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

摘要：拟议的研究建立在CRISP 1的基础上，CRISP 1是一项为期五年的慢性鼻窦炎（CRS）研究， 7847名受试者的队列，代表宾夕法尼亚州中部的一般人群，在整个研究中， CRS频谱CRISP 1包括美国第一个慢性鼻和鼻窦症状的纵向研究， 鼻窦炎的CT扫描在一般人群中。我们对CRS症状进行了新的观察， 和CT模式;与CRS相关的风险;和性别差异。改善CRS的预防、诊断和 管理，现在需要研究，以确定炎症的存在早于疾病 通过CT检测;识别与结果相关的表型和内型模式;识别长期- 长期结果;并进一步评估性别差异。我们将联合收割机CRISP 1数据与纵向EHR数据相结合 和新的前瞻性数据收集在五个独立的研究，以解决四个具体目标。具体目标1， 将开发CRS表型分析的新方法。我们假设纵向症状， 病史和CT扫描结果将识别与自然史相关的新CRS表型 和长期的结果。这一目标将在我们的几项研究中得到解决，包括重新接触 CRISP 1参与者具体目标2将评价用NLF生物标志物定义的CRS内型是否 与表型、自然史和结果相关。为此，将完成两项研究。在 首先，将招募450名受试者，进行基线鼻窦CT扫描和NLF采样，并随访18个月 调查问卷，另一个NLF样本，并与EHR数据联系。第二，我们会进行一项研究， 与西北大学平行，在50名单独患有CRS、CRS伴哮喘、 和CRS伴支气管扩张我们的数据将与西北大学的一项类似研究相结合， 使我们能够评估环境（一般人群与三级护理）对结果的影响。具体目标3是 评估CRS作为其他疾病的风险因素。我们假设CRS亚组将有差异， 与哮喘和支气管扩张的风险增加有关。为此，我们会进行一项 基于EHR的CRS回顾性队列研究，包括10，000例有CRS鼻窦CT证据的受试者和20，000例 没有的人;以及一项对1000名胸部CT证据表明 支气管扩张和4000对照没有。这些研究将评估CRS表型和 严重程度，有发生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、自然病程和长期结果之间的关联将 因性别而异。将在所有5项研究中评价性别差异。拟议的研究继续我们的小说 协作工作集中在CRS症状，炎症，合并症和自然 历史，与纵向EHR数据相关联，长达15-20年的总观察时间， 在疾病的全谱中推进对CRS的理解、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.