Estimating the Environmental Burden in Two Orphan Lung Diseases

描述（由申请人提供）：本申请涉及广泛的挑战领域（03）生物标志物研究和特定的挑战领域03-HL-101：“识别和验证临床相关的、可量化的生物标志物”背景：人群归因分数（PAF）估计由特定因素引起的疾病的数量，量化如果消除该因素将预防的疾病负担。对于选定的孤儿肺疾病，量化环境相关的PAF将为临床医生的诊断和疾病管理以及预防策略提供重要指导，以减少新疾病的负担。在综合风险建模方法中将生物标志物数据与其他暴露指标联系起来将产生更准确的PAF估计值。过敏性肺炎（HP）和肺泡蛋白沉积症（PAP）是应用这种生物标志物相关PAF策略的理想候选疾病。目的：对惠普而言，确定目前已知的环境因素以及未确定的原因的相对影响，特别是“未指定”的室内空气源。对于PAP，估计与粉尘吸入有关的PAF，特别是有薪职业和无薪职业中的二氧化硅（包括混凝土建筑），以及潜在的环境点源。对于HP和PAP，使用选定的生物标志物数据评价选定的风险因素与疾病活动-严重程度之间的关联，以区分病例之间以及病例与参考之间。实验计划：通过Kaiser Permanente Health Plan（KPHP）的数据库招募病例和参考。病例库将通过从基于大学的亚专科肺科实践（UCSF）中额外招募来补充。目标招募将在125例HP病例中进行访谈，并在其中75例病例中将推荐人与家访相匹配;对于PAP，46次访谈和25次家访加推荐人。环境暴露和生物标志物将通过结构化访谈和家访进行评估。将对居住地址进行地理编码，以便与补充环境暴露数据相联系。病历提取（仅病例）将用于确认诊断一致性和疾病严重程度的补充措施。病例将与环境暴露和疾病生物标志物的参考进行比较。将使用连续参数和非参数变量的方法以及二分测量的比值比来检验连续测量的病例和参考之间的差异，将估计环境相关疾病负担的PAF。重要性：职业、室外环境污染和家庭室内暴露于HP和PAP的不同贡献可能不仅与患者诊断相关，而且与管理和临床结局相关。在综合风险建模方法中将生物标志物数据与其他暴露指标联系起来是获得更准确PAF估计值的关键，这就是为什么这个挑战领域与这个问题如此相关。7.项目叙述本研究的目的是估计所选环境危险因素对两种孤儿肺疾病（过敏性肺炎和肺泡蛋白沉积症）负担的相对贡献。使用环境暴露数据，辅以与疾病活动和严重程度相关的生物标志物数据，该项目将导致与这些特定条件下的疾病预防相关的发现，并通过应用该方法，可能也会导致其他孤儿疾病。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Research and the specific Challenge Area 03-HL-101: "Identify and validate clinically relevant, quantifiable biomarkers" Background: The population attributable fraction (PAF) estimates the amount of a disease that is due to a specific factor, quantifying the burden of disease that would be prevented if that factor was eliminated. For selected orphan lung diseases, quantifying the environmentally-related PAF would provide important guidance for clinicians in diagnosis and disease management and for prevention strategies to reduce the burden of new disease prospectively. Linking biomarker data to other metrics of exposure in an integrated risk modeling approach will yield more accurate PAF estimates. Hypersensitivity pneumonitis (HP) and pulmonary alveolar proteinosis (PAP) are ideal candidate diseases for which to apply this biomarker-linked PAF strategy. Aims: For HP, identifying the relative contributions of currently known environmental factors, as well as un- identified causes, in particular "non-specified" indoor air sources. For PAP, estimating the PAF linked to dust inhalation, in particular silica (including concrete construction) in salaried occupations as well as in non- salaried avocations and, potentially, through ambient point sources. For both HP and PAP, evaluating the association between selected risk factors and disease activity-severity using selected biomarker data to differentiate among cases and between cases and referents. Experimental Plan: Cases and referents recruited through the data base of the Kaiser Permanente Health Plan (KPHP). The case pool will be supplemented through additional recruitment from a University-based sub- specialty pulmonary practice (UCSF). Target recruitment will yield interviews in 125 HP cases and matching referents with home visits in 75 of each; for PAP, 46 interviews and 25 home visits plus referents. Environ- mental exposures and biomarkers will assessed through structured interviews and through home visits. Residential addresses will be geocoded for linkage to supplemental environmental exposure data. Medical record extraction (cases only) will be used to confirm diagnostic consistency and supplement measures of disease severity. Cases will be compared to referents for environmental exposures and biomarkers of disease. Differences between cases and referents for continuous measures will be tested using approaches for continuous parametric and non-parametric variables and Odds Ratios for dichotomous measures, the PAF for the environmentally-related burden of disease will be estimated. Significance: The varying contributions of occupation, outdoor ambient pollution, and home indoor exposures to HP and PAP are likely to be relevant not only for patient diagnosis but also for management and clinical outcomes. Linking biomarker data to other metrics of exposure in an integrated risk modeling approach is key to deriving more accurate PAF estimates, which is why this Challenge Area is so relevant to this question. 7. Project Narrative The goal of this study is to estimate the relative contributions selected environmental risk factors to the burden to two orphan lung diseases, hypersensitivity pneumonitis and pulmonary alveolar proteinosis. Using environmental exposure data, supplemented with biomarker data relevant to disease activity and severity, this project will lead to findings relevant to disease prevention for these specific conditions and, by application of the approach, potentially to other orphan disease as well.