Ruberu Thanthirige Lakshika M, Braun Danielle, Parmigiani Giovanni, Biswas Swati
Department of Mathematical Sciences, University of Texas at Dallas, Richardson, Texas, USA.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Stat Med. 2025 Feb 10;44(3-4):e10323. doi: 10.1002/sim.10323.
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 these genes. A meta-analysis combining the reported risk estimates can provide an overall estimate of age-specific risk of developing BC, that is, penetrance for a gene. However, estimates reported by case-control studies often suffer from ascertainment bias. Currently, there is no method available to adjust for such bias in this setting. We consider a Bayesian random effect 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 in the 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 overall estimated BC risk for individuals with pathogenic variants are (1) 5.77% (3.22%-9.67%) by age 50 and 26.13% (20.31%-32.94%) by age 80 for ATM; (2) 12.99% (6.48%-22.23%) by age 50, and 44.69% (34.40%-55.80%) by age 80 for PALB2. The proposed method allows meta-analyses to include studies with ascertainment bias, resulting in inclusion of more studies and thereby more accurate estimates.
多基因panel检测能够有效检测癌症易感基因中的致病变异,包括ATM和PALB2等中度风险基因。越来越多的研究探讨了这些基因的致病变异所赋予的乳腺癌(BC)风险。一项综合报告的风险估计值的荟萃分析可以提供特定年龄患BC风险的总体估计,即一个基因的外显率。然而,病例对照研究报告的估计值往往存在确诊偏倚。目前,在这种情况下没有可用的方法来校正这种偏倚。我们考虑一种贝叶斯随机效应荟萃分析方法,该方法可以综合不同类型的风险测量,并将其扩展以纳入存在确诊偏倚的研究。这是通过在模型中引入一个偏倚项并赋予适当的先验分布来实现的。我们通过模拟研究验证了该方法,并将其应用于估计ATM和PALB2基因致病变异携带者的BC外显率。我们的模拟表明,如果不校正确诊偏倚或在分析中舍弃存在这种偏倚的研究,与这些情况相比,所提出的方法能得出更准确和精确的外显率估计值。ATM基因致病变异个体的总体估计BC风险为:50岁时为5.77%(3.22%-9.67%),80岁时为26.13%(20.31%-32.94%);PALB2基因致病变异个体的总体估计BC风险为:50岁时为12.99%(6.48%-22.23%),80岁时为44.69%(34.40%-55.80%)。所提出的方法允许荟萃分析纳入存在确诊偏倚的研究,从而纳入更多研究,进而得到更准确的估计值。