Multi-gene panel testing allows efficient detection of pathogenic variants in cancer susceptibility genes including moderate-risk genes such as ATM and PALB2. A growing number of studies examine the risk of breast cancer (BC) conferred by pathogenic variants of such genes. A meta-analysis combining the reported risk estimates can provide an overall age-specific risk of developing BC, i.e., penetrance for a gene. However, estimates reported by case-control studies often suffer from ascertainment bias. Currently there are no methods available to adjust for such ascertainment bias in this setting. We consider a Bayesian random-effects meta-analysis method that can synthesize different types of risk measures and extend it to incorporate studies with ascertainment bias. This is achieved by introducing a bias term in the model and assigning appropriate priors. We validate the method through a simulation study and apply it to estimate BC penetrance for carriers of pathogenic variants of ATM and PALB2 genes. Our simulations show that the proposed method results in more accurate and precise penetrance estimates compared to when no adjustment is made for ascertainment bias or when such biased studies are discarded from the analysis. The estimated overall BC risk for individuals with pathogenic variants in (1) ATM is 5.77% (3.22%-9.67%) by age 50 and 26.13% (20.31%-32.94%) by age 80; (2) PALB2 is 12.99% (6.48%-22.23%) by age 50 and 44.69% (34.40%-55.80%) by age 80. The proposed method allows for meta-analyses to include studies with ascertainment bias resulting in a larger number of studies included and thereby more robust estimates.

翻译：多基因面板检测能够高效检测癌症易感基因（包括ATM和PALB2等中等风险基因）的致病性变异。越来越多的研究关注此类基因致病性变异所导致的乳腺癌（BC）风险。通过荟萃分析整合已报道的风险估计值，可提供年龄特异性的乳腺癌总体发病风险，即基因外显率。然而，病例对照研究报道的估计值常受到确证偏倚的影响，目前尚无针对此类偏倚的校正方法。我们提出一种贝叶斯随机效应荟萃分析方法，既能综合不同类型的风险度量，又通过引入偏倚项并设置合适先验分布将其扩展至包含存在确证偏倚的研究。通过模拟研究验证该方法，并将其应用于ATM和PALB2基因致病性变异携带者的乳腺癌外显率估计。模拟结果表明，与未校正确证偏倚或剔除偏倚研究的方法相比，本方法能获得更准确且精确的外显率估计。携带ATM基因致病性变异者在50岁和80岁时的乳腺癌总体风险估计值分别为5.77%（3.22%-9.67%）和26.13%（20.31%-32.94%）；携带PALB2基因致病性变异者的相应风险估计值为12.99%（6.48%-22.23%）和44.69%（34.40%-55.80%）。该方法使荟萃分析能够纳入存在确证偏倚的研究，从而扩大纳入研究数量并增强估计稳健性。