Personalizing obstructive sleep apnea management: associating symptom subtype to objective sleep traits and physiological biomarkers

个性化阻塞性睡眠呼吸暂停管理：将症状亚型与客观睡眠特征和生理生物标志物相关联

• 批准号: 10002638
• 负责人: Jinyoung Kim
• 金额: $ 51.57万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002638
• 关键词: Adherence; Apnea; Arousal; Behavior; Biological; Biological Markers; Blood specimen; Cardiovascular Diseases; Categories; Characteristics; Clinical; Cluster Analysis; Comorbid Insomnia; Complex; Data; Databases; Diagnosis; Diagnostic; Disease; Drowsiness; Electroencephalogram; Event; Fasting; Frequencies; Future; Genomics; Home environment; Inadequate Sleep Hygiene; Individual Differences; Intervention; Link; Measures; Molecular; Observational Study; Obstruction; Obstructive Sleep Apnea; Odds Ratio; Ohio; Outcome; Participant; Patients; Pattern; Pennsylvania; Physiological; Physiology; Polysomnography; Prospective Studies; Proteomics; Questionnaires; Recurrence; Reporting; Residual state; Resistance; Risk Factors; Sampling; Severities; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep disturbances; Sleeplessness; Subgroup; Surveys; Symptoms; Techniques; Testing; Time; Universities; actigraphy; airway obstruction; associated symptom; base; behavioral pharmacology; clinical predictors; clinical research site; clinical subtypes; follow-up; indexing; metabolomics; mortality; novel; pressure; prospective; recruit; reduce symptoms; respiratory; response; sleep onset; symptom cluster; symptom management; symptomatic improvement; trait; treatment response

ABSTRACT Obstructive sleep apnea (OSA), characterized by repeated partial (hypopnea) and complete (apnea) obstruction of the upper aiways during sleep, is a broad diagnostic category with its complex phathophysiology and variable clinical presentations. Using cluster-analysis techniques, we recently identified three distinct OSA subtypes, based on predominant symptoms: (1) Insomnia (presenting with difficulty sleeping with little daytime sleepiness); (2) Excessively sleepy (presenting with excessive drowsines during the daytime, but few complaints about disturbed sleep); and (3) Minimally Symptomatic. Currently, Positive Airway Pressure (PAP) is the first-line treatment for all OSA patients, regardless of the symptom presentation. PAP is expected to improve symptoms by eliminating respiratory events; however, 50-72% of patients with comorbid insomnia and 18-55% of Sleepy patients still suffer from residual symptoms after PAP treatment, suggesting individual differences in symptom responses to the first-line treatment and a critical need for secondary symptom management strategies. Better understanding of physiological mechanisms underlying the 3 symptom subtypes and differential treatment responses will inform future personalized secondary treatments, including behavioral and pharmacologic interventions. The current proposal will directly evaluate these mechanisms using both an existing clinical sample from multiple sleep centers throughout the world and a newly recruited prospective sample. First, we will investigate the underlying physiological signatures of the symptom subtypes at diagnosis in a large database of OSA patients (n = 853) recruited from the Sleep Apnea Global Interdisciplinary Consortium (SAGIC). Second, we will prospectively recruit and follow new patients (n = 360, n = 120 for each subtype) to validate these physiological signatures at baseline, identify patterns of symptom responses to the first-line PAP treatment, and evaluate the physiological and clinical predictors of symptom response within each subtype. To better characterize physiological and clinical signatures, we will leverage novel electroencephalogram (EEG)-derived variables, including the odds ratio of product (ORP, a continuous index of sleep depth), as well as conventional measures from polysomnography (PSG). For the prospective observational study, diagnostic and follow-up PSG after 3 months of PAP treatment will be conducted in all participants. In addition, 2-week actigraphy and sleep questionnaires will be used to capture at-home sleep characteristics and behaviors. Symptoms will be assessed at diagnosis and monthly over follow-up. We will also obtain and bank fasting blood samples for biomarker and Omics (i.e., genomics, proteomics, and metabolomics) studies to explore molecular and biological mechanisms of OSA symptom subtypes in the future. Overall, this study will help us understand the underlying physiology of OSA symptom subtypes and predictors of better treatment response. Results will inform future symptom management strategies, personalized by patients' physiological and clinical information, for each subgroup.

抽象的 阻塞性睡眠呼吸暂停 (OSA)，其特征是反复部分（呼吸不足）和完全（呼吸暂停）阻塞 睡眠期间上呼吸道的疾病，是一个广泛的诊断类别，具有复杂的病理生理学和可变性 临床表现。使用聚类分析技术，我们最近确定了三种不同的 OSA 亚型， 根据主要症状：（1）失眠（表现为入睡困难，白天很少困倦）； (2) 过度嗜睡（白天表现出过度嗜睡，但很少抱怨 睡眠不安）； (3) 症状轻微。目前，气道正压通气（PAP）是一线治疗 对所有 OSA 患者进行治疗，无论症状如何。 PAP 有望改善症状 通过消除呼吸事件；然而，50-72% 的患者患有失眠症，18-55% 的患者患有困倦 PAP治疗后患者仍有残留症状，表明症状存在个体差异 对一线治疗的反应以及对次要症状管理策略的迫切需要。更好的 了解三种症状亚型的生理机制和差异化治疗 反应将为未来的个性化二级治疗提供信息，包括行为和药理学 干预措施。当前的提案将使用现有的临床样本直接评估这些机制 来自世界各地多个睡眠中心和新招募的前瞻性样本。首先，我们将 在大型数据库中研究诊断时症状亚型的潜在生理特征 OSA 患者 (n = 853) 是从睡眠呼吸暂停全球跨学科联盟 (SAGIC) 招募的。第二， 我们将前瞻性地招募和跟踪新患者（n = 360，每个亚型 n = 120）来验证这些 基线生理特征，确定一线 PAP 治疗的症状反应模式，以及 评估每个亚型内症状反应的生理和临床预测因子。为了更好 表征生理和临床特征，我们将利用新颖的脑电图 (EEG) 衍生 变量，包括乘积的优势比（ORP，睡眠深度的连续指数），以及传统的 多导睡眠图（PSG）测量。用于前瞻性观察研究、诊断和随访 PSG 3个月后，将对所有参与者进行PAP治疗。此外，为期两周的体动记录和睡眠 调查问卷将用于捕捉家庭睡眠特征和行为。将评估症状 诊断时和每月随访。我们还将获取并储存空腹血液样本以用于生物标志物和 组学（即基因组学、蛋白质组学和代谢组学）研究探索分子和生物学机制 未来的 OSA 症状亚型。总的来说，这项研究将帮助我们了解潜在的生理学 OSA 症状亚型和更好治疗反应的预测因素。结果将告知未来的症状 针对每个亚组，根据患者的生理和临床信息进行个性化的管理策略。