Epidemiologic Parameters of Rare Cancer Risk Factors

描述（由申请人提供）：近年来已经确定了几种主要的癌症基因。通常，这些基因的突变在人群中是罕见的，但它们会大大增加携带者的风险。估计其人口流行病学特征，如相对风险和外显率，是具有挑战性的，主要是因为它们的罕见性。因此，各种新的设计和分析技术被提出并用于间接估计这些参数。本修订建议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。第一个目标将集中于外显率估计。我们将研究亲属队列设计，当先证者从事件案例中确定时，已知会导致向上偏倚的配置，以开发偏倚校正技术。此外，我们将通过比较第二次原发性患者与第一次原发性患者的携带者频率来研究外显率的推导，这是一种不依赖于癌症家族史的方法。我们将努力利用这些结果开发风险预测，允许在已知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初级和第二初级来估计相对风险的设计之上。这里的目标将是识别和纠正潜在生存偏差的影响（如果基因与生存相关，则进行第二次初级长度偏差抽样），修改本研究设计中符合病例和对照条件的个体的影响分析，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推动的。

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.