Artificial intelligence in multi-objective drug design

The factors determining a drug's success are manifold, making de novo drug design an inherently multi-objective optimisation (MOO) problem. With the advent of machine learning and optimisation methods, the field of multi-objective compound design has seen a rapid increase in developments and applications. Population-based metaheuris-tics and deep reinforcement learning are the most commonly used artificial intelligence methods in the field, but recently conditional learning methods are gaining popularity. The former approaches are coupled with a MOO strat-egy which is most commonly an aggregation function, but Pareto-based strategies are widespread too. Besides these and conditional learning, various innovative approaches to tackle MOO in drug design have been proposed. Here we provide a brief overview of the field and the latest innovations.     

Multi-objective workflow scheduling in Amazon EC2

Nowadays, scientists and companies are confronted with multiple competing goals such as makespan in high-performance computing and economic cost in Clouds that have to be simultaneously optimised. Multi-objective scheduling of scientific applications in these systems is therefore receiving increasing research attention. Most existing approaches typically aggregate all objectives in a single function, defined a-priori without any knowledge about the problem being solved, which negatively impacts the quality of the solutions. In contrast, Pareto-based approaches having as outcome a set of (nearly) optimal solutions that represent a tradeoff among the different objectives, have been scarcely studied. In this paper, we analyse MOHEFT, a Pareto-based list scheduling heuristic that provides the user with a set of tradeoff optimal solutions from which the one that better suits the user requirements can be manually selected. We demonstrate the potential of our method for multi-objective workflow scheduling on the commercial Amazon EC2 Cloud. We compare the quality of the MOHEFT tradeoff solutions with two state-of-the-art approaches using different synthetic and real-world workflows: the classical HEFT algorithm for single-objective scheduling and the SPEA2* genetic algorithm used in multi-objective optimisation problems. The results demonstrate that our approach is able to compute solutions of higher quality than SPEA2*. In addition, we show that MOHEFT is more suitable than SPEA2* for workflow scheduling in the context of commercial Clouds, since the genetic-based approach is unable of dealing with some of the constraints imposed by these systems.     

On the use of multi-objective evolutionary algorithms for the induction of fuzzy classification rule systems

Extracting comprehensible and general classifiers from data in the form of rule systems is an important task in many problem domains. This study investigates the utility of a multi-objective evolutionary algorithm (MOEA) for this task. Multi-objective evolutionary algorithms are capable of finding several trade-off solutions between different objectives in a single run. In the context of the present study, the objectives to be optimised are the complexity of the rule systems, and their fit to the data. Complex rule systems are required to fit the data well. However, overly complex rule systems often generalise poorly on new data. In addition they tend to be incomprehensible. It is, therefore, important to obtain trade-off solutions that achieve the best possible fit to the data with the lowest possible complexity. The rule systems produced by the proposed multi-objective evolutionary algorithm are compared with those produced by several other existing approaches for a number of benchmark datasets. It is shown that the algorithm produces less complex classifiers that perform well on unseen data.     

Multi-objective optimal control of dynamic bioprocesses using ACADO Toolkit

The optimal design and operation of dynamic bioprocesses gives in practice often rise to optimisation problems with multiple and conflicting objectives. As a result typically not a single optimal solution but a set of Pareto optimal solutions exist. From this set of Pareto optimal solutions, one has to be chosen by the decision maker. Hence, efficient approaches are required for a fast and accurate generation of the Pareto set such that the decision maker can easily and systematically evaluate optimal alternatives. In the current paper the multi-objective optimisation of several dynamic bioprocess examples is performed using the freely available ACADO Multi-Objective Toolkit (http://www.acadotoolkit.org). This toolkit integrates efficient multiple objective scalarisation strategies (e.g., Normal Boundary Intersection and (Enhanced) Normalised Normal Constraint) with fast deterministic approaches for dynamic optimisation (e.g., single and multiple shooting). It has been found that the toolkit is able to efficiently and accurately produce the Pareto sets for all bioprocess examples. The resulting Pareto sets are added as supplementary material to this paper.     

