An application of genetic algorithms to chemotherapy treatment.

The present work investigates methods for optimising cancer chemotherapy within the bounds of clinical acceptability and making this optimisation easily accessible to oncologists. Clinical oncologists wish to be able to improve existing treatment regimens in a systematic, effective and reliable way. In order to satisfy these requirements a novel approach to chemotherapy optimisation has been developed, which utilises Genetic Algorithms in an intelligent search process for good chemotherapy treatments. The following chapters consequently address various issues related to this approach. Chapter 1 gives some biomedical background to the problem of cancer and its treatment. The complexity of the cancer phenomenon, as well as the multi-variable and multi-constrained nature of chemotherapy treatment, strongly support the use of mathematical modelling for predicting and controlling the development of cancer. Some existing mathematical models, which describe the proliferation process of cancerous cells and the effect of anti-cancer drugs on this process, are presented in Chapter 2. Having mentioned the control of cancer development, the relevance of optimisation and optimal control theory becomes evident for achieving the optimal treatment outcome subject to the constraints of cancer chemotherapy. A survey of traditional optimisation methods applicable to the problem under investigation is given in Chapter 3 with the conclusion that the constraints imposed on cancer chemotherapy and general non-linearity of the optimisation functionals associated with the objectives of cancer treatment often make these methods of optimisation ineffective. Contrariwise, Genetic Algorithms (GAs), featuring the methods of evolutionary search and optimisation, have recently demonstrated in many practical situations an ability to quickly discover useful solutions to highly-constrained, irregular and discontinuous problems that have been difficult to solve by traditional optimisation methods. Chapter 4 presents the essence of Genetic Algorithms, as well as their salient features and properties, and prepares the ground for the utilisation of Genetic Algorithms for optimising cancer chemotherapy treatment. The particulars of chemotherapy optimisation using Genetic Algorithms are given in Chapter 5 and Chapter 6, which present the original work of this thesis. In Chapter 5 the optimisation problem of single-drug chemotherapy is formulated as a search task and solved by several numerical methods. The results obtained from different optimisation methods are used to assess the quality of the GA solution and the effectiveness of Genetic Algorithms as a whole. Also, in Chapter 5 a new approach to tuning GA factors is developed, whereby the optimisation performance of Genetic Algorithms can be significantly improved. This approach is based on statistical inference about the significance of GA factors and on regression analysis of the GA performance. Being less computationally intensive compared to the existing methods of GA factor adjusting, the newly developed approach often gives better tuning results. Chapter 6 deals with the optimisation of multi-drug chemotherapy, which is a more practical and challenging problem. Its practicality can be explained by oncologists' preferences to administer anti-cancer drugs in various combinations in order to better cope with the occurrence of drug resistant cells. However, the imposition of strict toxicity constraints on combining various anticancer drugs together, makes the optimisation problem of multi-drug chemotherapy very difficult to solve, especially when complex treatment objectives are considered. Nevertheless, the experimental results of Chapter 6 demonstrate that this problem is tractable to Genetic Algorithms, which are capable of finding good chemotherapeutic regimens in different treatment situations. On the basis of these results a decision has been made to encapsulate Genetic Algorithms into an independent optimisation module and to embed this module into a more general and user-oriented environment - the Oncology Workbench. The particulars of this encapsulation and embedding are also given in Chapter 6. Finally, Chapter 7 concludes the present work by summarising the contributions made to the knowledge of the subject treated and by outlining the directions for further investigations. The main contributions are: (1) a novel application of the Genetic Algorithm technique in the field of cancer chemotherapy optimisation, (2) the development of a statistical method for tuning the values of GA factors, and (3) the development of a robust and versatile optimisation utility for a clinically usable decision support system. The latter contribution of this thesis creates an opportunity to widen the application domain of Genetic Algorithms within the field of drug treatments and to allow more clinicians to benefit from utilising the GA optimisation

