Man vs. machine: comparison of pharmacogenetic expert counselling with a clinical medication support system in a study with 200 genotyped patients

Background: Medication problems such as strong side effects or inefficacy occur frequently. At our university hospital, a consultation group of specialists takes care of patients suffering from medication problems. Nevertheless, the counselling of poly-treated patients is complex, as it requires the consideration of a large network of interactions between drugs and their targets, their metabolizing enzymes, and their transporters, etc. Purpose This study aims to check whether a score-based decision-support system (1) reduces the time and effort and (2) suggests solutions at the same quality level. Patients and methods: A total of 200 multimorbid, poly-treated patients with medication problems were included. All patients were considered twice: manually, as clinically established, and using the Drug-PIN decision-support system. Besides diagnoses, lab data (kidney, liver), phenotype (age, gender, BMI, habits), and genotype (genetic variants with actionable clinical evidence I or IIa) were considered, to eliminate potentially inappropriate medications and to select individually favourable drugs from existing medication classes. The algorithm is connected to automatically updated knowledge resources to provide reproducible up-to-date decision support. Results: The average turnaround time for manual poly-therapy counselling per patient ranges from 3 to 6 working hours, while it can be reduced to ten minutes using Drug-PIN. At the same time, the results of the novel computerized approach coincide with the manual approach at a level of > 90%. The holistic medication score can be used to find favourable drugs within a class of drugs and also to judge the severity of medication problems, to identify critical cases early and automatically. Conclusion: With the computerized version of this approach, it became possible to score all combinations of all alternative drugs from each class of drugs administered ("personalized medication landscape ") and to identify critical patients even before problems are reported ("medication alert"). Careful comparison of manual and score-based results shows that the incomplete manual consideration of genetic specialties and pharmacokinetic conflicts is responsible for most of the (minor) deviations between the two approaches. The meaning of the reduction of working time for experts by about 2 orders of magnitude should not be underestimated, as it enables practical application of personalized medicine in clinical routine

Review: to be or not to be an identifiable model. Is this a relevant question in animal science modelling?

International audienceWhat is a good (useful) mathematical model in animal science? For models constructed for prediction purposes, the question of model adequacy (usefulness) has been traditionally tackled by statistical analysis applied to observed experimental data relative to model-predicted variables. However, little attention has been paid to analytic tools that exploit the mathematical properties of the model equations. For example, in the context of model calibration, before attempting a numerical estimation of the model parameters, we might want to know if we have any chance of success in estimating a unique best value of the model parameters from available measurements. This question of uniqueness is referred to as structural identifiability; a mathematical property that is defined on the sole basis of the model structure within a hypothetical ideal experiment determined by a setting of model inputs (stimuli) and observable variables (measurements). Structural identifiability analysis applied to dynamic models described by ordinary differential equations (ODE) is a common practice in control engineering and system identification. This analysis demands mathematical technicalities that are beyond the academic background of animal science, which might explain the lack of pervasiveness of identifiability analysis in animal science modelling. To fill this gap, in this paper we address the analysis of structural identifiability from a practitioner perspective by capitalizing on the use of dedicated software tools. Our objectives are (i) to provide a comprehensive explanation of the structural identifiability notion for the community of animal science modelling, (ii) to assess the relevance of identifiability analysis in animal science modelling and (iii) to motivate the community to use identifiability analysis in the modelling practice (when the identifiability question is relevant). We focus our study on ODE models. By using illustrative examples that include published mathematical models describing lactation in cattle, we show how structural identifiability analysis can contribute to advancing mathematical modelling in animal science towards the production of useful models and highly informative experiments. Rather than attempting to impose a systematic identifiability analysis to the modelling community during model developments, we wish to open a window towards the discovery of a powerful tool for model construction and experiment design

STABLE ADAPTIVE STRATEGY of HOMO SAPIENS and EVOLUTIONARY RISK of HIGH TECH. Transdisciplinary essay

