Mathematically modelling tuberculosis: using lung scans to map infection, and a hybrid individual-based model to simulate infection and treatment

结核病（TB）是一种通常影响肺部的传染病。当细菌通过空气中的飞沫传播时，它就会发展起来。在过去，结核病或“消费”是世界范围内死亡的主要原因。在抗生素的发现和生活条件的普遍改善之后，这种疾病的流行率下降了。然而，自20世纪80年代以来，病例再次上升。结核病现在是最大的传染病杀手（超过艾滋病毒/艾滋病，现在是COVID-19）。该项目寻求在个性化结核病治疗方面向前迈进一步。目前在治疗结核病时，医生必须遵循严格的治疗方案，这些方案只允许患者体重的变化。这些治疗方案是多年前确定的，当时人们对这种疾病知之甚少。我们现在对结核细菌以及感染动态如何根据特定患者的免疫反应而改变有了更多的了解。例如，患有糖尿病和/或艾滋病毒的人往往患有更复杂和严重的结核病。我们还知道，感染的严重程度，即受影响的肺组织的数量，在治疗的成功程度中起着一定的作用。该项目试图根据结核病患者的细菌负担，即感染的程度，以及是否存在可能使其结核病更加复杂的任何其他疾病（如糖尿病或艾滋病毒），对结核病患者进行分组，以便找到治疗结核病的最佳方法。我将使用从南非的一项临床试验中采集的肺部扫描数据集来开发人工智能（AI）算法，以自动识别患者的结核病感染。该算法将能够识别肺部感染出现的位置以及感染的严重程度。这意味着未来结核病医生可以将单个结核病患者的肺部扫描结果输入到人工智能算法中，从而自动将患者的结核病感染情况映射到计算机上。一旦进入电脑，我将使用数学模型来模拟病人肺部的情况（也考虑到他们的特殊免疫反应，通过考虑他们是糖尿病患者还是艾滋病毒阳性）。我已经开发了能够模拟结核感染期间典型免疫反应的数学模型，并将与相关生物学家合作，整合患者同时患有糖尿病/艾滋病毒阳性时感染动态的差异。建立这种类型的数学模型是复杂的，并且有许多未知因素，这就是为什么我将与我的生物学合作者密切合作，以确保使用最新的实验室数据来量化所涉及的过程。我还将与数学/计算同事合作，使用相关技术来帮助模型开发，并测试模型的准确性。我还将使用来自南非临床试验的额外数据来测试模型预测。一旦我确信人工智能算法和模型是稳健的，我就会与医生合作，试图找到更多针对患者的治疗方案。这将意味着未来一些患者将不需要那么多的治疗（从而降低成本并减少这些患者的副作用），有些患者将需要改变目前处方的抗生素组合/剂量。最终，这将有助于提高治疗成功率，防止未来结核病复发，并减少出现抗生素耐药性的机会。

Tuberculosis (TB) is an infectious disease that usually affects the lungs. It can develop when bacteria spread through droplets in the air. In the past TB or "consumption" was a major cause of death worldwide. After the discovery of antibiotics and general improvement in living conditions, prevalence of the disease fell. However, since the 1980s cases have been rising again. TB is now the biggest infectious disease killer (above HIV/AIDS and now COVID-19). This project seeks to take a step forward in personalising TB treatment. Currently with treatment for TB disease, doctors must follow rigid treatment protocols that only allow for variations in patients' weights. These treatment regimens were defined years ago when very little was understood about this disease. We now know more about TB bacteria and how the infection dynamics can change depending on particular patients' immune responses. For example, people who have diabetes and/or HIV tend to have more complex and severe TB disease. We also know that the severity of infection, i.e. the amount of lung tissue affected, plays a part in how successful treatment will be. This project seeks to group TB patients according to their bacterial burden, i.e. how much infection is present, and the presence of any other conditions (such as diabetes or HIV) that could make their TB disease more complex, in order to find optimal ways of treating them.I will use a collection of lung scans taken from a clinical trial in South Africa to develop Artificial Intelligence (AI) algorithms to automatically identify TB infection in patients. This algorithm will be able to identify where in the lungs the infection appears and how severe it is. This will mean that in future TB doctors could take an individual TB patient's lung scan and feed it into the AI algorithm to automatically map that patient's TB infection onto a computer. Once on the computer, I will use mathematical modelling to simulate what would happen in that patient's lungs (also taking into account their particular immune response, by factoring in whether they are diabetic or HIV-positive). I have already developed mathematical models that are capable of simulating a typical immune response during TB infection and will work with relevant biologists to integrate the differences seen in infection dynamics when patients are also diabetic/HIV-positive.Building mathematical models of this type is complex and there are many unknowns, this is why I will work closely with my biological collaborators to ensure that the latest laboratory data is used to quantify the processes involved. I will also work with mathematical/computational colleagues to use relevant techniques to help with model development, and to test how accurate the models are. I will also use additional data from the South African clinical trial to test model predictions. Once I am confident that the AI algorithms and models are robust, I will work with doctors to try to find more patient-specific treatment protocols. This will mean in future that some patients won't need as much treatment (hence cutting costs and reducing side-effects for these patients), and some will need variations in the antibiotic combinations/doses that are currently prescribed. Ultimately this will help to increase treatment success, prevent future TB relapses, and reduce the chance of antibiotic resistance emerging.