive analytics, real options theory, and scenario-based optimization to represent dynamic corporate financial decisions. The numerical example demonstrated how the model adjusts strategic decisions in response to changes in market data and evaluates corporate value under optimistic, pessimistic, and baseline scenarios. The main results indicated that the DFGM is effective in optimizing corporate value by allowing for continuous adjustments and strategic flexibility, distinguishing itself from traditional static financial models that lack real-time adaptability. The findings highlighted the value of incorporating risk constraints and scenario analysis, resulting in a balanced approach that manages both growth and uncertainty. However, the study identified limitations, including the need for empirical validation, more complex predictive analytics, and accounting for behavioral factors affecting decision-making. The conclusion emphasizes that the DFGM provides an adaptable and data-driven framework that enhances corporate strategic agility, making it a valuable tool for managing growth in rapidly changing environments, while also suggesting future research to refine the model's practical application

The Impact of Enterprise Digital Transformation on Low-Carbon Supply Chains: Empirical Evidence from China

The vigorous development of the digital economy, alongside the collaborative promotion of enterprise digital transformation and low-carbon supply chains, has emerged as a critical pathway for achieving green and high-quality development in enterprises. In this paper, we utilize a mathematical model framework to empirically investigate the mechanisms and impacts of enterprise digital transformation on the low-carbon effect of supply chains, employing data from A-share-listed companies spanning 2011 to 2021. The findings indicate that (1) enhancing the degree of enterprise digital transformation can significantly decrease the carbon emission intensity of upstream suppliers, thereby promoting low-carbon supply chains. (2) “Innovation-driven” and “structural transformation” mechanisms are vital channels by which enterprise digital transformation promotes carbon reduction in supply chains. (3) The diffusion mechanism effect and demonstration effect exhibit heterogeneity in the process of enterprise digital transformation, driving low-carbon emission reductions in supply chains.

Investigation of Fractional Order Tumor Cell Concentration Equation Using Finite Difference Method

المعادلة التفاضلية الكسرية توفر إطارًا رياضيًا قويًا لنمذجة وفهم مجموعة واسعة من الظواهر المعقدة وغير المحلية والمعتمدة على الذاكرة في مختلف التطبيقات العلمية والهندسية والعالمية. تعد الاعتلالات الكبدية أورامًا سرطانية ثانوية تتطور في الكبد نتيجة انتشار خلايا السرطان منورام سرطاني أصلي ينشأ في جزء آخر من جسم الإنسان. التركيز الأساسي لهذه الدراسة هو فهم نمو الأورام في الكبد البشري، سواء بوجود أو بدون علاج دوائي. ولتحقيق ذلك، يتم استخدام معادلة تفاضلية جزئية معرفة بالترتيب الزمني والكسري، ويتم تحليلها باستخدام أساليب عددية. يتم استخدام المشتقة كابوتو لاستكشاف تأثير العلاج الدوائي على نمو الورم. لحل النموذج الرياضي عدديًا، تم تطوير طريقة الفروق المحدودة كرانك-نيكولسون. يتم اختيار هذه الطريقة بسبب خصائصها المميزة، بما في ذلك الاستقرار الغير مشروط والدقة من الدرجة الثانية في الأبعاد الزمنية والمكانية. الاستقرار والدقة التي توفرهما هاتان الخصائص أمران حاسمان لضمان موثوقية النتائج المحصلة في هذه البحث. يتم تقديم النتائج والتحققات المستمدة من هذه الدراسة بفعالية من خلال تمثيلات بصرية متنوعة. تعتبر هذه الوسائل البصرية أدوات لا غنى عنها لفهم التأثير العميق للعلاج الدوائي على نمو الأورام. من خلال هذا التمثيل البصري، يمكن للشخص الحصول على فهم أوضح وأكثر تفصيلًا للديناميات المعقدة التي تحدث. تم الوصول إلى الحل العددي لهذه المشكلة المعقدة من خلال تنفيذ خوارزميات تم تطويرها بدقة باستخدام لغة البرمجة بايثون المتعددة الاستخدامات والقوية. مرونة بايثون والمكتبات الشاملة وإمكانيات الحساب العددي القوية تجعلها الخيار المثالي للتعامل مع تعقيدات هذه الدراسة.