The co-evolutionary concept of Three-modal stable evolutionary strategy of Homo sapiens is developed. The concept based on the principle of evolutionary complementarity of anthropogenesis: value of evolutionary risk and evolutionary path of human evolution are defined by descriptive (evolutionary efficiency) and creative-teleological (evolutionary correctly) parameters simultaneously, that cannot be instrumental reduced to others ones. Resulting volume of both parameters define the trends of biological, social, cultural and techno-rationalistic human evolution by two gear mechanism ˗ gene-cultural co-evolution and techno- humanitarian balance. The resultant each of them can estimated by the ratio of socio-psychological predispositions of humanization/dehumanization in mentality. Explanatory model and methodology of evaluation of creatively teleological evolutionary risk component of NBIC technological complex is proposed. Integral part of the model is evolutionary semantics (time-varying semantic code, the compliance of the biological, socio-cultural and techno-rationalist adaptive modules of human stable evolutionary strategy)

Investigation of Optimization Targets for Predictive Simulation of Human Gait with Model Predictive Control

The design and development of gait-related treatments and devices is inhibited by anabsence of predictive gait models. Understanding of human gait and what motivates walkingpatterns is still limited, despite walking being one of the most routine human activities. While asignificant body of literature exists on gait modeling and optimization criteria to achievesimulated, normal gait, particularly with neuromuscular models, few studies have aimed to applyoptimization targets which approximate metabolic cost to mechanical gait models. Even fewerhave attempted this predictively, with no joint angle data specified a priori. The Sunmodel [31], [32] is one such mechanical framework which utilizes MPC to predict the dynamics ofhuman walking. This thesis expands the Sun model [31], [32] to simulate a full gait cycle (CG) andinvestigates the application of new optimization targets within an existing Model PredictiveControl (MPC) framework for predictive gait simulation developed by Sun [31], [32] .The Sun model [31], [32] was previously limited to a half gait cycle (GC) which assumedbilateral symmetry and optimized only according to characteristic constraints such as step lengthand velocity of the center of mass (COM). In this thesis, the Sun framework and MPC controlscheme were expanded to generate consecutive double support (DS), single support (SS), DS, andSS period simulations, which constitutes a full GC. The resulting GC simulation was not markedby GC events toe off (TO) and heel strike (HS), but did achieve continuity over the period whichwas not achieved by the Sun model [31], [32] . Additionally, new cost functions were developedconsistent with existing literature which suggests that the Central Nervous System (CNS) uses avariety of energy-related targets in generating gait. This thesis demonstrates that the applicationof optimization targets which approximate metabolic costs is possible with the proposed MPCframework for a mechanical gait model, but that the performance of resulting simulations shouldnot be evaluated until a full GC marked by TO and HS is achieved.While a continuous full GC simulation was achieved, the failure of the model to reliablymeet characteristic constraints, particularly in SS, prevents simulation of a GC marked by TO andHS. The work in this thesis points primarily to the failure of the optimization routine within theMPC framework to reliably find a solution that meets constraints as the cause of this problem. Ifthe optimization problem can be classified, an appropriate solution algorithm could be chosenwhich could reliably find a solution for any given set of constraints and initial conditions (IC).Identifying an appropriate solution algorithm could make the MPC framework proposed a viablemethod of gait prediction and simulation.This investigation provides researchers better understanding of the application ofenergy-based optimization in mechanical gait models and the current limitations of gaitprediction and simulation. In addition, direction is given to the future work necessary to establishMPC as a viable control method for gait simulation

