EPIDEMIOLOGY OF ALLERGIC DISEASE ENDOTYPES

描述（由申请人提供）：儿童过敏和哮喘是一个昂贵的公共卫生负担，但到目前为止，大量的研究工作还没有产生预防策略。一个可能的原因是，尽管医学界长期以来认为“哮喘”一词是指疾病的集合，但研究人员历来将该综合征视为单一疾病实体。流行病学上，不同表型（观察到的疾病模式）和内型（病理生理过程进一步描述的表型）的崩溃，成为一个单一的类别破坏了风险因素和疾病之间的关联。因此，过敏性疾病研究的进展受到阻碍。先前已经尝试鉴定这些表型和内型，但是不完整的数据和过于简化的统计方法的组合限制了进展。我们建议在一个大型的一般风险队列中应用复杂的潜在类别分析，结合免疫学标记物来精细区分哮喘和过敏疾病的表型和内源性，然后使用这些信息进行风险因素分析。在我们的WHEALS出生队列中使用这种方法，我们已经在2岁时描述了四个类别：1）低至无致敏性; 2）高度致敏性; 3）牛奶和鸡蛋主导的致敏性;和4）花生和/或吸入性过敏原-无牛奶致敏性。总IgE水平在两组之间存在差异，湿疹和医生诊断的哮喘（4岁时）的发生率也存在差异。高致敏组的发生率最高，低致敏至无致敏组的发生率最低，其他两个类别的发生率介于低致敏组和高致敏组之间。这些数据表明，使用潜在的类，而不是使用“传统”的定义特应性（任何过敏原特异性 IgE（sIgE）0.35 IU/mL），更具体地确定那些在过敏性疾病的轨迹，产生在过敏性疾病研究和临床护理的进步。使用主要（62%）非裔美国人出生队列WHEALS，我们将：目的1）确定在2岁时鉴定的哪些早期生活过敏性疾病表型与肺功能相关目的2）a）基于喘鸣的年度报告鉴定10岁儿童的过敏性疾病内在型; 10岁时的肺功能、eNO、肥胖、细胞因子和白色细胞计数和广泛免疫表型[评估细胞标志物，以识别和定量调节性T细胞（T细胞）、嗜碱性粒细胞和树突状细胞（DC）的活化];以及总IgE和致敏性（sIgE和皮肤点刺试验） B）估计生命早期风险因素（例如，分娩类型、宠物接触等）和所鉴定的目标2a内型;以及3）将与目标2中的内型相关的风险因素与使用特应性和哮喘的“传统”定义（医生诊断和药物使用和/或去年的症状）确定的风险因素相关进行比较和对比。将对所有900名WHEALS队列儿童进行分析，并分别对黑人儿童和白色儿童进行分析，以评估种族差异。

DESCRIPTION (provided by applicant): Pediatric allergy and asthma are a costly public health burden, but so far substantial research efforts have yielded no prevention strategies. A likely reason is that despite longstanding recognition by the medical community that the term 'asthma' refers to a colletcion of diseases, researchers have historically treated the syndrome as a single disease entity. Epidemiologically, the collapse of different phenotypes (observed disease patterns) and endotypes (phenotypes further delineated by pathophysiological processes), into a single category corrupts associations between risk factors and diseases. Thus, progress in allergic disease research has been hampered. Prior attempts have been made to identify such phenotypes and endotypes, but a combination of incomplete data and oversimplified statistical methods have limited progress. We propose to apply sophisticated latent class analyses in a large general risk cohort combined with immunological markers to finely discriminate asthma and allergy disease phenotypes and endotypes and then use this information to conduct risk factor analyses. Using this approach in our WHEALS birth cohort, we have already characterized four classes at age 2 years: 1) Low to No Sensitization; 2) Highly Sensitized; 3) Milk and Egg Dominated Sensitization; and 4) Peanut and/or Inhalant allergen - No Milk Sensitization. Total IgE levels varied between the groups, as did the rates of eczema and doctor diagnosis of asthma (at age 4 years). The Highly Sensitized had the greatest rates, the Low to No Sensitization had the lowest rates, and the other two classes had rates intermediate between the Low and High Sensitization groups. These data suggest the use of latent classes, rather than the use of the "traditional" definition of atopy (any allergen-specific IgE (sIgE) 0.35 IU/mL), more specifically identifies those on a trajectory for allergic disease, yielding advancement in both allergic disease research and clinical care. Using the predominantly (62%) African American birth cohort WHEALS, we will: Aim 1) Determine which early life allergic disease phenotypes identified at age 2 years are associated with lung function (spirometry and methacholine challenge) at age 10 years; Aim 2) a) Identify the allergic disease endotypes for 10 year old children based on annual report of wheeze; lung function, eNO, obesity, cytokines, and white cell counts and extensive immunophenotyping [assessment of cellular markers to identify and quantify activation of regulatory T cells (Tregs), basophils and dendritic cells (DCs)] at age 10 years; and total IgE and sensitization (sIgE and skin prick tests) at ages 2 and 10 years; and, b) Estimate associations between early life risk factors (e.g., delivery type, pet exposure, etc.) and the identified Aim 2a endotypes; and, 3) Compare and contrast the risk factor associations with the endotypes in Aim 2 to the risk factor associations determined using "traditional" definitions of atopy and asthma (doctor diagnosis and medication use and/or symptoms in the last year). Analyses will be performed for all 900 WHEALS cohort children and separately for Black children and White children to assess racial differences.