The Local Optima Level in Chemotherapy Schedule Optimisation

In this paper a multi-drug Chemotherapy Schedule Optimisation Problem (CSOP) is subject to Local Optima Network (LON) analysis. LONs capture global patterns in fitness landscapes. CSOPs have not previously been subject to fitness landscape analysis. We fill this gap: LONs are constructed and studied for meaningful structure. The CSOP formulation presents novel challenges and questions for the LON model because there are infeasible regions in the fitness landscape and an unknown global optimum; it also brings a topic from healthcare to LON analysis. Two LON Construction algorithms are proposed for sampling CSOP fitness landscapes: a Markov-Chain Construction Algorithm and a Hybrid Construction Algorithm. The results provide new insight into LONs of highly-constrained spaces, and into the proficiency of search operators on the CSOP. Iterated Local Search and Memetic Search, which are the foundations for the LON algorithms, are found to markedly out-perform a Genetic Algorithm from the literature

Directed Intervention Crossover Approaches in Genetic Algorithms with Application to Optimal Control Problems

Genetic Algorithms (GAs) are a search heuristic modeled on the processes of evolution. They have been used to solve optimisation problems in a wide variety of fields. When applied to the optimisation of intervention schedules for optimal control problems, such as cancer chemotherapy treatment scheduling, GAs have been shown to require more fitness function evaluations than other search heuristics to find fit solutions. This thesis presents extensions to the GA crossover process, termed directed intervention crossover techniques, that greatly reduce the number of fitness function evaluations required to find fit solutions, thus increasing the effectiveness of GAs for problems of this type. The directed intervention crossover techniques use intervention scheduling information from parent solutions to direct the offspring produced in the GA crossover process towards more promising areas of a search space. By counting the number of interventions present in parents and adjusting the number of interventions for offspring schedules around it, this allows for highly fit solutions to be found in less fitness function evaluations. The validity of these novel approaches are illustrated through comparison with conventional GA crossover approaches for optimisation of intervention schedules of bio-control application in mushroom farming and cancer chemotherapy treatment. These involve optimally scheduling the application of a bio-control agent to combat pests in mushroom farming and optimising the timing and dosage strength of cancer chemotherapy treatments to maximise their effectiveness. This work demonstrates that significant advantages are gained in terms of both fitness function evaluations required and fitness scores found using the proposed approaches when compared with traditional GA crossover approaches for the production of optimal control schedules

Chemotherapy drug regimen optimization using deterministic oscillatory search algorithm

Purpose: To schedule chemotherapy drug delivery using Deterministic Oscillatory Search algorithm, keeping the toxicity level within permissible limits and reducing the number of tumor cells within a predefined time period.Methods: A novel metaheuristic algorithm, deterministic oscillatory search, has been used to optimize the Gompertzian model of the drug regimen problem. The model is tested with fixed (fixed interval variable dose, FIVD) and variable (variable interval variable dose, VIVD) interval schemes and the dosage presented for 52 weeks. In the fixed interval, the treatment plan is fixed in such a way that doses are given on the first two days of every seven weeks such as day 7, day 14, etc.Results: On comparing the two schemes, FIVD provided a higher reduction in the number of tumor cells by 98 % compared to 87 % by VIVD after the treatment period. Also, a significant reduction in the number was obtained half way through the regimen. The dose level and toxicity are also reduced in the FIVD scheme. The value of drug concentration is more in FIVD scheme (50) compared to VIVD (41); however, it is well within the acceptable limits of concentration. The results proved the effectiveness of the proposed technique in terms of reduced drug concentration, toxicity, tumor size and drug level within a predetermined time period.Conclusion: Artificial intelligent techniques can be used as a tool to aid oncologists in the effective treatment of cancer through chemotherapy.Keywords: Deterministic Oscillatory Search, Chemotherapy scheduling, Drug schedule, Artificial intelligenc

Optimal Multi-Drug Chemotherapy Control Scheme for Cancer Treatment. Design and development of a multi-drug feedback control scheme for optimal chemotherapy treatment for cancer. Evolutionary multi-objective optimisation algorithms were used to achieve the optimal parameters of the controller for effective treatment of cancer with minimum side effects.

Cancer is a generic term for a large group of diseases where cells of the body lose their normal mechanisms for growth so that they grow in an uncontrolled way. One of the most common treatments of cancer is chemotherapy that aims to kill abnormal proliferating cells; however normal cells and other organs of the patients are also adversely affected. In practice, it¿s often difficult to maintain optimum chemotherapy doses that can maximise the abnormal cell killing as well as reducing side effects. The most chemotherapy drugs used in cancer treatment are toxic agents and usually have narrow therapeutic indices, dose levels in which these drugs significantly kill the cancerous cells are close to the levels which sometime cause harmful toxic side effects. To make the chemotherapeutic treatment effective, optimum drug scheduling is required to balance between the beneficial and toxic side effects of the cancer drugs. Conventional clinical methods very often fail to find drug doses that balance between these two due to their inherent conflicting nature. In this investigation, mathematical models for cancer chemotherapy are used to predict the number of tumour cells and control the tumour growth during treatment. A feedback control method is used so as to maintain certain level of drug concentrations at the tumour sites. Multi-objective Genetic Algorithm (MOGA) is then employed to find suitable solutions where drug resistances and drug concentrations are incorporated with cancer cell killing and toxic effects as design objectives. Several constraints and specific goal values were set for different design objectives in the optimisation process and a wide range of acceptable solutions were obtained trading off among different conflicting objectives. Abstract v In order to develop a multi-objective optimal control model, this study used proportional, integral and derivative (PID) and I-PD (modified PID with Integrator used as series) controllers based on Martin¿s growth model for optimum drug concentration to treat cancer. To the best of our knowledge, this is the first PID/I-PD based optimal chemotherapy control model used to investigate the cancer treatment. It has been observed that some solutions can reduce the cancer cells up to nearly 100% with much lower side effects and drug resistance during the whole period of treatment. The proposed strategy has been extended for more drugs and more design constraints and objectives.Libyan Ministry of Higher Educatio

Optimisation of cancer drug treatments using cell population dynamics

International audienceCancer is primarily a disease of the physiological control on cell population proliferation. Tissue proliferation relies on the cell division cycle: one cell becomes two after a sequence of molecular events that are physiologically controlled at each step of the cycle at so-called checkpoints, in particular at transitions between phases of the cycle [105]. Tissue proliferation is the main physiological process occurring in development and later in maintaining the permanence of the organism in adults, at that late stage mainly in fast renewing tissues such as bone marrow, gut and skin

Statistical optimisation and tuning of GA factors.

This paper presents a practical methodology of improving the efficiency of Genetic Algorithms through tuning the factors significantly affecting GA performance. This methodology is based on the methods of statistical inference and has been successfully applied to both binary- and integer-encoded Genetic Algorithms that search for good chemotherapeutic schedules

An Evolutionary Variable Neighborhood Search for Selecting Combinational Gene Signatures in Predicting Chemo-Response of Osteosarcoma

In genomic studies of cancers, identification of genetic biomarkers from analyzing microarray chip that interrogate thousands of genes is important for diagnosis and therapeutics. However, the commonly used statistical significance analysis can only provide information of each single gene, thus neglecting the intrinsic interactions among genes. Therefore, methods aiming at combinational gene signatures are highly valuable. Supervised classification is an effective way to assess the function of a gene combination in differentiating various groups of samples. In this paper, an evolutionary variable neighborhood search (EVNS) that integrated the approaches of evolutionary algorithm and variable neighborhood search (VNS) is introduced.It consists of a population of solutions that evolution is performed by a variable neighborhood search operator, instead of the more usual reproduction operators, crossover and mutation used in evolutionary algorithms. It is an efficient search algorithm especially suitable for tremendous solution space. The proposed EVNS can simultaneously optimize the feature subset and the classifier through a common solution coding mechanism. This method was applied in searching the combinational gene signatures for predicting histologic response of chemotherapy on osteosarcoma patients, which is the most common malignant bone tumor in children. Cross-validation results show that EVNS outperforms the other existing approaches in classifying initial biopsy samples