An evolutionary metaphysics of human enhancement technologies

The monograph is an English, expanded and revised version of the book Cheshko, V. T., Ivanitskaya, L.V., & Glazko, V.I. (2018). Anthropocene. Philosophy of Biotechnology. Moscow, Course. The manuscript was completed by me on November 15, 2019. It is a study devoted to the development of the concept of a stable evolutionary human strategy as a unique phenomenon of global evolution. The name “An Evolutionary Metaphysics (Cheshko, 2012; Glazko et al., 2016). With equal rights, this study could be entitled “Biotechnology as a result and factor of the evolutionary processˮ. The choice in favor of used “The Evolutionary Metaphysics of Human Enhancement Technologiesˮ was made in accordance with the basic principle of modern post-academician and human-sized science, a classic example of which is biotechnology. The “Metaphysics of Evolution” and “Evolutionary Metaphysics” concepts are used in several ways in modern philosophical discourse. In any case, the values contain a logical or associative reference to the teleological nature of the evolutionary process (Hull, 1967, 1989; Apel, 1995; Faye, 2016; Dupre, 2017; Rose, 2018, etc). In our study, the “evolutionary metaphysics” serves to denote the thesis of the rationalization and technologization of global evolution and anthropogenesis, in particular. At the same time, the postulate of an open future remains relevant in relation to the results of the evolutionary process. The theory of evolution of complex, including the humans system and algorithm for its constructing are а synthesis of evolutionary epistemology, philosophical anthropology and concrete scientific empirical basis in modern science. ln other words, natural philosophy is regaining the status bar element theoretical science in the era of technology-driven evolution. The co-evolutionary concept of 3-modal stable evolutionary strategy of Homo sapiens is developed. The concept based оn the principle of evolutionary complementarity of anthropogenesis: value of evolutionary risk and evolutionary path of human evolution are defined bу descriptive (evolutionary efficiency) and creative-teleological (evolutionary correctness) parameters simultaneously, that cannot bе instrumental reduced to others ones. Resulting volume of both parameters define the vectors of blological, social, cultural and techno-rationalistic human evolution Ьу two gear mechanism genetic and cultural co-evolution and techno-humanitarian balance. The resultant each of them сап estimated Ьу the ratio of socio-psychological predispositions of humanization / dehumanization in mentality. Explanatory model and methodology of evaluation of creatively teleological evolutionary risk component of NBIC technological complex is proposed. Integral part of the model is evolutionary semantics (time-varying semantic code, the compliance of the blological, socio-cultural and techno-rationalist adaptive modules of human stable evolutionary strategy). It is seem necessary to make three clarifications. First, logical construct, “evolutionary metaphysics” contains an internal contradiction, because it unites two alternative explanatory models. “Metaphysics”, as a subject, implies deducibility of the process from the initial general abstract principle, and, consequently, the outcome of the development of the object is uniquely determined by the initial conditions. Predicate, “evolutionary”, means stochastic mechanism of realizing the same principle by memorizing and replicating random choices in all variants of the post-Darwin paradigm. In philosophy, random choice corresponds to the category of “free will” of a reasonable agent. In evolutionary theory, the same phenomenon is reflected in the concept of “covariant replication”. Authors will attempt to synthesize both of these models in a single transdisciplinary theoretical framework. Secondly, the interpretation of the term “evolutionary (adaptive) strategyˮ is different from the classical definition. The difference is that the adaptive strategy in this context is equivalent to the survival, i.e. it includes the adaptation to the environment and the transformation (construction) of the medium in accordance with the objectives of survival. To emphasize this difference authors used verbal construction “adaptiveˮ (rather than “evolutionaryˮ) strategy as more adequate. In all other cases, the two terms may be regarded as synonymous. Thirdly, the initial two essays of this series were published in one book in 2012. Their main goal was the development of the logically consistent methodological concept of stable adaptive (evolutionary) strategy of hominines and the argumentation of its heuristic possibilities as a transdisciplinary scientific paradigm of modern anthropology. The task was to demonstrate the possibilities of the SESH concept in describing and explaining the evolutionary prospects for the interaction of social organization and technology (techno-humanitarian balance) and the associated biological and cultural mechanisms of the genesis of religion (gene-cultural co-evolution). In other words, it was related to the sphere of cultural and philosophical anthropology, i.e. to the axiological component of any theoretical constructions describing the behavior of self-organizing systems with human participation. In contrast, the present work is an attempt to introduce this concept into the sphere of biological anthropology and, consequently, its main goal is to demonstrate the possibility of verification of its main provisions by means of procedures developed by natural science, i.e. refers to the descriptive component of the same theoretical constructions. The result of this in the future should be methods for assessing, calculating and predicting the risk of loss of biological and cultural identity of a person, associated with a permanent and continuously deepening process of development of science and technology

