Matheuristic algorithms for solving multi-objective/stochastic scheduling and routing problems

In der Praxis beinhalten Optimierungsprobleme oft unterschiedliche Ziele, welche optimiert werden sollen. Oft ist es nicht möglich die Ziele zu einem einzelnen Ziel zusammenzufassen. Mehrzieloptimierung beschäftigt sich damit, solche Probleme zu lösen. Wie in der Einzieloptimierung muss eine Lösung alle Nebenbedingungen des Problems erfüllen. Im Allgemeinen sind die Ziele konfligierend, sodass es nicht möglich ist eine einzelne Lösung zu finden welche optimal im Sinne aller Ziele ist. Algorithmen zum Lösen von Mehrziel-Optimierungsproblemen, präsentieren dem Entscheider eine Menge von effizienten Alternativen. Effizienz in der Mehrzieloptimierung ist als Pareto-Optimalität ausgedrückt. Eine Lösung eines Optimierungsproblems ist genau dann Pareto-optimal wenn es keine andere zulässige Lösung gibt, welche in allen Zielen mindestens gleich gut wie die betrachtete Lösung ist und besser in mindestens einem Ziel. In dieser Arbeit werden Mehrziel-Optimierungsprobleme aus zwei unterschiedlichen Anwendungsgebieten betrachtet. Das erste Problem, das Multi-objective Project Selection, Scheduling and Staffing with Learning Problem (MPSSSL), entstammt dem Management in forschungsorientierten Organisationen. Die Entscheider in solchen Organisationen stehen vor der Frage welche Projekte sie aus einer Menge von Projektanträgen auswählen sollen, und wie diese Teilmenge von Projekten (ein Projektportfolio) mit den benötigten Ressourcen ausgestattet werden kann (dies beinhaltet die zeitliche und personelle Planung). Aus unterschiedlichen Gründen ist dieses Problem schwer zu lösen, z.B. (i) die Auswahl von Projekten unter Beachtung der beschränkten Ressourcen ist ein Rucksackproblem (und ist damit NP-schwer) (ii) ob ein Projektportfolio zulässig ist oder nicht hängt davon ab ob, man dafür einen Zeitplan erstellen kann und genügend Mitarbeiter zur Verfügung stehen. Da in diesem Problem die Mitarbeiterzuordnung zu den einzelnen Projekten einbezogen wird, muss der Entscheider Ziele unterschiedlicher Art berücksichtigen. Manche Ziele sind ökonomischer Natur, z.B. die Rendite, andere wiederum beziehen sich auf die Kompetenzentwicklung der einzelnen Mitarbeiter. Ziele, die sich auf die Kompetenzentwicklung beziehen, sollen sicherstellen, dass das Unternehmen auch in Zukunft am Markt bestehen kann. Im Allgemeinen können diese unterschiedlichen Ziele nicht zu einem einzigen Ziel zusammengefasst werden. Daher werden Methoden zur Lösung von Mehrziel-Optimierungsproblemen benötigt. Um MPSSSL Probleme zu lösen werden in dieser Arbeit zwei unterschiedliche hybride Algorithmen betrachtet. Beide kombinieren nämlich Metaheuristiken (i) den Nondominated Sorting Genetic (NSGA-II) Algorithmus, und den (ii)~Pareto Ant Colony (P-ACO) Algorithmus, mit einem exakten Algorithmus zum Lösen von Linearen Programmen kombinieren. Unsicherheit ist ein weiterer wichtiger Aspekt der in der Praxis auftaucht. Unterschiedliche Parameter des Problems können unsicher sein (z.B. der aus einem Projekt erzielte Gewinn oder die Zeit bzw. der Aufwand, der benötigt wird, um die einzelnen Vorgänge eines Projekts abzuschließen). Um in diesem Fall das ``beste'' Projektportfolio zu finden, werden Methoden benötigt, welche stochastische Mehrziel-Optimierungsprobleme lösen können. Zur Lösung der stochastischen Erweiterung (SMPSSSL) des MPSSSL Problems zu lösen, präsentieren wir eine Methode, die den zuvor genannten hybriden NSGA-II Algorithmus mit dem Adaptive Pareto Sampling (APS) Algorithmus kombiniert. APS wird verwendet, um das Zusammenspiel von Simulation und Optimierung zu koordinieren. Zur Steigerung der Performance des Simulationsprozesses, verwenden wir Importance Sampling (IS). Das zweite Problem dieser Arbeit, das Bi-Objective Capacitated Vehicle Routing Problem with Route Balancing (CVRPB), kommt aus dem Bereich Logistik. Wenn man eine Menge von Kunden zu beliefern hat, steht man als Entscheider vor der Frage, wie man die Routen für eine fixe Anzahl von Fahrzeugen (mit beschränkter Kapazität) bestimmt, sodass alle Kunden beliefert werden können. Die Routen aller Fahrzeuge starten und enden dabei immer bei einem Depot. Die Einziel-Variante dieses Problems ist als Capacitated Vehicle Routing Problem (CVRP) bekannt, dessen Ziel es ist die Lösung zu finden, die die Gesamtkosten aller Routen minimiert. Dabei tritt jedoch das Problem auf, dass die Routen der optimalen Lösung sehr unterschiedliche Fahrtzeiten haben können. Unter bestimmten Umständen ist dies jedoch nicht erwünscht. Um dieses Problem zu umgehen, betrachten wir in dieser Arbeit eine Variante des (bezeichnet als CVRPB) CVRP, welche als zweite Zielfunktion die Balanziertheit der einzelnen Routen einbezieht. Zur Lösung von CVRPB Problemen verwenden wir die Adaptive Epsilon-Constraint Method in Kombination mit einem Branch-and-Cut Algorithmus und zwei unterschiedlichen Genetischen Algorithmen (GA), (i) einem Einziel-GA und (ii) dem NSGA-II. In dieser Arbeit werden Optimierungsalgorithmen präsentiert, welche es erlauben, Mehrziel- und stochastische Mehrziel-Optimierungsprobleme zu lösen. Unterschiedliche Algorithmen wurden implementiert und basierend auf aktuellen Performance-Maßen