Dynamic Operations of a Mobile Charging Crowdsourcing Platform

This paper investigates the operation of a novel electric vehicles (EVs) charging service mode, that is, crowdsourced mobile charging service for EVs, whereby a crowdsourcing platform is established to arrange suppliers (crowdsourced chargers) to deliver charging service to customers’ electric vehicles (parked EVs) at low-battery levels. From the platform operator’s perspective, we aim to determine the optimal operation strategies for mobile charging crowdsourcing platforms to achieve specific objectives. A mathematical modeling framework is developed to capture the interactions among supply, demand, and service operations in the crowdsourced mobile charging market. To design an efficient solution method to solve the formulated model, we first analyze the model properties by rigorously proving that a crucial variable set for operating the mobile charging crowdsourcing system includes charging price, commission control, and period-specific aggregate demand control. Besides, we provide both an equivalent condition and a necessary condition for checking the feasibility of these crucial variables. On top of this, we construct a search tree according to the operation periods in a day to solve the optimal operation strategies, wherein a nondominated principle is adopted as an accelerating technique in the searching process. The solution obtained from the proposed solution algorithm is proved to be sufficiently close to the actual global optimal solutions of the formulated model up to the resolution of the discretization scheme adopted. Numerical examples provide evidence verifying the model’s validity and the solution method’s efficiency. Overall, the research outcome of this work can offer service operators structured and valuable guidelines for operating mobile charging crowdsourcing platforms. Funding: This work was supported by the Singapore Ministry of Education [Grant RG124/21]. Supplemental Material: The online appendices are available at https://doi.org/10.1287/trsc.2023.0126 .

Understanding patient-derived tumor organoid growth through an integrated imaging and mathematical modeling framework.

Patient-derived tumor organoids (PDTOs) are novel cellular models that maintain the genetic, phenotypic and structural features of patient tumor tissue and are useful for studying tumorigenesis and drug response. When integrated with advanced 3D imaging and analysis techniques, PDTOs can be used to establish physiologically relevant high-throughput and high-content drug screening platforms that support the development of patient-specific treatment strategies. However, in order to effectively leverage high-throughput PDTO observations for clinical predictions, it is critical to establish a quantitative understanding of the basic properties and variability of organoid growth dynamics. In this work, we introduced an innovative workflow for analyzing and understanding PDTO growth dynamics, by integrating a high-throughput imaging deep learning platform with mathematical modeling, incorporating flexible growth laws and variable dormancy times. We applied the workflow to colon cancer organoids and demonstrated that organoid growth is well-described by the Gompertz model of growth. Our analysis showed significant intrapatient heterogeneity in PDTO growth dynamics, with the initial exponential growth rate of an organoid following a lognormal distribution within each dataset. The level of intrapatient heterogeneity varied between patients, as did organoid growth rates and dormancy times of single seeded cells. Our work contributes to an emerging understanding of the basic growth characteristics of PDTOs, and it highlights the heterogeneity in organoid growth both within and between patients. These results pave the way for further modeling efforts aimed at predicting treatment response dynamics and drug resistance timing.

Cyber-Physical Distributed Intelligent Motor Fault Detection.

This research paper explores the realm of fault detection in distributed motors through the vision of the Internet of electrical drives. This paper aims at employing artificial neural networks supported by the data collected by the Internet of distributed devices. Cross-verification of results offers reliable diagnosis of industrial motor faults. The proposed methodology involves the development of a cyber-physical system architecture and mathematical modeling framework for efficient fault detection. The mathematical model is designed to capture the intricate relationships within the cyber-physical system, incorporating the dynamic interactions between distributed motors and their edge controllers. Fast Fourier transform is employed for signal processing, enabling the extraction of meaningful frequency features that serve as indicators of potential faults. The artificial neural network based fault detection system is integrated with the solution, utilizing its ability to learn complex patterns and adapt to varying motor conditions. The effectiveness of the proposed framework and model is demonstrated through experimental results. The experimental setup involves diverse fault scenarios, and the system's performance is evaluated in terms of accuracy, sensitivity, and false positive rates.

The long-term effects of domestic and international tuberculosis service improvements on tuberculosis trends within the USA: a mathematical modelling study

For settings with low tuberculosis incidence, disease elimination is a long-term goal. We investigated pathways to tuberculosis pre-elimination (incidence <1·0 cases per 100 000 people) and elimination (incidence <0·1 cases per 100 000 people) in the USA, where incidence was estimated at 2·9 per 100 000 people in 2023. Using a mathematical modelling framework, we simulated how US tuberculosis incidence could be affected by changes in tuberculosis services in the countries of origin for future migrants to the USA, as well as changes in tuberculosis services inside the USA. To do so, we used a linked set of transmission dynamic models, calibrated to demographic and epidemiological data for each setting. We constructed intervention scenarios representing improvements in tuberculosis services internationally and within the USA, individually and in combination, plus a base-case scenario representing continuation of current services. We simulated health and economic outcomes until 2100, using a Bayesian approach to quantify uncertainty in these outcomes. Under the base-case scenario, US tuberculosis incidence was projected to decline to 1·8 cases per 100 000 (95% uncertainty interval [UI] 1·5-2·1) in the total population by 2050. Intervention scenarios produced substantial reductions in tuberculosis incidence, with the combination of all domestic and international interventions projected to achieve pre-elimination by 2033 (95% UI 2031-2037). Compared with the base-case scenario, this combination of interventions could avert 101 000 tuberculosis cases (95% UI 84 000-120 000) and 13 300 tuberculosis deaths (95% UI 10 500-16 300) in the USA from 2025 to 2050. Tuberculosis elimination was not projected before 2100. Strengthening tuberculosis services domestically, promoting the development of more effective technologies and interventions, and supporting tuberculosis programmes in countries with a high tuberculosis burden are key strategies for accelerating progress towards tuberculosis elimination in the USA. US Centers for Disease Control and Prevention.

When should lockdown be implemented? Devising cost-effective strategies for managing epidemics amid vaccine uncertainty.

During an infectious disease outbreak, public health policy makers are tasked with strategically implementing interventions whilst balancing competing objectives. To provide a quantitative framework that can be used to guide these decisions, it is helpful to devise a clear and specific objective function that can be evaluated to determine the optimal outbreak response. In this study, we have developed a mathematical modelling framework representing outbreaks of a novel emerging pathogen for which non-pharmaceutical interventions (NPIs) are imposed or removed based on thresholds for hospital occupancy. These thresholds are set at different levels to define four unique strategies for disease control. We illustrate that the optimal intervention strategy is contingent on the choice of objective function. Specifically, the optimal strategy depends on the extent to which policy makers prioritise reducing health costs due to infection over the costs associated with maintaining interventions. Motivated by the scenario early in the COVID-19 pandemic, we incorporate the development of a vaccine into our modelling framework and demonstrate that a policy maker's belief about when a vaccine will become available in future, and its eventual coverage (and/or effectiveness), affects the optimal strategy to adopt early in the outbreak. Furthermore, we show how uncertainty in these quantities can be accounted for when deciding which interventions to introduce. This research highlights the benefits of policy makers being explicit about the precise objectives of introducing interventions.

A modelling framework for cancer ecology and evolution.