On the use of multi-objective evolutionary algorithms for survival analysis

This paper proposes and evaluates a multi-objective evolutionary algorithm for survival analysis. One aim of survival analysis is the extraction of models from data that approximate lifetime/failure time distributions. These models can be used to estimate the time that an event takes to happen to an object. To use of multi-objective evolutionary algorithms for survival analysis has several advantages. They can cope with feature interactions, noisy data, and are capable of optimising several objectives. This is important, as model extraction is a multi-objective problem. It has at least two objectives, which are the extraction of accurate and simple models. Accurate models are required to achieve good predictions. Simple models are important to prevent overfitting, improve the transparency of the models, and to save computational resources. Although there is a plethora of evolutionary approaches to extract models for classification and regression, the presented approach is one of the first applied to survival analysis. The approach is evaluated on several artificial datasets and one medical dataset. It is shown that the approach is capable of producing accurate models, even for problems that violate some of the assumptions made by classical approaches.     

Artificial Evolution by Viability Rather than Competition

Evolutionary algorithms are widespread heuristic methods inspired by natural evolution to solve difficult problems for which analytical approaches are not suitable. In many domains experimenters are not only interested in discovering optimal solutions, but also in finding the largest number of different solutions satisfying minimal requirements. However, the formulation of an effective performance measure describing these requirements, also known as fitness function, represents a major challenge. The difficulty of combining and weighting multiple problem objectives and constraints of possibly varying nature and scale into a single fitness function often leads to unsatisfactory solutions. Furthermore, selective reproduction of the fittest solutions, which is inspired by competition-based selection in nature, leads to loss of diversity within the evolving population and premature convergence of the algorithm, hindering the discovery of many different solutions.Here we present an alternative abstraction of artificial evolution, which does not require the formulation of a composite fitness function. Inspired from viability theory in dynamical systems, natural evolution and ethology, the proposed method puts emphasis on the elimination of individuals that do not meet a set of changing criteria, which are defined on the problem objectives and constraints.Experimental results show that the proposed method maintains higher diversity in the evolving population and generates more unique solutions when compared to classical competition-based evolutionary algorithms. Our findings suggest that incorporating viability principles into evolutionary algorithms can significantly improve the applicability and effectiveness of evolutionary methods to numerous complex problems of science and engineering, ranging from protein structure prediction to aircraft wing design.     

A Multi-objective variable neighborhood search for the maximal covering location problem with customer preferences

This paper considers a variant of maximal covering location problem with customer preferences and two objectives involved: maximization of the weighted sum of the covered demand and minimization of the number of uncovered customers. The problem has important applications in service network design, such as telecommunication and computer networks, service placement problem, etc. This paper proposes a multi-objective variable neighborhood search (MO-VNS) as a metaheuristic approach for the considered problem. Following the concepts of basic, reduced, and general VNS in single-objective optimization, three MO-VNS variants are proposed: MO-BVNS, MO-RVNS, and MO-GVNS. The proposed MO-VNS implementations were compared with each other and with the existing multi-objective evolutionary algorithms (MOEAs). The MO-VNS concept showed to be superior over MOEA, as all MO-VNS variants outperform MOEAs in the sense of solution quality, especially on the largest size test instances.

     

Computational Models to Synthesize Human Walking

The synthesis of human walking is of great interest in biomechanics and biomimetic engineering due to its predictive capabilities and potential applications in clinical biomechanics, rehabilitation engineering and biomimetic robotics. In this paper, the various methods that have been used to synthesize humanwalking are reviewed from an engineering viewpoint. This involves a wide spectrum of approaches, from simple passive walking theories to large-scale computational models integrating the nervous, muscular and skeletal systems. These methods are roughly categorized under four headings： models inspired by the concept of a CPG （Central Pattern Generator）, methods based on the principles of control engineering, predictive gait simulation using optimisation, and models inspired by passive walking theory. The shortcomings and advantages of these methods are examined, and future directions are discussed in the context of providing insights into the neural control objectives driving gait and improving the stability of the predicted gaits. Future advancements are likely to be motivated by improved understanding of neural control strategies and the subtle complexities of the musculoskeletal system during human locomotion. It is only a matter of time before predictive gait models become a practical and valuable tool in clinical diagnosis, rehabilitation engineering and robotics.     

