DOSE RESPONSE MODELING IN EPIDEMIOLOGIC COHORT STUDIES

该建议通过探索两种更灵活的回归策略解决了环境和职业队列研究中的非线性剂量反应估计问题：广义加性模型（非参数回归）和非线性剂量度量。 通常，剂量反应模型假设在某种尺度上关系是线性的。 然而，许多疾病机制，如致敏或致癌作用，可能会产生剂量-反应曲线的非线性。 此外，线性模型可能是不合适的职业队列研究中，健康的工人的影响，可能会导致一个明显的高原，甚至下降的风险之间的更高的曝光。 将使用一般加法模型描述累积暴露与三项队列死亡率研究中选定结局之间的剂量-反应曲线形状，这些研究具有明确的暴露-反应相关性。 可用于剂量反应建模的三个数据集是：46，400名汽车工人暴露于金属加工液，5，414名佛蒙特州花岗岩工人暴露于石英形式的二氧化硅，2，342名粘土矿工暴露于方石英形式的结晶二氧化硅。 关注的疾病结局将包括金属加工液队列中的胃癌、食道癌、胰腺癌和肝癌，以及两个二氧化硅队列中的肺癌。 将在所有队列中检查非恶性呼吸系统疾病死亡率。 此外，我们将对金属加工液和结晶二氧化硅应用灵活的剂量模型，其中包括作为特殊情况的简单累积暴露。 不像标准的分析是有限的线性关系与累积曝光，这个模型，提出了Seixas，是足够灵活的，使调查的非线性剂量率效应和可变的疾病诱导/潜伏期间隔。 次要目的包括直接比较四种类型的金属加工液（矿物油、可溶物、合成和半合成）以及结晶二氧化硅的石英和方石英多晶型物的致癌性。

This proposal addresses the problem of nonlinear dose response estimation in environmental and occupational cohort studies by exploring two more flexible regression strategies: Generalized Additive Models (non-parametric regression) and a nonlinear dose metric. Typically, dose response models assume that the relationship is linear on some scale. Many disease mechanisms, however, such as sensitization or carcinogenesis, may produce nonlinearities in the dose-response curve. Moreover, linear models may be inappropriate in occupational cohort studies where the healthy worker effect can lead to an apparent plateau or even downturn in risk among the more highly exposed. General additive models will be used to describe the shapes of the dose-response curve between cumulative exposures and selected outcomes in three cohort mortality studies with well established exposure response associations. The three data sets available for dose-response modeling are: 46,400 autoworkers exposed to metalworking fluids, 5,414 Vermont granite workers exposed to silica in quartz form and 2,342 diatomaceous earth miners exposed to crystalline silica in cristobalite form. Disease outcomes of interest will include cancers of the stomach, esophagus, pancreas, and liver in the metalworking fluid cohort, and cancer of the lung in the two silica cohorts. Nonmalignant respiratory disease mortality will be examined in all cohorts. In addition, we will apply a flexible dose model for metalworking fluids and crystalline silica that includes simple cumulative exposure as a special case. Unlike standard analyses that are limited to linear relations with cumulative exposure, this model, proposed by Seixas, is sufficiently flexible to enable investigation of nonlinear dose-rate effects and variable disease induction/latency intervals. Secondary objectives include the direct comparisons of the carcinogenicity of the four types of metalworking fluids (mineral oil, solubles, synthetic, and semi- synthetics) and of quartz and cristobalite polymorphs of crystalline silica.