Development of a stratification tool to predict Disease Modifying Treatment response in Paediatric Onset Multiple Sclerosis

多发性硬化症（MS）是一种毁灭性的疾病，在儿童中很少见。它是由身体的免疫系统破坏部分髓鞘引起的，髓鞘是大脑和脊柱中神经的脂肪保护层，是从大脑向身体其他部位传递信息所必需的。目前没有治愈方法，随着时间的推移，个人会逐渐丧失能力。在儿童和青少年中，这可能会影响他们的运动，视力，特别是他们的思维。近年来，可用的治疗方法激增，其中大多数尚未在儿童中试用。目前有14种不同的治疗方法，旨在改变身体的炎症反应。为每个孩子选择正确的治疗方法是困难的，因为没有工具可以帮助我们预测哪种药物可能对他们最有效。很多时候，儿科医生需要依赖成人数据。儿童多发性硬化症与成人不同;他们比成人有更多的复发，更多的脑损伤和更多的学习问题。迄今为止完成的唯一一项儿科试验确定了与成人不同的治疗益处和风险。这使得在儿童中收集信息变得至关重要，而不是依赖于在成人中获得的信息。我是一名专门研究MS的儿科神经学家。在这个项目中，我将与Ciccarelli教授合作，他在2018年被授予NIHR研究教授职位，开发一种工具来预测成人MS患者使用的最佳药物，通过使用特殊的数学模型，从个人MS档案（人口统计学和饮食，生活方式，临床发现，特定的血液检查，遗传学和MRI图像）中学习，并对未来进行预测。我将把这一目标扩展到儿童，我们将共同开发一种工具，帮助指导任何MS患者的治疗选择，无论他们的年龄如何。MS是一种高度专业化和复杂的儿童疾病，NHS英格兰最近同意在英格兰资助5个高度专业化服务（HSS），以确保提供卓越的护理。我将领导其中一个部门，并将与其他中心合作。在这个项目中，我将研究两组：第一组是英格兰现有的100名MS儿童队列，第二组包括80名新诊断的MS儿童。我们将在临床中使用平板电脑记录有关饮食、生活方式、阳光和尼古丁暴露等参数以及生活质量的信息。我们还将记录他们的临床考试和他们的教育表现和学术能力。我们将抽取血液，寻找炎症的标志物，这可能会提供重要的线索。我们还将记录他们的复发情况，以记录他们的MS疾病活动控制得有多好。所有这些信息，连同作为NHS HSS的一部分常规采集的重复MRI扫描，将通过计算机单独分析和与成人数据一起分析。我们将使用分层的方法来确定可能预测哪种药物对任何一个MS患者最有效的因素。所有这些数据将存储在国家登记处，从而为英格兰的这些年轻人提供有关长期结果的有价值的信息。所有药物和任何严重副作用也将记录在数据库中。随着时间的推移，这将使我们能够及早发现药物的任何意外安全性问题。该项目的最终目标是了解临床环境中的个体治疗反应和副作用，并帮助儿童及其父母选择最适合他们的药物。

Multiple sclerosis (MS) is a devastating condition, which is rare in children. It is caused by the body's immune system destroying parts of the myelin sheath, a fatty protective covering of nerves in the brain and spine, which is essential for transmission of messages from the brain to the rest of the body. Currently there is no cure, and over time individuals accumulate progressive disability. In children and young people this can affect movement, vision and particularly their thinking. There has been an explosion in recent years in the treatments available, most of which have not been trialled in children. There are currently 14 different treatments available which aim to modify the body's inflammatory response. Choosing the right treatment for the individual child is difficult, as there are no tools to help us predict which medication is likely to work best for them. Much of the time paediatricians need to rely on adult data. MS in children though is different from that in adults; they have more relapses, more brain lesions and develop more learning problems than adults. The only paediatric trial so far completed, identified benefits and risks of treatment which are different from those seen in adults. This makes it crucial to gather information in children, rather than relying on information acquired in adults.I am a Paediatric Neurologist who specialises in MS. In this project, I will partner with Prof Ciccarelli, who in 2018 was awarded a NIHR Research Professorship, to develop a tool to predict the best medicine to use for the individual with adult MS, by using special mathematical models that learn from the individual MS profile (demographic and diet, lifestyle, clinical findings, specific blood tests, genetics and MRI images) and make prediction about the future. I will extend this goal to children, and together we will develop a tool to help guide treatment choice for any patient with MS, independently of their age. I will take this unique opportunity to focus on cognitive impairment in children with MS. MS is a highly specialised and complex condition in childhood, and NHS England has recently agreed to fund 5 Highly Specialist Services (HSS) across England, to ensure excellence in delivering care. I lead one of these services and will collaborate with the other centres. In this project, I will look at two groups: the first group is the existing cohort of 100 children with MS across England, the second group includes 80 children with newly diagnosed MS. Children who do not wish to start a medication will still have their data recorded and will be used as a control group. We will use tablet computers in clinic to record information about diet, lifestyle, exposure to sunlight and nicotine, amongst other parameters, as well as quality of life. We will also document their clinical examination and their educational performance and academic ability. We will take blood to look for markers of inflammation which might provide important clues. We will also record their relapses, to document how well controlled their MS disease activity is. All this information, together with repeat MRI scans acquired routinely as part of the NHS HSS, will be analysed by computer both separately and together with the adult data. We will use a tiered approach to identify factors which are likely to predict which medicine will work best for any one person with MS. All these data will be stored in a national registry, thereby providing valuable information on the long-term outcome for these young people in England. All the medications and any serious side effects will also be recorded on the database. This will allow us over time to identify early any unexpected safety concerns with the medications. The ultimate goal of the project is to learn about the individual treatment response and side effects in the clinical setting and to help the child and their parents choose the best medication for them as an individual.