verglichen. Experimente haben gezeigt, dass die entwickelten Methoden gut geeignet sind, die betrachteten Optimierungsprobleme zu lösen. Die hybriden Algorithmen, welche Metaheuristiken mit exakten Methoden kombinieren, waren entweder ausschlaggebend um das Problem zu lösen (im Fall des Project Portfolio Selection Problems) oder konnten die Performance des Lösungsprozesses signifikant verbessern (im Fall des Vehicle Routing Problems).In practice decision problems often include different goals which can hardly be aggregated to a single objective for different reasons. In the field of multi-objective optimization several objective functions are considered. As in single objective optimization a solution has to satisfy all constraints of the problem. In general the goals are conflicting and there will be no solution, that is optimal for all objectives. Algorithms for multi-objective optimization problems provide the decision maker a set of efficient solutions, among which she or he can choose the most suitable alternative. In multi-objective optimization efficiency of a solution is expressed as Pareto-optimality. Pareto-optimality of a solution is defined as the property that no other solution exists that is better than the proposed one in at least one objective and at least equally good in all criteria. The first application that is considered in this thesis, the Multi-objective Project Selection, Scheduling and Staffing with Learning problem (MPSSSL) arises from the field of management in research-centered organizations. Given a set of project proposals the decision makers have to select the ``best'' subset of projects (a project portfolio) and set these up properly (schedule them and provide the necessary resources). This problem is hard to solve for different reasons: (i) selecting a subset of projects considering limited resources is a knapsack-type problem that is known to be NP-hard, and (ii) to determine the feasibility of a given portfolio, the projects have to be scheduled and staff must be assigned to them. As in this problem the assignment of workers is influenced by the decision which portfolio should be selected, the decision maker has to consider goals of different nature. Some objectives are related to economic goals (e.g. return of investment), others are related to the competence development of the workers. Competence oriented goals are motivated by the fact that competencies determine the attainment and sustainability of strategic positions in market competition. In general the objectives cannot be combined to a single objective, therefore methods for solving multi-objective optimization problems are used. To solve the problem we use two different hybrid algorithms that combine metaheuristic algorithms, (i) the Nondominated Sorting Genetic Algorithm (NSGA-II), and (ii) Pareto Ant Colony (P-ACO) algorithm with a linear programming solver as a subordinate. In practice, uncertainty is another typically encountered aspect. Different parameters of the problem can be uncertain (e.g. benefits of a project, or the time and effort required to perform the single activities required by a project). To determine the ``best'' portfolio, methods are needed that are able to handle uncertainty in optimization. To solve the stochastic extension (SMPSSSL) of the MPSSSL problem we present an algorithm that combines the aforementioned NSGA-II algorithm with the Adaptive Pareto Sampling (APS) algorithm. APS is used to handle the interplay between multi-objective optimization and simulation. The performance of the simulation process is increased by using importance sampling (IS). The second problem, the Bi-objective Capacitated Vehicle Routing Problem with Route Balancing (CVRPB) arises from the field of vehicle routing. Given a set of customers, the decision makers have to construct routes for a fixed number of vehicles, each starting and ending at the same depot, such that the demands of all customers can be fulfilled, and the capacity constraints of each vehicle are not violated. The traditional objective of this problem (known as the Capacitated Vehicle Routing Problem (CVRP)) is minimizing the total costs of all routes. A problem that may arise by this approach is that the resulting routes can be very unbalanced (in the sense of drivers workload). To overcome this problem a second objective function that measures the balance of the routes of a solution is introduced. In this work, we use the Adaptive Epsilon-Constraint Method in combination with a branch-and-cut algorithm and two genetic algorithms (i) a single-objective GA and (ii) the multi-objective NSGA-II, to solve the considered problem. Prototypes of different algorithms to solve the problems are developed and their performance is assessed by using state of the art performance measures. The computational experiments show that the developed solution procedures will be well suited to solve the considered optimization problems. The hybrid algorithms combining metaheuristic and exact optimization methods, turned out to be crucial to solve the problem (application to project portfolio selection) or to improve the performance of the solution procedure (application to vehicle routing)

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar