In numerous contexts today we are faced with making decisions of increasing size and complexity, where many different considerations interlock in complex ways. Consider a staff rostering problem to assign staff to shifts while respecting required shift patterns and staffing levels, physical and staff resources, and staff working preferences. The decision-making process is often further complicated by the need also to optimise an objective, such as to maximise profit or to minimise waste. It is natural to characterise such problems as a set of decision variables, each representing a choice that must be made in order to solve the problem at hand (e.g. which staff member is on duty for the Friday night shift), and a set of constraints describing allowed combinations of variable assignments (e.g. a staff member cannot be assigned to a day shift immediately following a night shift). A solution is an assignment of a value to each variable satisfying all constraints. Many decision-making and optimisation formalisms take this general form. In all of these formalisms the model of the problem is crucial to the efficiency with which it can be solved. A model in this sense is the set of decision variables and constraints chosen to represent a given problem. There are typically many possible models and formulating an effective model is notoriously difficult. Therefore automating modelling is a key challenge. Over the last decade, in the context of Constraint Programming we have taken a novel approach to addressing this challenge. The user writes a problem specification in the abstract constraint specification language 'Essence', capturing the structure of the problem above the level of abstraction at which modelling decisions are made. Our modelling pipeline, on which our proposed research is based, automatically generates a model from this specification. This removes the need for user constraint modelling expertise, and also preserves the structure of the specified problem, allowing the system easily to explore alternative models and to exploit properties such as symmetry. Our pipeline generates constraint models equivalent in quality to those of a competent human constraint programmer, and so represents a significant milestone towards fully automated modelling. Important challenges do, however, remain. The first is to generate models of the quality that human experts are capable. Given the inherent difficulty of these problems, and the importance of the model in mitigating that difficulty, raising the quality of the generated models is crucial. The second is to expand the range of output models beyond the constraint programming formalism. The substantial challenge we address in this proposal is to overcome these two limitations to produce a powerful, general automated modelling and solving system unique in targeting a range of solving formalisms from a single abstract constraint specification. Our existing pipeline is ideal for extension to other formalisms. The impact of this change will be substantial: combinatorial search problems are ubiquitous across the public and private sectors, and academia. We will deliver better solutions to these problems more rapidly, increasing efficiency and reducing cost.

Heart disease is the leading cause of disability and death in the UK and worldwide, resulting in enormous health care costs. Risk prediction on an individual patient basis is imperfect. Advanced medical development has already saved many lives, particularly in systolic heart failure. However, there is currently no treatment option for diastolic heart failure (with preserved ejection fraction) due to its complexity of multiple mechanisms and co-modality. Structural heart diseases, such as myocardial infarction (MI- commonly known as heart attack) and mitral regurgitation (MR, a leakage of blood through the mitral valve to left atrium in systole), where biomechanical factors are crucial, are often precursors to heart failure. MI can eventually lead to dilated heart failure despite immediate treatments post-MI. MR can induce pulmonary hypertension and oedema and subsequently, right heart overload and heart failure. The grand challenge is for these situations the heart simply cannot be modelled as an isolated left ventricle (as in most of the current studies); flow-structure interaction (FSI), heart-valve interaction, multiscale soft tissue mechanics, and tissue growth and remodelling (G&R) all play important roles in the progression of the structural diseases. This project is set up to meet this challenge by delivering a multiscale computational framework to include Whole-Heart FSI with G&R. Making use of the novel mathematical tools (constitutive laws, G&R, upscaling and statistical inference) developed by SofTMech, I will build a realistic four-chamber heart model that include heart-valve, chamber-chamber, heart-blood, and heart-circulation interactions, which will be powerful enough to model MI, MR and their pathological consequences. This work will be in close collaboration with my clinical, industrial and academic collaborators. The model will quantify which factors lead to adverse G&R and what variations are to be expected as the disease progresses. We will also identify significant biomechanical markers (e.g. constitutive parameters, energy indices, stress/strain evolution). The predictive values of these biomechanical parameters will be assessed against other established predictors of adverse remodellings, such as duration of ischaemia, final coronary flow grade after a primary percutaneous coronary intervention, and microvascular obstruction revealed by MRI. Thus, this project will generate new testable hypotheses and will be a significant step up towards more consistent decision-support for clinicians, since increasingly the pace and complexity of medical advances outstrip the ability of individual clinicians to cope with. Due to the statistical emulation and uncertainty quantification built into the project, the model predictions will be fast and quantified with error bounds on the outcome of alternative treatments. Consequently, we will also address the critical aspect of convincing clinicians that information obtained from simulations will be correct and relevant to their daily practice. The proposed research is right within the Healthcare Technologies "Optimising Treatment" and "Developing Future Therapies" priority areas, as well as targeting "New Connections from Mathematical Sciences", and "Statistics and Applied Probability" of Mathematical Sciences.