Population-based CRS epidemiology: sex differences, natural history, and long-term outcomes based on clinically-defined phenotypes and biologically-based endotypes - Geisinger

摘要：建议的研究建立在CRISP1的基础上，CRISP1是一项为期五年的慢性鼻-鼻窦炎(CRS)研究。 7847名受试者组成的队列，代表宾夕法尼亚州中部的总体人口 CRS的光谱。CRISP1包括美国第一项关于慢性鼻窦症状和鼻窦症状的纵向研究 普通人群鼻窦炎的CT扫描结果。我们对CRS症状有了新的观察 和CT模式；与CRS相关的风险；性别差异。改进CRS预防、诊断和 管理，现在需要研究，以确定在疾病中比现在更早的炎症存在 通过CT检测；识别与结果相关的表型和内型模式；识别较长时间- 并进一步评估性别差异。我们将结合CRISP1数据和纵向EHR数据 并在五项单独的研究中收集新的前瞻性数据，以解决四个具体目标。在具体目标1中，我们 将开发CRS表型的新方法。我们假设纵向症状的模式， 病史和CT扫描结果将识别与自然病史相关的新的CRS表型 和长期结果。这一目标将在我们的几项研究中得到解决，包括通过重新联系 CRISP1参与者。特殊目标2将评估用NLF生物标记物定义的CRS内型是否 与表型、自然病史和结果相关。为此，将完成两项研究。在 首先，450名受试者将被纳入，进行基线鼻窦CT扫描和NLF采样，并跟踪观察18个月 通过问卷调查，另一个NLF样本，以及与EHR数据的链接。在第二项研究中，我们将在 与西北大学平行测量NLF生物标志物50例，分别为单纯CRS、CRS伴哮喘、 慢性阻塞性肺疾病伴支气管扩张。我们的数据将与西北大学的一项类似研究的数据结合起来， 使我们能够评估环境(普通人口与三级护理)对结果的影响。具体目标3是 将CRS作为其他疾病的危险因素进行评估。我们假设CRS子群将是不同的 与发展为哮喘和支气管扩张症的风险增加有关。为此，我们将进行一项 基于EHR的CRS回顾性队列研究--1万例有鼻窦CT证据的CRS患者和20000例CRS患者 1000例有胸部CT证据的支气管扩张症病例对照研究 支气管扩张症和4000例正常对照。这些研究将评估CRS表型和 病情严重，有发展成哮喘和支气管扩张的风险。具体目标4将评估性别差异。 我们假设内型、表型、自然病史和长期结果之间的关联将 性别不同。性别差异将在所有五项研究中进行评估。拟议的研究延续了我们的小说 协作工作侧重于测量CRS症状、炎症、并存和自然 与纵向EHR数据相关联的历史，总观测时间长达15-20年，其方式应 促进对CRS的全面了解、诊断和管理。

ABSTRACT: The proposed studies build upon CRISP1, a five-year study of chronic rhinosinusitis (CRS) in a cohort of 7847 subjects, representative of the general population in central Pennsylvania, across the full spectrum of CRS. CRISP1 included the first U.S. longitudinal studies of chronic nasal and sinus symptoms and sinus inflammation by CT scan in the general population. We made novel observations regarding CRS symptom and CT patterns; risks associated with CRS; and sex differences. To improve CRS prevention, diagnosis, and management, studies are now needed to identify the presence of inflammation earlier in the disease than is detected by CT; identify phenotypic and endotypic patterns associated with outcomes; identify risk of longer- term outcomes; and further evaluate sex differences. We will combine CRISP1 data with longitudinal EHR data and new prospective data collection in five separate studies to address four specific aims. In Specific Aim 1 we will develop new approaches to CRS phenotyping. We hypothesize that patterns of longitudinal symptoms, medical history, and CT scan findings will identify new CRS phenotypes that are associated with natural history and long-term outcomes. This aim will be addressed across several of our studies, including by re-contacting CRISP1 participants. Specific Aim 2 will evaluate if CRS endotypes, defined with NLF biomarkers, are associated with phenotype, natural history, and outcomes. For this aim, two studies will be completed. In the first, 450 subjects will be enrolled, have a baseline sinus CT scan and NLF sampling and followed for 18 months with questionnaires, another NLF sample, and linkage to EHR data. In the second, we will conduct a study in parallel with Northwestern to measure NLF biomarkers in 50 subjects each with CRS alone, CRS with asthma, and CRS with bronchiectasis. Our data will be combined with those from a similar study at Northwestern, enabling us to evaluate the impact of setting (general population vs. tertiary care) on findings. Specific Aim 3 is to evaluate CRS as a risk factor for other diseases. We hypothesize that CRS subgroups will be differentially associated with increased risk for development of asthma and bronchiectasis. For this aim, we will conduct an EHR-based CRS retrospective cohort study of 10,000 subjects with sinus CT evidence of CRS and 20,000 persons without; and a bronchiectasis case-control study of 1000 persons with chest CT evidence of bronchiectasis and 4000 controls without. These studies will evaluate associations of CRS phenotypes and severity with risk of development of asthma and bronchiectasis. Specific Aim 4 will evaluate sex differences. We hypothesize that associations among endotypes, phenotypes, natural history, and longer-term outcomes will differ by sex. Sex differences will be evaluated in all five studies. The proposed research continues our novel collaborative work focused on measurement of CRS symptoms, inflammation, co-morbidities, and natural history, linked to longitudinal EHR data, for up to 15-20 years of total observation time, in ways that should advance understanding, diagnosis, and management of CRS across the full spectrum of disease.