Review of QSAR Models and Software Tools for predicting Biokinetic Properties

In the assessment of industrial chemicals, cosmetic ingredients, and active substances in pesticides and biocides, metabolites and degradates are rarely tested for their toxicologcal effects in mammals. In the interests of animal welfare and cost-effectiveness, alternatives to animal testing are needed in the evaluation of these types of chemicals. In this report we review the current status of various types of in silico estimation methods for Absorption, Distribution, Metabolism and Excretion (ADME) properties, which are often important in discriminating between the toxicological profiles of parent compounds and their metabolites/degradation products. The review was performed in a broad sense, with emphasis on QSARs and rule-based approaches and their applicability to estimation of oral bioavailability, human intestinal absorption, blood-brain barrier penetration, plasma protein binding, metabolism and. This revealed a vast and rapidly growing literature and a range of software tools. While it is difficult to give firm conclusions on the applicability of such tools, it is clear that many have been developed with pharmaceutical applications in mind, and as such may not be applicable to other types of chemicals (this would require further research investigation). On the other hand, a range of predictive methodologies have been explored and found promising, so there is merit in pursuing their applicability in the assessment of other types of chemicals and products. Many of the software tools are not transparent in terms of their predictive algorithms or underlying datasets. However, the literature identifies a set of commonly used descriptors that have been found useful in ADME prediction, so further research and model development activities could be based on such studies.JRC.DG.I.6-Systems toxicolog

