Department of Mathematical Sciences, University of Texas at Dallas, Richardson, TX 75080, United States.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States.
Biometrics. 2024 Mar 27;80(2). doi: 10.1093/biomtc/ujae038.
Multi-gene panel testing allows many cancer susceptibility genes to be tested quickly at a lower cost making such testing accessible to a broader population. Thus, more patients carrying pathogenic germline mutations in various cancer-susceptibility genes are being identified. This creates a great opportunity, as well as an urgent need, to counsel these patients about appropriate risk-reducing management strategies. Counseling hinges on accurate estimates of age-specific risks of developing various cancers associated with mutations in a specific gene, ie, penetrance estimation. We propose a meta-analysis approach based on a Bayesian hierarchical random-effects model to obtain penetrance estimates by integrating studies reporting different types of risk measures (eg, penetrance, relative risk, odds ratio) while accounting for the associated uncertainties. After estimating posterior distributions of the parameters via a Markov chain Monte Carlo algorithm, we estimate penetrance and credible intervals. We investigate the proposed method and compare with an existing approach via simulations based on studies reporting risks for two moderate-risk breast cancer susceptibility genes, ATM and PALB2. Our proposed method is far superior in terms of coverage probability of credible intervals and mean square error of estimates. Finally, we apply our method to estimate the penetrance of breast cancer among carriers of pathogenic mutations in the ATM gene.
多基因panel 检测可在降低成本的情况下快速检测多种癌症易感性基因,使更广泛的人群能够接受这种检测。因此,越来越多的携带有致病性种系突变的患者被发现存在于各种癌症易感性基因中。这既带来了巨大的机会,也产生了迫切的需求,即需要为这些患者提供关于适当的降低风险的管理策略的咨询。咨询的关键在于准确估计与特定基因突变相关的各种癌症的特定年龄风险,即外显率估计。我们提出了一种基于贝叶斯分层随机效应模型的荟萃分析方法,通过整合报告不同类型风险测量(例如外显率、相对风险、优势比)的研究来获得外显率估计值,同时考虑相关的不确定性。通过马尔可夫链蒙特卡罗算法估计参数的后验分布后,我们估计外显率和可信区间。我们通过基于报道 ATM 和 PALB2 两种中度风险乳腺癌易感基因风险的研究的模拟来研究所提出的方法并与现有方法进行比较。在所提出的方法中,可信区间的覆盖率和估计的均方误差都远远优于现有方法。最后,我们应用我们的方法来估计 ATM 基因致病性突变携带者的乳腺癌外显率。