The effect of disease penetrance, family size, and age of onset on family history with application to setting eligibility criteria for genetic testing.
The effect of disease penetrance, family size, and age of onset on family history with application to setting eligibility criteria for genetic testing.
复制标题
疾病外显率、家庭规模和发病年龄对家族史的影响，并应用于设定基因检测的资格标准。
DOI：
10.1023/a:1023208707085
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发表时间：
2003
期刊：
影响因子：
2.2
通讯作者：
Goldgar,DavidE
中科院分区：
文献类型：
--
作者：
Sibert,Alexandre;Goldgar,DavidE
在许多流行病学研究中，疾病家族史的概念已被用作遗传易感性的替代物，并且作为选择个体进行基因检测的标准也很重要。然而，很少有人知道真正的遗传模型（基因型特异性突变，发病年龄分布），预期寿命和生殖模式之间的精确相互作用，在确定家庭史的水平。为了解决这些问题，我们进行了模拟研究，以解决这些关系。研究的因素包括疾病的年龄、性别和基因型特异性发病率以及每个家庭后代数量的分布。当考虑突变阳性先证者一级亲属中受影响个体的平均数量时，突变相关因素占受影响一级亲属平均数量方差的64%，占受影响一级或二级亲属数量方差的58%。一般来说，突变阳性先证者至少有一个受影响的一级亲属的平均比例很低，特别是对于性别限制性疾病，范围在20%和46%之间，这取决于突变携带者的终身患病率。突变阳性先证者的一级亲属中缺乏家族史并不一定是意料之外的，即使是对于赋予相对高的终生风险的基因座。在选择先证者进行基因检测时，我们发现在各种条件下，基于一级和二级亲属中受影响人数的标准上级仅基于一级家族史的标准。
The concept of family history of disease has been used as a surrogate for genetic susceptibility in many epidemiological studies and has also been important as a criterion for selecting individuals for genetic testing. However, little is known about the precise interplay between the true genetic model (genotype-specific penetrances, age of onset distribution), life expectancy, and reproductive patterns in determining the level of family history. In order to address these questions, we performed a simulation study to address these relationships. Factors examined were the age-, sex-, and genotype-specific penetrance of the disease and the distribution of the number of offspring per family. When considering the average number of affected individuals among first-degree relatives of mutation positive probands, penetrance-related factors accounted for 64% of the variance in the average number of affected first-degree relatives, and 58% of the variance in the number of affected first- or second-degree relatives. In general, the average proportion of mutation-positive probands with at least one affected first-degree relative was low, especially for a sex-limited disease, ranging between 20% and 46%, depending on the lifetime penetrance in mutation carriers. Lack of family history among first-degree relatives of mutation positive probands is not necessarily unexpected even for loci conferring relatively high lifetime risk. In selecting probands for genetic testing, we found that under a wide variety of conditions, criteria based on the number of affected among first- and second-degree relatives were superior to those based on first-degree family history alone.