Evaluating the Clinical Validity of Novel Gene-Environment Risk Profiles

描述(由申请者提供)：该项目将利用护士健康研究(NHS)和卫生专业人员后续研究(HPFS)的数据，基于最近全基因组关联研究中经过验证的风险标记，开发和评估乳腺癌和2型糖尿病的遗传和基因环境风险概况。由于NHS和HPFS是拥有关于已知的、可修改的环境、生活方式和人体测量风险因素的大量前瞻性收集数据的队列，该项目将首次经验性地检验与仅使用非遗传因素的标准风险预测模型相比，纳入遗传因素和基因-环境交互作用在多大程度上改善了临床有效性。特别是，该项目将计算不同个人资料的乳腺癌和2型糖尿病的经验绝对风险(5年、10年和终生风险)。这些绝对风险评估是评估“个人化预防”策略的风险-收益平衡所必需的，例如建议具有特定基因环境特征的妇女在较早的年龄开始乳房X光检查。该项目还将开发新的统计方法，通过将在嵌套病例对照中收集的遗传标记和环境暴露数据与在整个基本队列中收集的环境暴露数据结合起来，推断遗传和基因-环境风险概况的绝对疾病风险。这些方法将广泛适用于其他队列研究和其他与公共卫生相关的常见疾病和特征。 相关性：该项目将利用护士健康研究和卫生专业人员后续研究的数据，基于最近全基因组关联研究中经过验证的风险标记，开发和评估乳腺癌和2型糖尿病的遗传和基因-环境风险概况。这项工作将根据这些情况对“个性化预防”战略的净效益进行估计。为该项目开发的统计方法将广泛适用于其他队列研究和其他与公共卫生有关的常见疾病和特征。

DESCRIPTION (provided by applicant): This project will develop and evaluate genetic and gene-environment risk profiles for breast cancer and type 2 diabetes using data from the Nurses' Health Study (NHS) and Health Professionals' Follow-Up Study (HPFS), based on validated risk markers from recent genome-wide association studies. Because the NHS and HPFS are cohorts with extensive prospectively-collected data on known, modifiable environmental, lifestyle and anthropometric risk factors, this project will be the first to empirically examine how much the inclusion of genetic factors and gene-environment interactions improves clinical validity relative to standard risk prediction models which only use non-genetic factors. In particular, the project will calculate empirical absolute risks (5-, 10-year and lifetime risks) of breast cancer and type 2 diabetes for individuals with different profiles. These absolute risk estimates are needed to evaluate the risk-benefit balance for "personalized prevention" strategies, such as recommending that women with a particular gene-environment profile start mammography screening at earlier ages. This project will also develop new statistical methods to infer absolute disease risks for genetic and gene-environment risk profiles by combining data on genetic markers and environmental exposures collected in a nested case-control with data on environmental exposures collected on the entire underlying cohort. These methods will be broadly applicable to other cohort studies and other common diseases and traits of public health relevance. RELEVANCE: This project will develop and evaluate genetic and gene-environment risk profiles for breast cancer and type 2 diabetes using data from the Nurses' Health Study and Health Professionals' Follow-Up Study, based on validated risk markers from recent genome-wide association studies. This work will provide estimates of the net benefits of "personalized prevention" strategies based on these profiles. The statistical methods developed for this project will be broadly applicable to other cohort studies and other common diseases and traits of public health relevance.