Title: How can we Prognosticate airway and Respiratory functiOn decline in Mucopolysaccharidosis type IVA? From ‘bIg data’ in rare diseases to preciSion medicinE (PROMISE)
Funder: Department of Health and Social Care

Abstract: Background What is MPS-IVA?Mucopolysaccharidosis (MPS) type-IVA, is a rare, autosomal recessive disease, resulting from a enzyme deficiency of N-acetyl-galactosamine-6-sulfatase. The accumulation of partially-degraded metabolites has multisystemic ramifications and the characteristic phenotype. Progressive airway obstruction and respiratory failure are the primary cause of death, with patients rarely surviving past their second decade. What are the management options? There is no cure for MPS-IVA and until recently there was no treatment, other than palliation. Enzyme-replacement-therapy (ERT) has become the mainstay of treatment and although ERT attenuates disease-progression, individual response varies. Why important to develop a precision medicine approach? Currently, clinicians don't know how best to monitor the response to treatment, thereby identifying 'non-responders' early, and when to modulate treatment before the development of irreversible changes and significant deterioration. Likewise, surgical-options are only considered in end-stage disease, when fitness-for-surgery is poor and the risk of life-threatening complications are high. Long-term treatment with ERT is expensive. Therefore, it is vital for patients and healthcare professionals to ensure we choose the right treatment, for the right patient, at the right time. Aims To advance the care of individuals with MPS-IVA beyond the static assessment of current health status by disease-registry, to the dynamic prediction of decline in airway and respiratory function, by the development and validation of a clinical risk prediction model (CRPM). Specific Objectives: To determine important predictors for airway and respiratory complications in MPS-IVA Evaluate the data quality and completeness of the MARS registry and undertake further data collection The development and validation of a CRPM To explore how information from 'big-data' in rare diseases can be used to improve clinical practice and inform patients Methods Building upon preparatory work already undertaken, we will extend the international MARS registry (583 patients across 59 sites) to establish an individual's risk of disease progression to support personalised decision making in MPS-IVA. Multiple-methods will be employed divided into three interlinked work-packages (WP):WP1.Agreement of important candidate prognostic factors, database design and consolidation of research communities' priorities (0-12 months) WP2.To extend the international MARS-registry by undertaking further retrospective and prospective data collection (genetics, demographics, clinical measurements and imaging) by utilising dynamic model updating (12-40 months) WP3 Development and validation of a CRPM using a range of statistical and machine-learning methods. Evaluating how resulting risk information can be fed-back to clinicians and patients and expanding upon our international-collaborations to change clinical practise (24-51 months) Anticipated impact and dissemination This study would be the first application of prognostic-modelling to the Mucopolysaccharidoses, with lessons learned being potentially applicable across the spectrum of this incurable, life-threatening and expensive to treat diseases. We have recently undertaken two successful tracheal surgeries to address the mismatch in tracheal growth. This DF will help identify ERT treatment failure and when surgery should be considered. Through our existing, strong partnership with the MPS Society we will ensure that those effected by MPS-IVA have direct access to the study findings. We will disseminate widely to clinicians through peer reviewed publications and conference contributions.

Lay abstract: Aim(s)We aim to use data on individual patients' disease progression and treatment response to help doctors predict future negative outcomes before they happen, thereby allowing treatment decisions to be more informed.BackgroundMucopolysaccharidosis Type-IVA (MPS-IVA, Morquio syndrome) is a rare illness that affects how the skeleton, heart and airways develop and grow. People are born with MPS-IVA, are often confined to a wheelchair by a young age, and die by early adulthood. The cause of death is usually a combination of blockage of the air passages leading to the lungs (airway obstruction), and the lungs not working properly (obstructive and restrictive lung disease).Although there is no cure, replacing the missing enzyme has been developed and can improve symptoms. How people respond to this new treatment varies; early identification of patients whose treatment is failing could help doctors to consider alternative treatments, before permanent deterioration or death has occurred. We have pioneered a new operation to improve the size of the wind-pipe by taking some of the cartilage away to make it shorter. My research will help patients, families and doctors to decide 'when' and 'if' this new procedure is needed. This operation has been very successful in the two young people that have had it so far, with two more young people scheduled to have the operation this summer. Gene therapy is also being developed to help the body start producing the missing chemical for itself. All of these treatments are risky and expensive, so it is important for patients, healthcare professionals and the NHS to ensure we choose the right treatment, for the right patient, at the right time (precision medicine).Design and methodsSeveral methods will be used to achieve our aim: Consolidation of candidate prognostic factors, stakeholders priorities and database design (0-12 months) Building upon work that has already undertaken, we will systematically identify which routine medical tests of people with Morquio are the best predictors of future clinical outcomes (changes in the severity of airway and lung problems). Such as tests that measure how well one's lungs are working, how much oxygen there is in the bloodstream and how far you can walk.We will also create a bespoke database for subsequent-analysis. To evaluate the data quality and completeness. We will examine an existing international registry (MARS) comprsisng of 583 Morquio patients from 59 sites worldwide). We will then use old and new test results from patients with Morquio to explore whether prognostic factors (patient details, genetics, physiological and biomarker tests) can be used to predict future clinical outcomes. Development of a Prognostic Model Using information from stages 1 and 2, we will produce a mathematical model that uses a set of identified prognostic factors to calculate the risk of worsening airway and lung problems in MPS-IVA, exploring both conventional statistical approaches and machine learning.Patient and public involvement and engagement The MPS society (www.mpssociety.org.uk) considers this to be an important study, and have agreed to help us to ensure that the opinions of people with Morquio and their families are listened to by the research team. They will contact people and parents when we need to ask questions about the running of the study. The MPS society helped to write this plain English summary and will review study documentation. Dissemination Through the MPS society we will tell people about the study as it progresses and at the end. Information will be spread via social media (e.g. @MPSSocietyUK), newsletters (MPS Magazine), digital dashboards and the MPS society national conference. Doctors, Nurses and Researchers will be told about the study findings using presentations at conferences.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CONGENITAL DISORDERS