Evaluating the Clinical Validity of Novel Gene-Environment Risk Profiles

描述（由申请人提供）：本项目将利用护士健康研究（NHS）和卫生专业人员随访研究（HPFS）的数据，基于最近全基因组关联研究中验证的风险标记，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是具有广泛的前瞻性收集已知的，可修改的环境，生活方式和人体测量风险因素的数据的队列，该项目将是第一个经验检验包含遗传因素和基因-环境相互作用相对于仅使用非遗传因素的标准风险预测模型提高临床有效性的程度。特别是，该项目将计算不同个体患乳腺癌和2型糖尿病的经验绝对风险（5年、10年和终生风险）。这些绝对风险估计是评估“个性化预防”策略的风险-收益平衡所必需的，例如建议具有特定基因-环境特征的妇女在更早的年龄开始乳房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潜在队列中收集的环境暴露数据相结合，推断遗传和基因-环境风险档案的绝对疾病风险。这些方法将广泛适用于其他队列研究以及与公共卫生相关的其他常见疾病和特征。

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.