Connecting Lung Structure and Function in Cystic Fibrosis Through Physiological Modelling, Image Analysis, and Uncertainty Quantification

人类的肺是一个非常复杂的器官，由数百万个长度从几厘米到微米不等的气道组成。这种复杂性使得难以可靠地将肺功能测试的结果与肺结构中的潜在物理变化相关联。囊性纤维化是一种遗传性疾病，目前在英国影响着大约9000人。囊性纤维化患者肺结构的变化（例如气道阻塞）可以指示与需要治疗的疾病相关的感染的进展。因此，及早发现这些变化对改善患者护理至关重要。目前，肺活量测定测试（通过监测通过设备强制呼吸期间的流速来有效测量肺部的大小和强度）最常用于检测这些变化，但这些测试已被证明对与早期相关的变化相对不敏感囊性纤维化进展。多次呼吸冲洗测试（涉及患者通过面罩吸入气体混合物，该面罩跟踪流速和气体浓度）包含比肺活量测定更多的信息。存在各种公式和指数来从该测试数据中总结肺功能，但仍不清楚这些公式和指数与潜在结构变化的关系。该项目的目标是使用数学和计算模型，使这种联系更加清晰，并开发工具来量化这些变化。我将开发软件，可以模拟与早期囊性纤维化相关的肺部结构变化的气体流动。这些模拟将直接与多次呼吸冲洗测试的数据和MRI数据进行比较，MRI数据可以成像患者呼吸时肺部内的气体分布。使用开发的模拟，我们将了解早期囊性纤维化进展对这些肺功能测试的影响，可以用于开发更灵敏和可靠的结构变化测量方法。进一步，我将开发软件工具，可以用来自动从这些数据集直接判断患者的病情是否恶化。此外，该项目将通过将这些方法扩展到其他疾病组，特别是肺移植患者，COPD和哮喘，为未来的研究合作提供支持。该项目包括在最先进的肺部建模和必要的先进数学技术的具体专业知识的培训。

The human lung is a very complex organ comprised of millions of airways that range from several centimetres down to micrometers in length. This complexity makes it difficult to reliably relate the outcomes of lung function tests to underlying physical changes in the lung structure. Cystic Fibrosis is a genetic condition that currently affects around 9000 people in the UK. Changes in the lung structure (e.g. airway blockages) of cystic fibrosis patients can indicate progression of an infection associated with the disease that requires treatment. Therefore, catching such changes early is paramount to improving patient care. Currently, spirometry tests (which effectively measure the size and strength of the lungs by monitoring the flow rate during forced breathing through the device) are most commonly used to detect these changes, but these have been shown to be relatively insensitive to the changes associated with early Cystic Fibrosis progression. The Multiple-Breath Washout test (which involves a patient breathing in a gas mixture through a mask that traces the flow rate and gas concentrations) contains much more information than spirometry. Various formulae and indices exist to summarise lung function from this test data, but it remains unclear how these relate to the underlying structural changes. The goal of this project is to use mathematical and computational modelling to make this connection clearer and develop tools to quantify these changes. I will develop software that can simulate gas flow in lungs with structural changes that are associated with early Cystic Fibrosis. These simulations will be compared directly with data from Multiple-Breath Washout tests and MRI data which images the gas distribution within the lungs as a patient is breathing.Using the simulations developed we will gain an understanding of the effects of early Cystic Fibrosis progression on these lung function tests, which can be used to develop more sensitive and reliable measures of structural change. Further on, I will develop software tools that can be used to automatically whether a patient's condition is worsening directly from these datasets. Additionally, this project will feed into future research collaborations by expanding these approaches to other disease groups, notably lung transplant patients, COPD and asthma. This project incorporates training in specific expertise in state-of-the-art lung modelling and the necessary advanced mathematical techniques.