Cancer incidence increases rapidly with age, typically as a polynomial. The somatic mutation theory explains this increase through the waiting time for enough mutations to build up to generate cells with the full set of traits needed to grow without control. However, lines of evidence ranging from tumour reversion and dormancy to the prevalence of presumed cancer mutations in non-cancerous tissues argue that this is not the whole story, and that cancer is also an ecological process, and that mutations only lead to cancer when the systems of control within and across cells have broken down. Aging thus has two effects: the build-up of mutations and the breakdown of control. This paper presents a mathematical modelling framework to unify these theories with novel approaches to model the mutation and diversification of cell lineages and of the breakdown of the layers of control both within and between cells. These models correctly predict the polynomial increase of cancer with age, show how germline defects in control accelerate cancer initiation, and compute how the positive feedback between cell replication, ecology and layers of control leads to a doubly exponential growth of cell populations.

Modeling and analyzing competitive epidemic diseases with partial and waning virus-specific and cross-immunity

In this paper, we consider a novel mathematical modeling framework for the spread of two competitive diseases in a well-mixed population. The proposed framework, which we term a bivirus SIRIS model, encapsulates key real-world features of natural immunity, accounting for different levels of (partial and waning) virus-specific and cross protection acquired after recovery. Formally, the proposed framework consists of a system of coupled nonlinear ordinary differential equations that builds on a classical bivirus susceptible–infected–susceptible model by means of the addition of further states to account for (temporarily) protected individuals. Through the analysis of the proposed framework and of two specializations, we offer analytical insight into how natural immunity can shape a wide range of complex emergent behaviors, including eradication of both diseases, survival of the fittest one, or even steady-state co-existence of the two diseases.

Deterministic mathematical modeling, sensitivity analysis, and dynamic optimization of cross-flow ultrafiltration systems for concentration of monoclonal antibody solutions

This manuscript proposes a general new framework for mathematical modeling, extended sensitivity analysis and dynamic optimization of tangential flow filtration (TFF) systems for concentration of monoclonal antibody (mAb) products and, potentially, other biologics. This framework is comprised of four major components: (I) a new first-principles-inspired TFF model; (II) dedicated parameter estimation strategies for automated model training; (III) new extended sensitivity analysis techniques for enhancing TFF phenomenological understanding and providing general guidance on TFF process development; and (IV) novel mono-objective and multi-objective dynamic optimization strategies for optimal TFF design and operation. The application of this framework to Bovine immunoglobulin γ (IgG) – a mAb analog in terms of physicochemical properties – shows the potential benefits it may offer in terms of overall TFF performance and rapid TFF development for new mAb candidates, compared to the current state of the art.

The Hidden Hand of Asymptomatic Infection Hinders Control of Neglected Tropical Diseases: A Modeling Analysis.

Neglected tropical diseases are responsible for considerable morbidity and mortality in low-income populations. International efforts have reduced their global burden, but transmission is persistent and case-finding-based interventions rarely target asymptomatic individuals. We develop a generic mathematical modeling framework for analyzing the dynamics of visceral leishmaniasis in the Indian sub-continent (VL), gambiense sleeping sickness (gHAT), and Chagas disease and use it to assess the possible contribution of asymptomatics who later develop disease (pre-symptomatics) and those who do not (non-symptomatics) to the maintenance of infection. Plausible interventions, including active screening, vector control, and reduced time to detection, are simulated for the three diseases. We found that the high asymptomatic contribution to transmission for Chagas and gHAT and the apparently high basic reproductive number of VL may undermine long-term control. However, the ability to treat some asymptomatics for Chagas and gHAT should make them more controllable, albeit over relatively long time periods due to the slow dynamics of these diseases. For VL, the toxicity of available therapeutics means the asymptomatic population cannot currently be treated, but combining treatment of symptomatics and vector control could yield a quick reduction in transmission. Despite the uncertainty in natural history, it appears there is already a relatively good toolbox of interventions to eliminate gHAT, and it is likely that Chagas will need improvements to diagnostics and their use to better target pre-symptomatics. The situation for VL is less clear, and model predictions could be improved by additional empirical data. However, interventions may have to improve to successfully eliminate this disease.