Emulation of Quantitative Systems Pharmacology models to accelerate virtual population inference in immuno-oncology.

Quantitative Systems Pharmacology (QSP) models are increasingly being applied for target discovery and dose selection in immuno-oncology (IO). Typical application involves virtual trial, a simulation of a virtual population of hundreds of model instances with model inputs reflecting individual variability. While the structure of the model and initial parameterisation are based on literature describing the underlying biology, calibration of the virtual population by existing clinical data is frequently required to create tumour and patient population specific model instances. Since comparison of a virtual trial with clinical output requires hundreds of large-scale, non-linear model evaluations, the inference of a virtual population is computationally expensive, frequently becoming a bottleneck. Here, we present novel approach to virtual population inference in IO using emulation of the QSP model and an objective function based on Kolmogorov-Smirnov statistics to maximise congruence of simulated and observed clinical tumour size distributions. We sample the parameter space of a QSP IO model to collect a set of tumour growth time profiles. We evaluate performance of several machine learning approaches in interpolating these time profiles and create a surrogate model, which computes tumor growth profiles faster than the original model and allows examination of tens of millions of virtual patients. We use the surrogate model to infer a virtual population maximising congruence with the waterfall plot of a pembrolizumab clinical trial. We believe that our approach is applicable not only in QSP IO, but also in other applications where virtual populations need to be inferred for computationally expensive mechanistic models.

Constrained Dynamic Matrix Control under International Electrotechnical Commission Standard 61499 and the Open Platform Communications Unified Architecture.

This paper focuses on the implementation of a constrained Dynamic Matrix Control (DMC) approach within the level processes of the FESTO™ MPS-PA Compact Workstation plant in the context of the Industrial Internet of Things (IIoT) paradigm. The goal is to develop an industrial control application with decentralized logic that optimizes the operation of the plant while adhering to specific constraints. The implementation is carried out using the IEC-61499 standard and the OPC-UA protocol, enabling seamless communication between devices and systems. The authors utilize the 4diac-IDE and 4diac-FORTE as the development and runtime environments, respectively, to enable the execution of the control application on low-cost devices. The Beagle Bone Black (BBB) card is used for data acquisition and actuator control. Three types of constraints are considered: control increment (Δu(k)), output (ym(k)), and control (u(k)) constraints, to prevent unnecessary stress on the actuator and avoid damage to the plant. The QP algorithm is employed to optimize the objective function and address these constraints effectively. By integrating advanced control strategies into industrial processes in the IIoT paradigm and implementing them on low-cost devices, this paper demonstrates the feasibility and effectiveness of improving system performance, resource utilization, and overall productivity while considering system limitations and constraints.

Semiparametric regression modeling of the global percentile outcome.

When no single outcome is sufficient to capture the multidimensional impairments of a disease, investigators often rely on multiple outcomes for comprehensive assessment of global disease status. Methods for assessing covariate effects on global disease status include the composite outcome and global test procedures. One global test procedure is the O'Brien's rank-sum test, which combines information from multiple outcomes using a global rank-sum score. However, existing methods for the global rank-sum do not lend themselves to regression modeling. We consider sensible regression strategies for the global percentile outcome (GPO), under the transformed linear model and the monotonic index model. Posing minimal assumptions, we develop estimation and inference procedures that account for the special features of the GPO. Asymptotics are established using U-statistic and U-process techniques. We illustrate the practical utilities of the proposed methods via extensive simulations and application to a Parkinson's disease study.

Cramér-Rao bound-informed training of neural networks for quantitative MRI.

PURPOSE: To improve the performance of neural networks for parameter estimation in quantitative MRI, in particular when the noise propagation varies throughout the space of biophysical parameters. THEORY AND METHODS: A theoretically well-founded loss function is proposed that normalizes the squared error of each estimate with respective Cramér-Rao bound (CRB)-a theoretical lower bound for the variance of an unbiased estimator. This avoids a dominance of hard-to-estimate parameters and areas in parameter space, which are often of little interest. The normalization with corresponding CRB balances the large errors of fundamentally more noisy estimates and the small errors of fundamentally less noisy estimates, allowing the network to better learn to estimate the latter. Further, proposed loss function provides an absolute evaluation metric for performance: A network has an average loss of 1 if it is a maximally efficient unbiased estimator, which can be considered the ideal performance. The performance gain with proposed loss function is demonstrated at the example of an eight-parameter magnetization transfer model that is fitted to phantom and in vivo data. RESULTS: Networks trained with proposed loss function perform close to optimal, that is, their loss converges to approximately 1, and their performance is superior to networks trained with the standard mean-squared error (MSE). The proposed loss function reduces the bias of the estimates compared to the MSE loss, and improves the match of the noise variance to the CRB. This performance gain translates to in vivo maps that align better with the literature. CONCLUSION: Normalizing the squared error with the CRB during the training of neural networks improves their performance in estimating biophysical parameters.

