A Method for Validating Gene - Disease Associations

描述（由申请人提供）： 病例对照研究越来越多地用于评估常见遗传变异的癌症风险。在这些研究中收集有关疾病家族史的详细信息是常见的。这项研究的基本原理是认为这些家族史数据没有被研究者有效利用。一级亲属的家族史数据可以在一个回顾性的“亲属队列”中收集，并使用队列研究方法进行分析，从而将基因“携带者”亲属中研究的癌症发病率与“非携带者”亲属中的发病率进行比较。在这个应用程序中，我们表明，从亲属队列分析这种性质的率比可以表示为感兴趣的率比的函数（即，在病例对照研究中直接估计的参数）。因此，亲属队列分析原则上可用作病例对照研究中观察到的任何遗传关联的独立验证。我们目前的证据表明，亲属队列可能有很好的统计能力，为这一目的的研究常见的癌症。在本申请中，我们计划详细研究亲属队列分析相对于亲属队列数据来源的病例对照研究的统计功效。我们将检查亲属队列分析的相对效率与所研究癌症的潜在发病率、人群频率和基因型的相对风险的关系。该方法还可推广到两种基因型联合效应的研究和单倍型的评价。预计该项目将证明，对于常见的癌症，亲属队列分析可以立即独立确认（或反驳）在病例对照研究中偶然观察到的遗传关联。

DESCRIPTION (provided by applicant): The case-control study is being used increasingly to evaluate cancer risks of common genetic variants. It is commonplace for detailed information on family history of disease to be collected in these studies. The rationale for this investigation is the belief that these data on family history are not utilized efficiently by investigators. Data on the family history of first degree relatives can be assembled in a retrospective "kin-cohort", and analyzed using cohort-study methodology, whereby the incident rates of the cancer under study in relatives of gene "carriers" are compared with the rates in relatives of "non-carriers". In this application we show that the rate ratio from a kin-cohort analysis of this nature can be expressed as a function of the rate ratio of interest (i.e. the parameter that is directly estimated in the case-control study). Thus the kin-cohort analysis can be used, in principle, as an independent verification of any genetic associations observed in the case-control study. We present evidence to suggest that the kin-cohort might have good statistical power for this purpose for the study of common cancers. In this application we plan to study in detail the statistical power of the kin-cohort analysis relative to that of the case-control study from which the data for the kin-cohort are derived. We will examine the relative efficiency of the kin-cohort analysis in relation to the underlying incidence rate of the cancer under study, the population frequency and the relative risk of the genotype. The method will also be extended to the study of the joint effect of two genotypes, and the evaluation of haplotypes. It is anticipated that the project will demonstrate that for commonly occurring cancers the kin-cohort analysis can provide an immediate independent confirmation (or refutation) of genetic associations that are observed serendipitously in case-control studies.