Parallel high-dimensional multi-objective feature selection for EEG classification with dynamic workload balancing on CPU–GPU architectures

Many bioinformatics applications that analyse large volumes of high-dimensional data comprise complex problems requiring metaheuristics approaches with different types of implicit parallelism. For example, although functional parallelism would be used to accelerate evolutionary algorithms, the fitness evaluation of the population could imply the computation of cost functions with data parallelism. This way, heterogeneous parallel architectures, including central processing unit (CPU) microprocessors with multiple superscalar cores and accelerators such as graphics processing units (GPUs) could be very useful. This paper aims to take advantage of such CPU–GPU heterogeneous architectures to accelerate electroencephalogram classification and feature selection problems by evolutionary multi-objective optimization, in the context of brain computing interface tasks. In this paper, we have used the OpenCL framework to develop parallel master-worker codes implementing an evolutionary multi-objective feature selection procedure in which the individuals of the population are dynamically distributed among the available CPU and GPU cores.     

A hybrid approach for efficient and robust parameter estimation in biochemical pathways

Developing suitable dynamic models of biochemical pathways is a key issue in Systems Biology. Predictive models for cells or whole organisms could ultimately lead to model-based predictive and/or preventive medicine. Parameter estimation (i.e. model calibration) in these dynamic models is therefore a critical problem. In a recent contribution [Moles, C.G., Mendes, P., Banga, J.R., 2003b. Parameter estimation in biochemical pathways: a comparison of global optimisation methods. Genome Res. 13, 2467-2474], the challenging nature of such inverse problems was highlighted considering a benchmark problem, and concluding that only a certain type of stochastic global optimisation method, Evolution Strategies (ES), was able to solve it successfully, although at a rather large computational cost. In this new contribution, we present a new integrated optimisation methodology with a number of very significant improvements: (i) computation time is reduced by one order of magnitude by means of a hybrid method which increases efficiency while guaranteeing robustness, (ii) measurement noise (errors) and partial observations are handled adequately, (iii) automatic testing of identifiability of the model (both local and practical) is included and (iv) the information content of the experiments is evaluated via the Fisher information matrix, with subsequent application to design of new optimal experiments through dynamic optimisation.     

A theoretical examination of the relative importance of evolution management and drug development for managing resistance

Drug resistance is a serious public health problem that threatens to thwart our ability to treat many infectious diseases. Repeatedly, the introduction of new drugs has been followed by the evolution of resistance. In principle, there are two complementary ways to address this problem: (i) enhancing drug development and (ii) slowing the evolution of drug resistance through evolutionary management. Although these two strategies are not mutually exclusive, it is nevertheless worthwhile considering whether one might be inherently more effective than the other. We present a simple mathematical model that explores how interventions aimed at these two approaches affect the availability of effective drugs. Our results identify an interesting feature of evolution management that, all else equal, tends to make it more effective than enhancing drug development. Thus, although enhancing drug development will necessarily be a central part of addressing the problem of resistance, our results lend support to the idea that evolution management is probably a very significant component of the solution as well.     

Bio-Inspired Binary Bees Algorithm for a Two-Level Distribution Optimisation Problem

<正> Two uncoupleable distributions, assigning missions to robots and allocating robots to home stations, accompany the use ofmobile service robots in hospitals.In the given problem, two workload-related objectives and five groups of constraints areproposed.A bio-mimicked Binary Bees Algorithm (BBA) is introduced to solve this multiobjective multiconstraint combinatorialoptimisation problem, in which constraint handling technique (Multiobjective Transformation, MOT), multiobjectiveevaluation method (nondominance selection), global search strategy (stochastic search in the variable space), local searchstrategy (Hamming neighbourhood exploitation), and post-processing means (feasibility selection) are the main issues.TheBBA is then demonstrated with a case study, presenting the execution process of the algorithm, and also explaining the change ofelite number in evolutionary process.Its optimisation result provides a group of feasible nondominated two-level distributionschemes.     

