Choi Yun-Hee, Briollais Laurent, Green Jane, Parfrey Patrick, Kopciuk Karen
The Department of Epidemiology and Biostatistics, The University of Western Ontario, London, ON N6A 5C1, Canada.
Stat Med. 2014 Feb 20;33(4):618-38. doi: 10.1002/sim.5938. Epub 2013 Aug 15.
Lynch Syndrome (LS) families harbor mutated mismatch repair genes,which predispose them to specific types of cancer. Because individuals within LS families can experience multiple cancers over their lifetime, we developed a progressive three-state model to estimate the disease risk from a healthy (state 0) to a first cancer (state 1) and then to a second cancer (state 2). Ascertainment correction of the likelihood was made to adjust for complex sampling designs with carrier probabilities for family members with missing genotype information estimated using their family's observed genotype and phenotype information in a one-step expectation-maximization algorithm. A sandwich variance estimator was employed to overcome possible model misspecification. The main objective of this paper is to estimate the disease risk (penetrance) for age at a second cancer after someone has experienced a first cancer that is also associated with a mutated gene. Simulation study results indicate that our approach generally provides unbiased risk estimates and low root mean squared errors across different family study designs, proportions of missing genotypes, and risk heterogeneities. An application to 12 large LS families from Newfoundland demonstrates that the risk for a second cancer was substantial and that the age at a first colorectal cancer significantly impacted the age at any LS subsequent cancer. This study provides new insights for developing more effective management of mutation carriers in LS families by providing more accurate multiple cancer risk estimates.
林奇综合征（LS）家族携带错配修复基因突变，这使他们易患特定类型的癌症。由于LS家族中的个体在其一生中可能会患多种癌症，我们开发了一种渐进三状态模型，以估计从健康状态（状态0）到首次患癌（状态1），再到第二次患癌（状态2）的疾病风险。对似然性进行了确定校正，以调整复杂的抽样设计，使用一步期望最大化算法，根据其家族观察到的基因型和表型信息估计缺失基因型信息的家庭成员的携带概率。采用三明治方差估计器来克服可能的模型误设。本文的主要目的是估计在某人经历了与基因突变相关的首次癌症后，第二次患癌时的疾病风险（外显率）。模拟研究结果表明，我们的方法通常能提供无偏风险估计，并且在不同的家族研究设计、缺失基因型比例和风险异质性情况下，均具有较低的均方根误差。对来自纽芬兰的12个大型LS家族的应用表明，第二次患癌的风险很大，首次患结直肠癌的年龄对任何后续LS相关癌症的年龄有显著影响。本研究通过提供更准确的多种癌症风险估计，为制定更有效的LS家族突变携带者管理策略提供了新见解。