A Field Guide to Genetic Programming

xiv, 233 p. : il. ; 23 cm.Libro ElectrónicoA Field Guide to Genetic Programming (ISBN 978-1-4092-0073-4) is an introduction to genetic programming (GP). GP is a systematic, domain-independent method for getting computers to solve problems automatically starting from a high-level statement of what needs to be done. Using ideas from natural evolution, GP starts from an ooze of random computer programs, and progressively refines them through processes of mutation and sexual recombination, until solutions emerge. All this without the user having to know or specify the form or structure of solutions in advance. GP has generated a plethora of human-competitive results and applications, including novel scientific discoveries and patentable inventions. The authorsIntroduction -- Representation, initialisation and operators in Tree-based GP -- Getting ready to run genetic programming -- Example genetic programming run -- Alternative initialisations and operators in Tree-based GP -- Modular, grammatical and developmental Tree-based GP -- Linear and graph genetic programming -- Probalistic genetic programming -- Multi-objective genetic programming -- Fast and distributed genetic programming -- GP theory and its applications -- Applications -- Troubleshooting GP -- Conclusions.Contents xi 1 Introduction 1.1 Genetic Programming in a Nutshell 1.2 Getting Started 1.3 Prerequisites 1.4 Overview of this Field Guide I Basics 2 Representation, Initialisation and GP 2.1 Representation 2.2 Initialising the Population 2.3 Selection 2.4 Recombination and Mutation Operators in Tree-based 3 Getting Ready to Run Genetic Programming 19 3.1 Step 1: Terminal Set 19 3.2 Step 2: Function Set 20 3.2.1 Closure 21 3.2.2 Sufficiency 23 3.2.3 Evolving Structures other than Programs 23 3.3 Step 3: Fitness Function 24 3.4 Step 4: GP Parameters 26 3.5 Step 5: Termination and solution designation 27 4 Example Genetic Programming Run 4.1 Preparatory Steps 29 4.2 Step-by-Step Sample Run 31 4.2.1 Initialisation 31 4.2.2 Fitness Evaluation Selection, Crossover and Mutation Termination and Solution Designation Advanced Genetic Programming 5 Alternative Initialisations and Operators in 5.1 Constructing the Initial Population 5.1.1 Uniform Initialisation 5.1.2 Initialisation may Affect Bloat 5.1.3 Seeding 5.2 GP Mutation 5.2.1 Is Mutation Necessary? 5.2.2 Mutation Cookbook 5.3 GP Crossover 5.4 Other Techniques 32 5.5 Tree-based GP 39 6 Modular, Grammatical and Developmental Tree-based GP 47 6.1 Evolving Modular and Hierarchical Structures 47 6.1.1 Automatically Defined Functions 48 6.1.2 Program Architecture and Architecture-Altering 50 6.2 Constraining Structures 51 6.2.1 Enforcing Particular Structures 52 6.2.2 Strongly Typed GP 52 6.2.3 Grammar-based Constraints 53 6.2.4 Constraints and Bias 55 6.3 Developmental Genetic Programming 57 6.4 Strongly Typed Autoconstructive GP with PushGP 59 7 Linear and Graph Genetic Programming 61 7.1 Linear Genetic Programming 61 7.1.1 Motivations 61 7.1.2 Linear GP Representations 62 7.1.3 Linear GP Operators 64 7.2 Graph-Based Genetic Programming 65 7.2.1 Parallel Distributed GP (PDGP) 65 7.2.2 PADO 67 7.2.3 Cartesian GP 67 7.2.4 Evolving Parallel Programs using Indirect Encodings 68 8 Probabilistic Genetic Programming 8.1 Estimation of Distribution Algorithms 69 8.2 Pure EDA GP 71 8.3 Mixing Grammars and Probabilities 74 9 Multi-objective Genetic Programming 75 9.1 Combining Multiple Objectives into a Scalar Fitness Function 75 9.2 Keeping the Objectives Separate 76 9.2.1 Multi-objective Bloat and Complexity Control 77 9.2.2 Other Objectives 78 9.2.3 Non-Pareto Criteria 80 9.3 Multiple Objectives via Dynamic and Staged Fitness Functions 80 9.4 Multi-objective Optimisation via Operator Bias 81 10 Fast and Distributed Genetic Programming 83 10.1 Reducing Fitness Evaluations/Increasing their Effectiveness 83 10.2 Reducing Cost of Fitness with Caches 86 10.3 Parallel and Distributed GP are Not Equivalent 88 10.4 Running GP on Parallel Hardware 89 10.4.1 Master–slave GP 89 10.4.2 GP Running on GPUs 90 10.4.3 GP on FPGAs 92 10.4.4 Sub-machine-code GP 93 10.5 Geographically Distributed GP 93 11 GP Theory and its Applications 97 11.1 Mathematical Models 98 11.2 Search Spaces 99 11.3 Bloat 101 11.3.1 Bloat in Theory 101 11.3.2 Bloat Control in Practice 104 III Practical Genetic Programming 12 Applications 12.1 Where GP has Done Well 12.2 Curve Fitting, Data Modelling and Symbolic Regression 12.3 Human Competitive Results – the Humies 12.4 Image and Signal Processing 12.5 Financial Trading, Time Series, and Economic Modelling 12.6 Industrial Process Control 12.7 Medicine, Biology and Bioinformatics 12.8 GP to Create Searchers and Solvers – Hyper-heuristics xiii 12.9 Entertainment and Computer Games 127 12.10The Arts 127 12.11Compression 128 13 Troubleshooting GP 13.1 Is there a Bug in the Code? 13.2 Can you Trust your Results? 13.3 There are No Silver Bullets 13.4 Small Changes can have Big Effects 13.5 Big Changes can have No Effect 13.6 Study your Populations 13.7 Encourage Diversity 13.8 Embrace Approximation 13.9 Control Bloat 13.10 Checkpoint Results 13.11 Report Well 13.12 Convince your Customers 14 Conclusions Tricks of the Trade A Resources A.1 Key Books A.2 Key Journals A.3 Key International Meetings A.4 GP Implementations A.5 On-Line Resources 145 B TinyGP 151 B.1 Overview of TinyGP 151 B.2 Input Data Files for TinyGP 153 B.3 Source Code 154 B.4 Compiling and Running TinyGP 162 Bibliography 167 Inde