PERSPECTIVE: COMPLEX ADAPTATIONS AND THE EVOLUTION OF EVOLVABILITY

The problem of complex adaptations is studied in two largely disconnected research traditions: evolutionary biology and evolutionary computer science. This paper summarizes the results from both areas and compares their implications. In evolutionary computer science it was found that the Darwinian process of mutation, recombination and selection is not universally effective in improving complex systems like computer programs or chip designs. For adaptation to occur, these systems must possess “evolvability,” i.e., the ability of random variations to sometimes produce improvement. It was found that evolvability critically depends on the way genetic variation maps onto phenotypic variation, an issue known as the representation problem. The genotype-phenotype map determines the variability of characters, which is the propensity to vary. Variability needs to be distinguished from variations, which are the actually realized differences between individuals. The genotype-phenotype map is the common theme underlying such varied biological phenomena as genetic canalization, developmental constraints, biological versatility, developmental dissociability, and morphological integration. For evolutionary biology the representation problem has important implications: how is it that extant species acquired a genotype-phenotype map which allows improvement by mutation and selection? Is the genotype-phenotype map able to change in evolution? What are the selective forces, if any, that shape the genotype-phenotype map? We propose that the genotype-phenotype map can evolve by two main routes: epistatic mutations, or the creation of new genes. A common result for organismic design is modularity. By modularity we mean a genotype-phenotype map in which there are few pleiotropic effects among characters serving different functions, with pleiotropic effects falling mainly among characters that are part of a single functional complex. Such a design is expected to improve evolvability by limiting the interference between the adaptation of different functions. Several population genetic models are reviewed that are intended to explain the evolutionary origin of a modular design. While our current knowledge is insufficient to assess the plausibility of these models, they form the beginning of a framework for understanding the evolution of the genotype-phenotype map.     

Mode and tempo in the evolution of socio-political organization: reconciling 'Darwinian' and 'Spencerian' evolutionary approaches in anthropology

Traditional investigations of the evolution of human social and political institutions trace their ancestry back to nineteenth century social scientists such as Herbert Spencer, and have concentrated on the increase in socio-political complexity over time. More recent studies of cultural evolution have been explicitly informed by Darwinian evolutionary theory and focus on the transmission of cultural traits between individuals. These two approaches to investigating cultural change are often seen as incompatible. However, we argue that many of the defining features and assumptions of 'Spencerian' cultural evolutionary theory represent testable hypotheses that can and should be tackled within a broader 'Darwinian' framework. In this paper we apply phylogenetic comparative techniques to data from Austronesian-speaking societies of Island South-East Asia and the Pacific to test hypotheses about the mode and tempo of human socio-political evolution. We find support for three ideas often associated with Spencerian cultural evolutionary theory: (i) political organization has evolved through a regular sequence of forms, (ii) increases in hierarchical political complexity have been more common than decreases, and (iii) political organization has co-evolved with the wider presence of hereditary social stratification.     

Algorithmic approaches to clonal reconstruction in heterogeneous cell populations

Background: The reconstruction of clonal haplotypes and their evolutionary history in evolving populations is a common problem in both microbial evolutionary biology and cancer biology. The clonal theory of evolution provides a theoretical framework for modeling the evolution of clones.Results: In this paper, we review the theoretical framework and assumptions over which the clonal reconstruction problem is formulated. We formally define the problem and then discuss the complexity and solution space of the problem. Various methods have been proposed to find the phylogeny that best explains the observed data. We categorize these methods based on the type of input data that they use (space-resolved or time-resolved), and also based on their computational formulation as either combinatorial or probabilistic. It is crucial to understand the different types of input data because each provides essential but distinct information for drastically reducing the solution space of the clonal reconstruction problem. Complementary information provided by single cell sequencing or from whole genome sequencing of randomly isolated clones can also improve the accuracy of clonal reconstruction. We briefly review the existing algorithms and their relationships. Finally we summarize the tools that are developed for either directly solving the clonal reconstruction problem or a related computational problem.Conclusions: In this review, we discuss the various formulations of the problem of inferring the clonal evolutionary history from allele frequeny data, review existing algorithms and catergorize them according to their problem formulation and solution approaches. We note that most of the available clonal inference algorithms were developed for elucidating tumor evolution whereas clonal reconstruction for unicellular genomes are less addressed. We conclude the review by discussing more open problems such as the lack of benchmark datasets and comparison of performance between available tools.     

