Epidemiologic Parameters of Rare Cancer Risk Factors

描述（由申请人提供）：近年来，已经鉴定了几种主要的癌症基因。通常，这些基因的突变在人群中很少见，但它们会大大增加携带者的风险。估计他们的人群流行病学特征，如相对风险和发病率，是具有挑战性的，主要是因为他们的罕见性。因此，各种新颖的设计和分析技术已被提出并利用间接估计这些参数。本修订提案的总体目标是批判性地评估这些方法的统计特性，比较不同的方法，并根据需要开发新方法。第一个目标将集中在预测率估计。我们将研究亲属队列设计，当先证者已确定从事件的情况下，已知的配置，导致向上的偏见，以期开发技术偏差校正。我们还将研究通过比较第二原发灶患者和第一原发灶患者的载波频率来推导出癌症的频率，这种方法不依赖于癌症的家族史。我们将努力利用这些结果发展风险预测，允许在已知的癌症家族史的基础上进行风险调整。在第二个目标中，我们将建立在利用第一和第二原色来估计相对风险的设计基础上。这里的目标将是识别和纠正潜在的生存偏倚的影响（如果基因与生存相关，则对第二初级的长度偏倚采样），修改对本研究设计中既有资格作为病例又有资格作为对照的个体的影响的分析，并检查与感兴趣的基因型相互作用的未知风险因素的影响。所有这些目标都是由目前正在进行的黑色素瘤遗传流行病学的国际研究所激发的。

DESCRIPTION (provided by applicant): In recent years several major cancer genes have been identified. Typically, mutations in these genes are rare in the population, but they confer a substantially increased risk to carriers. Estimation of their population epidemiologic characteristics, such as relative risks and penetrances, is challenging, primarily because of their rarity. As a result, various novel designs and analytic techniques have been proposed and utilized to estimate these parameters indirectly. The general goal of this revised proposal is to critically evaluate the statistical properties of these methods, to compare different approaches, and to develop new methods as needed. The first aim will focus on penetrance estimation. We will examine the kin-cohort design, when probands have been identified from incident cases, a configuration known to result in upward bias, with a view to developing techniques for bias correction. Also we will study the derivation of penetrance from comparing carrier frequencies in patients with second primaries with patients with first primaries, an approach that does not depend on family histories of cancer. We will endeaver to use these results develop risk predictions that allow for risk adjustment on the basis of known family history of cancer. In the second aim we will build on the design that utilizes first and second primaries to estimate relative risks. The goals here will be to identify and correct the impact of potential survival bias (length biased sampling of second primaries if the gene is associated with survival), to modify analyses for the impact of individuals who qualify as both cases and controls in this study design, and to examine the impact of unknown risk factors that interact with the genotype of interest. All of these aims are motivated by an international study of the genetic epidemiology of melanoma that is currently in progress.