In-silico-Systemanalyse von Biopathways

Chen M. In silico systems analysis of biopathways. Bielefeld (Germany): Bielefeld University; 2004.In the past decade with the advent of high-throughput technologies, biology has migrated from a descriptive science to a predictive one. A vast amount of information on the metabolism have been produced; a number of specific genetic/metabolic databases and computational systems have been developed, which makes it possible for biologists to perform in silico analysis of metabolism. With experimental data from laboratory, biologists wish to systematically conduct their analysis with an easy-to-use computational system. One major task is to implement molecular information systems that will allow to integrate different molecular database systems, and to design analysis tools (e.g. simulators of complex metabolic reactions). Three key problems are involved: 1) Modeling and simulation of biological processes; 2) Reconstruction of metabolic pathways, leading to predictions about the integrated function of the network; and 3) Comparison of metabolism, providing an important way to reveal the functional relationship between a set of metabolic pathways. This dissertation addresses these problems of in silico systems analysis of biopathways. We developed a software system to integrate the access to different databases, and exploited the Petri net methodology to model and simulate metabolic networks in cells. It develops a computer modeling and simulation technique based on Petri net methodology; investigates metabolic networks at a system level; proposes a markup language for biological data interchange among diverse biological simulators and Petri net tools; establishes a web-based information retrieval system for metabolic pathway prediction; presents an algorithm for metabolic pathway alignment; recommends a nomenclature of cellular signal transduction; and attempts to standardize the representation of biological pathways. Hybrid Petri net methodology is exploited to model metabolic networks. Kinetic modeling strategy and Petri net modeling algorithm are applied to perform the processes of elements functioning and model analysis. The proposed methodology can be used for all other metabolic networks or the virtual cell metabolism. Moreover, perspectives of Petri net modeling and simulation of metabolic networks are outlined. A proposal for the Biology Petri Net Markup Language (BioPNML) is presented. The concepts and terminology of the interchange format, as well as its syntax (which is based on XML) are introduced. BioPNML is designed to provide a starting point for the development of a standard interchange format for Bioinformatics and Petri nets. The language makes it possible to exchange biology Petri net diagrams between all supported hardware platforms and versions. It is also designed to associate Petri net models and other known metabolic simulators. A web-based metabolic information retrieval system, PathAligner, is developed in order to predict metabolic pathways from rudimentary elements of pathways. It extracts metabolic information from biological databases via the Internet, and builds metabolic pathways with data sources of genes, sequences, enzymes, metabolites, etc. The system also provides a navigation platform to investigate metabolic related information, and transforms the output data into XML files for further modeling and simulation of the reconstructed pathway. An alignment algorithm to compare the similarity between metabolic pathways is presented. A new definition of the metabolic pathway is proposed. The pathway defined as a linear event sequence is practical for our alignment algorithm. The algorithm is based on strip scoring the similarity of 4-hierarchical EC numbers involved in the pathways. The algorithm described has been implemented and is in current use in the context of the PathAligner system. Furthermore, new methods for the classification and nomenclature of cellular signal transductions are recommended. For each type of characterized signal transduction, a unique ST number is provided. The Signal Transduction Classification Database (STCDB), based on the proposed classification and nomenclature, has been established. By merging the ST numbers with EC numbers, alignments of biopathways are possible. Finally, a detailed model of urea cycle that includes gene regulatory networks, metabolic pathways and signal transduction is demonstrated by using our approaches. A system biological interpretation of the observed behavior of the urea cycle and its related transcriptomics information is proposed to provide new insights for metabolic engineering and medical care