Using Bayesian inference to estimate plausible muscle forces in musculoskeletal models.

BACKGROUND: Musculoskeletal modeling is currently a preferred method for estimating the muscle forces that underlie observed movements. However, these estimates are sensitive to a variety of assumptions and uncertainties, which creates difficulty when trying to interpret the muscle forces from musculoskeletal simulations. Here, we describe an approach that uses Bayesian inference to identify plausible ranges of muscle forces for a simple motion while representing uncertainty in the measurement of the motion and the objective function used to solve the muscle redundancy problem. METHODS: We generated a reference elbow flexion-extension motion and computed a set of reference forces that would produce the motion while minimizing muscle excitations cubed via OpenSim Moco. We then used a Markov Chain Monte Carlo (MCMC) algorithm to sample from a posterior probability distribution of muscle excitations that would result in the reference elbow motion. We constructed a prior over the excitation parameters which down-weighted regions of the parameter space with greater muscle excitations. We used muscle excitations to find the corresponding kinematics using OpenSim, where the error in position and velocity trajectories (likelihood function) was combined with the sum of the cubed muscle excitations integrated over time (prior function) to compute the posterior probability density. RESULTS: We evaluated the muscle forces that resulted from the set of excitations that were visited in the MCMC chain (seven parallel chains, 500,000 iterations per chain). The estimated muscle forces compared favorably with the reference forces generated with OpenSim Moco, while the elbow angle and velocity from MCMC matched closely with the reference (average RMSE for elbow angle = 2°; and angular velocity = 32°/s). However, our rank plot analyses and potential scale reduction statistics, which we used to evaluate convergence of the algorithm, indicated that the chains did not fully mix. CONCLUSIONS: While the results from this process are a promising step towards characterizing uncertainty in muscle force estimation, the computational time required to search the solution space with, and the lack of MCMC convergence indicates that further developments in MCMC algorithms are necessary for this process to become feasible for larger-scale models.

Enabling Energy Harvesting-Based Wi-Fi System for an e-Health Application: A MAC Layer Perspective.

The adverse impacts of using conventional batteries in the Internet of Things (IoT) devices, such as cost-effective maintenance, numerous battery replacements, and environmental hazards, have led to an interest in integrating energy harvesting technology into IoT devices to extend their lifetime and sustainably effectively. However, this requires improvements in different IoT protocol stack layers, especially in the MAC layer, due to its high level of energy consumption. These improvements are essential in critical applications such as IoT medical devices. In this paper, we simulated a dense solar-based energy harvesting Wi-Fi network in an e-Health environment, introducing a new algorithm for energy consumption mitigation while maintaining the required Quality of Service (QoS) for e-Health. In compliance with the upcoming Wi-Fi amendment 802.11be, the Access Point (AP) coordination-based optimization technique is proposed, where an AP can request dynamic resource rescheduling along with its nearby APs, to reduce the network energy consumption through adjustments within the standard MAC protocol. This paper shows that the proposed algorithm, alongside using solar energy harvesting technology, increases the energy efficiency by more than 40% while maintaining the e-Health QoS requirements. We believe this research will open new opportunities in IoT energy harvesting integration, especially in QoS-restricted environments.

Optimization of reservoir operating curves and hedging rules using genetic algorithm with a new objective function and smoothing constraint: application to a multipurpose dam in Morocco.

Long-term operation optimization of multipurpose reservoirs is highly important in arid and semi-arid countries challenged by climate change. This paper suggests an objective function combining two competitive shortage indicators for multi-objective reservoir operation optimization. An improved genetic algorithm including a smoothing constraint, reducing infeasible fluctuations of the operation policy, is developed to solve this problem. Operating curves were optimized jointly to hedging factors aiming at avoiding severe droughts and high damages for users. The proposed function was compared with the conventional objective function of minimizing the sum of squared deviations (SSD) between releases and demands. Different combinations of weights of the objectives linked to the Moroccan reservoir were studied. The proposed objective function yields to improved results in terms of computation requirements since it converges quicker and it leads to better supply performance. For drinking water use, the frequency of shortage was reduced by 66% and the maximum deficit by 14% whereas for irrigation the frequency of shortage was curtailed by 6%. The operating curves obtained by the developed optimization model were then compared with static operating rule curves simulated in RIBASIM. The superiority of variable optimized rule curves was proven compared with stable operating mode over time.