Dynamic multi-objective optimisation using deep reinforcement learning::benchmark, algorithm and an application to identify vulnerable zones based on water quality

Dynamic multi-objective optimisation problem (DMOP) has brought a great challenge to the reinforcement learning (RL) research area due to its dynamic nature such as objective functions, constraints and problem parameters that may change over time. This study aims to identify the lacking in the existing benchmarks for multi-objective optimisation for the dynamic environment in the RL settings. Hence, a dynamic multi-objective testbed has been created which is a modified version of the conventional deep-sea treasure (DST) hunt testbed. This modified testbed fulfils the changing aspects of the dynamic environment in terms of the characteristics where the changes occur based on time. To the authors’ knowledge, this is the first dynamic multi-objective testbed for RL research, especially for deep reinforcement learning. In addition to that, a generic algorithm is proposed to solve the multi-objective optimisation problem in a dynamic constrained environment that maintains equilibrium by mapping different objectives simultaneously to provide the most compromised solution that closed to the true Pareto front (PF). As a proof of concept, the developed algorithm has been implemented to build an expert system for a real-world scenario using Markov decision process to identify the vulnerable zones based on water quality resilience in São Paulo, Brazil. The outcome of the implementation reveals that the proposed parity-Q deep Q network (PQDQN) algorithm is an efficient way to optimise the decision in a dynamic environment. Moreover, the result shows PQDQN algorithm performs better compared to the other state-of-the-art solutions both in the simulated and the real-world scenario

TEDA: A Targeted Estimation of Distribution Algorithm

This thesis discusses the development and performance of a novel evolutionary algorithm, the Targeted Estimation of Distribution Algorithm (TEDA). TEDA takes the concept of targeting, an idea that has previously been shown to be effective as part of a Genetic Algorithm (GA) called Fitness Directed Crossover (FDC), and introduces it into a novel hybrid algorithm that transitions from a GA to an Estimation of Distribution Algorithm (EDA). Targeting is a process for solving optimisation problems where there is a concept of control points, genes that can be said to be active, and where the total number of control points found within a solution is as important as where they are located. When generating a new solution an algorithm that uses targeting must first of all choose the number of control points to set in the new solution before choosing which to set. The hybrid approach is designed to take advantage of the ability of EDAs to exploit patterns within the population to effectively locate the global optimum while avoiding the tendency of EDAs to prematurely converge. This is achieved by initially using a GA to effectively explore the search space before transitioning into an EDA as the population converges on the region of the global optimum. As targeting places an extra restriction on the solutions produced by specifying their size, combining it with the hybrid approach allows TEDA to produce solutions that are of an optimal size and of a higher quality than would be found using a GA alone without risking a loss of diversity. TEDA is tested on three different problem domains. These are optimal control of cancer chemotherapy, network routing and Feature Subset Selection (FSS). Of these problems, TEDA showed consistent advantage over standard EAs in the routing problem and demonstrated that it is able to find good solutions faster than untargeted EAs and non evolutionary approaches at the FSS problem. It did not demonstrate any advantage over other approaches when applied to chemotherapy. The FSS domain demonstrated that in large and noisy problems TEDA’s targeting derived ability to reduce the size of the search space significantly increased the speed with which good solutions could be found. The routing domain demonstrated that, where the ideal number of control points is deceptive, both targeting and the exploitative capabilities of an EDA are needed, making TEDA a more effective approach than both untargeted approaches and FDC. Additionally, in none of the problems was TEDA seen to perform significantly worse than any alternative approaches