DOSE RESPONSE MODELING IN EPIDEMIOLOGIC COHORT STUDIES

这一建议通过探索两种更灵活的回归策略来解决环境和职业队列研究中的非线性剂量响应估计问题：广义加性模型(非参数回归)和非线性剂量度量。通常，剂量反应模型假定这种关系在一定范围内是线性的。然而，许多疾病机制，如致敏或致癌，可能会在剂量-反应曲线中产生非线性。此外，线性模型在职业队列研究中可能是不合适的，因为在职业队列研究中，健康工人效应可能会导致较高暴露人群的风险明显停滞甚至下降。一般的相加模型将被用来描述累积暴露与三项具有良好暴露反应相关性的队列死亡率研究中选定结果之间的剂量-反应曲线的形状。可用于剂量-反应模型的三个数据集是：46,400名接触金属加工液的汽车工人，5,414名接触石英形式的二氧化硅的佛蒙特州花岗岩工人，以及2,342名接触方石英形式的结晶二氧化硅的硅藻土矿工人。值得关注的疾病结果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。将对所有队列中的非恶性呼吸道疾病死亡率进行检查。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，该模型将简单的累积暴露作为特例。与仅限于与累积暴露的线性关系的标准分析不同，Seixas提出的这个模型具有足够的灵活性，可以研究非线性剂量率效应和可变的疾病诱导/潜伏期间隔。次要目标包括直接比较四种金属加工液(矿物油、可溶物、合成和半合成)以及晶态二氧化硅的石英和方石英晶型的致癌性。

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.