In silico design of ligand triggered RNA switches.

This contribution sketches a work flow to design an RNA switch that is able to adapt two structural conformations in a ligand-dependent way. A well characterized RNA aptamer, i.e., knowing its Kd and adaptive structural features, is an essential ingredient of the described design process. We exemplify the principles using the well-known theophylline aptamer throughout this work. The aptamer in its ligand-binding competent structure represents one structural conformation of the switch while an alternative fold that disrupts the binding-competent structure forms the other conformation. To keep it simple we do not incorporate any regulatory mechanism to control transcription or translation. We elucidate a commonly used design process by explicitly dissecting and explaining the necessary steps in detail. We developed a novel objective function which specifies the mechanistics of this simple, ligand-triggered riboswitch and describe an extensive in silico analysis pipeline to evaluate important kinetic properties of the designed sequences. This protocol and the developed software can be easily extended or adapted to fit novel design scenarios and thus can serve as a template for future needs.

A Smooth Nonparametric Approach to Determining Cut-Points of A Continuous Scale.

The problem of determining cut-points of a continuous scale according to an establish categorical scale is often encountered in practice for the purposes such as making diagnosis or treatment recommendation, determining study eligibility, or facilitating interpretations. A general analytic framework was recently proposed for assessing optimal cut-points defined based on some pre-specified criteria. However, the implementation of the existing nonparametric estimators under this framework and the associated inferences can be computationally intensive when more than a few cut-points need to be determined. To address this important issue, a smoothing-based modification of the current method is proposed and is found to substantially improve the computational speed as well as the asymptotic convergence rate. Moreover, a plug-in type variance estimation procedure is developed to further facilitate the computation. Extensive simulation studies confirm the theoretical results and demonstrate the computational benefits of the proposed method. The practical utility of the new approach is illustrated by an application to a mental health study.

Thermo-ecological analysis of industrial kilns.

In this study, thermo-ecological analysis has been applied by using ecologic objective function "ECO" and ecological coefficient of performance "ECOP" to the kilns used in the firing process of the ceramic plant. Five different environmental (dead state) temperatures (between 10 °C and 30 °C) are taken into account. The irreversibility, which are the most important criteria affecting ecological performance, occurs during the heat transfer in the burners and cooling in the kiln. The irreversibility and product exergy values are compared under different environmental temperatures. The ECO and ECOP values are inversely proportional to the environment temperatures. The maximum ECO and ECOP values are determined as -2387.156 kW and 0.051, respectively, while their corresponding minimum values are -2577.394 kW and 0.026, respectively. The results obtained can be a guide for the thermo-ecological design of industrial kilns. The losses of the kiln are high. It is necessary to reduce the losses to increase the performance and ecologic indicator results. The kilns are not environmentally benign at higher ambient temperatures. The optimum working condition of the kiln can be considered as 10 °C. Better insulations are necessary for the side, bottom and top surfaces of the kilns to reduce the losses. In this regard, the waste heat recovery for the gases can be taken into account for better efficiency and environmental assessment.

MoleGear: A Java-Based Platform for Evolutionary De Novo Molecular Design.

A Java-based platform, MoleGear, is developed for de novo molecular design based on the chemistry development kit (CDK) and other Java packages. MoleGear uses evolutionary algorithm (EA) to explore chemical space, and a suite of fragment-based operators of growing, crossover, and mutation for assembling novel molecules that can be scored by prediction of binding free energy or a weighted-sum multi-objective fitness function. The EA can be conducted in parallel over multiple nodes to support large-scale molecular optimizations. Some complementary utilities such as fragment library design, chemical space analysis, and graphical user interface are also integrated into MoleGear. The candidate molecules as inhibitors for the human immunodeficiency virus 1 (HIV-1) protease were designed by MoleGear, which validates the potential capability for de novo molecular design.

Monitoring dynamic spatio-temporal ecological processes optimally.