Organic Codes: A Unifying Concept for Life

Although the knowledge about biological systems has advanced exponentially in recent decades, it is surprising to realize that the very definition of Life keeps presenting theoretical challenges. Even if several lines of reasoning seek to identify the essence of life phenomenon, most of these thoughts contain fundamental problem in their basic conceptual structure. Most concepts fail to identify either necessary or sufficient features to define life. Here, we analyzed the main conceptual frameworks regarding theoretical aspects that have been supporting the most accepted concepts of life, such as (i) the physical, (ii) the cellular and (iii) the molecular approaches. Based on an ontological analysis, we propose that Life should not be positioned under the ontological category of Matter. Yet, life should be better understood under the top-level ontology of “Process”. Exercising an epistemological approach, we propose that the essential characteristic that pervades each and every living being is the presence of organic codes. Therefore, we explore theories in biosemiotics and code biology in order to propose a clear concept of life as a macrocode composed by multiple inter-related coding layers. This way, as life is a sort of metaphysical process of encoding, the living beings became the molecular materialization of that process. From the proposed concept, we show that the evolutionary process is a fundamental characteristic for life’s maintenance but it is not necessary to define life, as many organisms are clearly alive but they do not participate in the evolutionary process (such as infertile hybrids). The current proposition opens a fertile field of debate in astrobiology, epistemology, biosemiotics, code biology and robotics.

     

The Structure of the Two Ecological Paradigms

Ecological theory is built upon assumptions about the fundamental nature of organism-environment interactions. We argue that two mutually exclusive sets of such assumptions are available and that they have given rise to alternative approaches to studying ecology. The fundamentally different premises of these approaches render them irreconcilable with one another. In this paper, we present the first logical formalisation of these two paradigms.The more widely-accepted approach - which we label the demographic paradigm - includes both population ecology and community ecology (synecology). Demographic ecology assumes that the environment is relatively stable and that biotic processes, governed predominantly by resource availability, are the most important of ecological and evolutionary influences. Moreover, ecological processes are assumed to translate into directional selection pressures that drive significant evolutionary change on a local scale through the process of optimisation.Serious deficiencies in aspects of the demographic approach have been identified over the past few decades by various ecologists, including Gleason, Andrewartha and Birch, White, Den Boer, Strong, Simberloff, and others. Short-term evolutionary optimisation has also been seriously questioned.The development of the alternative approach (autecology) has been subverted by the prominence of demographic ecology. Moreover, it has not been recognised that autecology is underpinned by robust principles and that they are independent of the underlying demographic principles. Components of the autecological approach have been developed to some extent, but they have not been integrated with ancillary fields of study. We therefore articulate the assumptions from which autecology is derived, and use this as a basis for integrating the various spheres of autecological research.We add to the ongoing development of autecology by linking autecological understanding, in so far as it is developed, with the evolutionary justification for species' characteristics being stable in an environment that is continuously dynamic in space and time. The ecology of organisms is essentially an ongoing matching of their species-specific characteristics to the prevailing environmental factors and dynamics. We thus provide a consistent logic through the following subject areas; climate and climate change, spatial and temporal environmental heterogeneity and dynamic theory, physiology, behaviour, migration, and evolution. We demonstrate why adaptation cannot be an ongoing process, but takes place only when organisms are prevented, by incidental influences, from matching the overall dynamics of the environment.