Population dynamics vary in space and time. Survey designs that ignore these dynamics may be inefficient and fail to capture essential spatio-temporal variability of a process. Alternatively, dynamic survey designs explicitly incorporate knowledge of ecological processes, the associated uncertainty in those processes, and can be optimized with respect to monitoring objectives. We describe a cohesive framework for monitoring a spreading population that explicitly links animal movement models with survey design and monitoring objectives. We apply the framework to develop an optimal survey design for sea otters in Glacier Bay. Sea otters were first detected in Glacier Bay in 1988 and have since increased in both abundance and distribution; abundance estimates increased from 5 otters to >5,000 otters, and they have spread faster than 2.7 km/yr. By explicitly linking animal movement models and survey design, we are able to reduce uncertainty associated with forecasting occupancy, abundance, and distribution compared to other potential random designs. The framework we describe is general, and we outline steps to applying it to novel systems and taxa.

Accounting for robustness in modeling signal transduction responses.

A classical question in systems biology is to find a Boolean model which is able to predict the observed responses of a signaling network. It has been previously shown that such models can be tailored based on experimental data. While fitting a minimum-size network to the experimentally observed data is a natural assumption, it can potentially result in a network which is not so robust against the noises in the training dataset. Indeed, it is widely accepted now that biological systems are generally evolved to be very robust. Therefore, in the present work, we extended the classical formulation of Boolean network construction in order to put weight on the robustness of the created network. We show that our method results generally in more relevant networks. Consequently, considering robustness as a design principle of biological networks can result in more realistic models.

Sigma Routing Metric for RPL Protocol.

This paper presents the adaptation of a specific metric for the RPL protocol in the objective function MRHOF. Among the functions standardized by IETF, we find OF0, which is based on the minimum hop count, as well as MRHOF, which is based on the Expected Transmission Count (ETX). However, when the network becomes denser or the number of nodes increases, both OF0 and MRHOF introduce long hops, which can generate a bottleneck that restricts the network. The adaptation is proposed to optimize both OFs through a new routing metric. To solve the above problem, the metrics of the minimum number of hops and the ETX are combined by designing a new routing metric called SIGMA-ETX, in which the best route is calculated using the standard deviation of ETX values between each node, as opposed to working with the ETX average along the route. This method ensures a better routing performance in dense sensor networks. The simulations are done through the Cooja simulator, based on the Contiki operating system. The simulations showed that the proposed optimization outperforms at a high margin in both OF0 and MRHOF, in terms of network latency, packet delivery ratio, lifetime, and power consumption.

CoAR: Congestion-Aware Routing Protocol for Low Power and Lossy Networks for IoT Applications.

The IPv6 routing protocol for low power and lossy networks (RPL) was designed to satisfy the requirements of a wide range of Internet of Things (IoT) applications, including industrial and environmental monitoring. In most scenarios, different from an ordinary environment, the industrial monitoring system under emergency scenarios needs to not only periodically collect the information from the sensing region, but also respond rapidly to some unusual situations. In the monitoring system, particularly when an event occurs in the sensing region, a surge of data generated by the sensors may lead to congestion at parent node as data packets converge towards the root. Congestion problem degrades the network performance that has an impact on quality of service. To resolve this problem, we propose a congestion-aware routing protocol (CoAR) which utilizes the selection of an alternative parent to alleviate the congestion in the network. The proposed mechanism uses a multi-criteria decision-making approach to select the best alternative parent node within the congestion by combining the multiple routing metrics. Moreover, the neighborhood index is used as the tie-breaking metric during the parent selection process when the routing score is equal. In order to determine the congestion, CoAR adopts the adaptive congestion detection mechanism based on the current queue occupancy and observation of present and past traffic trends. The proposed protocol has been tested and evaluated in different scenarios in comparison with ECRM and RPL. The simulation results show that CoAR is capable of dealing successfully with congestion in LLNs while preserving the required characteristics of the IoT applications.

A Novel RPL Algorithm Based on Chaotic Genetic Algorithm.

RPL (routing protocol for low-power and lossy networks) is an important candidate routing algorithm for low-power and lossy network (LLN) scenarios. To solve the problems of using a single routing metric or no clearly weighting distribution theory of additive composition routing metric in existing RPL algorithms, this paper creates a novel RPL algorithm according to a chaotic genetic algorithm (RPL-CGA). First of all, we propose a composition metric which simultaneously evaluates packet queue length in a buffer, end-to-end delay, residual energy ratio of node, number of hops, and expected transmission count (ETX). Meanwhile, we propose using a chaotic genetic algorithm to determine the weighting distribution of every routing metric in the composition metric to fully evaluate candidate parents (neighbors). Then, according to the evaluation results of candidate parents, we put forward a new holistic objective function and a new method for calculating the rank values of nodes which are used to select the optimized node as the preferred parent (the next hop). Finally, theoretical analysis and a series of experimental consequences indicate that RPL-CGA is significantly superior to the typical existing relevant routing algorithms in the aspect of average end-to-end delay, average success rate, etc.

Multiple Instances QoS Routing in RPL: Application to Smart Grids.

The Smart Grid (SG) aims to transform the current electric grid into a "smarter" network where the integration of renewable energy resources, energy efficiency and fault tolerance are the main benefits. This is done by interconnecting every energy source, storage point or central control point with connected devices, where heterogeneous SG applications and signalling messages will have different requirements in terms of reliability, latency and priority. Hence, data routing and prioritization are the main challenges in such networks. So far, RPL (Routing Protocol for Low-Power and Lossy networks) protocol is widely used on Smart Grids for distributing commands over the grid. RPL assures traffic differentiation at the network layer in wireless sensor networks through the logical subdivision of the network in multiple instances, each one relying on a specific Objective Function. However, RPL is not optimized for Smart Grids, as its main objective functions and their associated metric does not allow Quality of Service differentiation. To overcome this, we propose OFQS an objective function with a multi-objective metric that considers the delay and the remaining energy in the battery nodes alongside with the dynamic quality of the communication links. Our function automatically adapts to the number of instances (traffic classes) providing a Quality of Service differentiation based on the different Smart Grid applications requirements. We tested our approach on a real sensor testbed. The experimental results show that our proposal provides a lower packet delivery latency and a higher packet delivery ratio while extending the lifetime of the network compared to solutions in the literature.

A Proposal for IoT Dynamic Routes Selection Based on Contextual Information.

The Internet of Things (IoT) is based on interconnection of intelligent and addressable devices, allowing their autonomy and proactive behavior with Internet connectivity. Data dissemination in IoT usually depends on the application and requires context-aware routing protocols that must include auto-configuration features (which adapt the behavior of the network at runtime, based on context information). This paper proposes an approach for IoT route selection using fuzzy logic in order to attain the requirements of specific applications. In this case, fuzzy logic is used to translate in math terms the imprecise information expressed by a set of linguistic rules. For this purpose, four Objective Functions (OFs) are proposed for the Routing Protocol for Low Power and Loss Networks (RPL); such OFs are dynamically selected based on context information. The aforementioned OFs are generated from the fusion of the following metrics: Expected Transmission Count (ETX), Number of Hops (NH) and Energy Consumed (EC). The experiments performed through simulation, associated with the statistical data analysis, conclude that this proposal provides high reliability by successfully delivering nearly 100% of data packets, low delay for data delivery and increase in QoS. In addition, an 30% improvement is attained in the network life time when using one of proposed objective function, keeping the devices alive for longer duration.

Statistical inference in mechanistic models: time warping for improved gradient matching.

Inference in mechanistic models of non-linear differential equations is a challenging problem in current computational statistics. Due to the high computational costs of numerically solving the differential equations in every step of an iterative parameter adaptation scheme, approximate methods based on gradient matching have become popular. However, these methods critically depend on the smoothing scheme for function interpolation. The present article adapts an idea from manifold learning and demonstrates that a time warping approach aiming to homogenize intrinsic length scales can lead to a significant improvement in parameter estimation accuracy. We demonstrate the effectiveness of this scheme on noisy data from two dynamical systems with periodic limit cycle, a biopathway, and an application from soft-tissue mechanics. Our study also provides a comparative evaluation on a wide range of signal-to-noise ratios.

MOTA: A Many-Objective Tuning Algorithm Specialized for Tuning under Multiple Objective Function Evaluation Budgets.

Control parameter studies assist practitioners to select optimization algorithm parameter values that are appropriate for the problem at hand. Parameter values are well suited to a problem if they result in a search that is effective given that problem's objective function(s), constraints, and termination criteria. Given these considerations a many-objective tuning algorithm named MOTA is presented. MOTA is specialized for tuning a stochastic optimization algorithm according to multiple performance measures, each over a range of objective function evaluation budgets. MOTA's specialization consists of four aspects: (1) a tuning problem formulation that consists of both a speed objective and a speed decision variable; (2) a control parameter tuple assessment procedure that utilizes information from a single assessment run's history to gauge that tuple's performance at multiple evaluation budgets; (3) a preemptively terminating resampling strategy for handling the noise present when tuning stochastic algorithms; and (4) the use of bi-objective decomposition to assist in many-objective optimization. MOTA combines these aspects together with differential evolution operators to search for effective control parameter values. Numerical experiments consisting of tuning NSGA-II and MOEA/D demonstrate that MOTA is effective at many-objective tuning.