PDF(Pubmed)
Abstract：
UNASSIGNED: Breast cancer (BC) screening with mammography reduces mortality but considers currently only age as a risk factor. Personalized risk-based screening has been proposed as a more efficient alternative. For that, risk prediction tools are necessary. Genome-wide association studies have identified numerous genetic variants (single-nucleotide polymorphisms [SNPs]) associated with BC. The effects of SNPs are combined into a polygenic risk score (PRS) as a risk prediction tool.
UNASSIGNED: We aimed to develop a clinical-grade PRS test suitable for BC risk-stratified screening with clinical recommendations and implementation in clinical practice.
UNASSIGNED: In the first phase of our study, we gathered previously published PRS models for predicting BC risk from the literature and validated them using the Estonian Biobank and UK Biobank data sets. We selected the best performing model based on prevalent data and independently validated it in both incident data sets. We then conducted absolute risk simulations, developed risk-based recommendations, and implemented the PRS test in clinical practice. In the second phase, we carried out a retrospective analysis of the PRS test\'s performance results in clinical practice.
UNASSIGNED: The best performing PRS included 2803 SNPs. The C-index of the Cox regression model associating BC status with PRS was 0.656 (SE = 0.05) with a hazard ratio of 1.66. The PRS can stratify individuals with more than a 3-fold risk increase. A total of 2637 BC PRS tests have been performed for women between the ages 30 and 83. Results in clinical use overlap well with expected PRS performance with 5.7% of women with more than 2-fold and 1.4% with more than 3-fold higher risk than the population average.
UNASSIGNED: The PRS test separates different BC risk levels and is feasible to implement in clinical practice.
UNASSIGNED: We aimed to develop a clinical-grade PRS test suitable for BC risk-stratified screening with clinical recommendations and implementation in clinical practice.
UNASSIGNED: In the first phase of our study, we gathered previously published PRS models for predicting BC risk from the literature and validated them using the Estonian Biobank and UK Biobank data sets. We selected the best performing model based on prevalent data and independently validated it in both incident data sets. We then conducted absolute risk simulations, developed risk-based recommendations, and implemented the PRS test in clinical practice. In the second phase, we carried out a retrospective analysis of the PRS test\'s performance results in clinical practice.
UNASSIGNED: The best performing PRS included 2803 SNPs. The C-index of the Cox regression model associating BC status with PRS was 0.656 (SE = 0.05) with a hazard ratio of 1.66. The PRS can stratify individuals with more than a 3-fold risk increase. A total of 2637 BC PRS tests have been performed for women between the ages 30 and 83. Results in clinical use overlap well with expected PRS performance with 5.7% of women with more than 2-fold and 1.4% with more than 3-fold higher risk than the population average.
UNASSIGNED: The PRS test separates different BC risk levels and is feasible to implement in clinical practice.
摘要：
■乳房X线检查乳腺癌（BC）筛查可降低死亡率，但目前仅将年龄视为危险因素。个性化的基于风险的筛查已被提出作为更有效的替代方案。为此，风险预测工具是必要的。全基因组关联研究已经确定了许多与BC相关的遗传变异(单核苷酸多态性[SNP])。将SNP的影响组合成多基因风险评分(PRS)作为风险预测工具。
■我们旨在开发一种适用于BC风险分层筛查的临床级PRS测试，并提供临床建议并在临床实践中实施。
■在我们研究的第一阶段，我们从文献中收集了以前发表的预测BC风险的PRS模型,并使用爱沙尼亚生物库和英国生物库数据集进行了验证.我们根据流行数据选择了性能最佳的模型，并在两个事件数据集中对其进行了独立验证。然后我们进行了绝对风险模拟，制定了基于风险的建议，并在临床实践中实施了PRS测试。在第二阶段,我们对PRS试验在临床实践中的表现结果进行了回顾性分析.
■表现最好的PRS包括2803个SNP。将BC状态与PRS相关联的Cox回归模型的C指数为0.656(SE=0.05),风险比为1.66。PRS可以对风险增加超过3倍的个体进行分层。对30至83岁的女性进行了总共2637次BCPRS测试。临床使用结果与预期的PRS表现很好地重叠，其中5.7％的女性比人口平均水平高2倍以上，1.4％的女性风险高3倍以上。
■PRS测试将不同的BC风险水平分开，并且在临床实践中实施是可行的。
■我们旨在开发一种适用于BC风险分层筛查的临床级PRS测试，并提供临床建议并在临床实践中实施。
■在我们研究的第一阶段，我们从文献中收集了以前发表的预测BC风险的PRS模型,并使用爱沙尼亚生物库和英国生物库数据集进行了验证.我们根据流行数据选择了性能最佳的模型，并在两个事件数据集中对其进行了独立验证。然后我们进行了绝对风险模拟，制定了基于风险的建议，并在临床实践中实施了PRS测试。在第二阶段,我们对PRS试验在临床实践中的表现结果进行了回顾性分析.
■表现最好的PRS包括2803个SNP。将BC状态与PRS相关联的Cox回归模型的C指数为0.656(SE=0.05),风险比为1.66。PRS可以对风险增加超过3倍的个体进行分层。对30至83岁的女性进行了总共2637次BCPRS测试。临床使用结果与预期的PRS表现很好地重叠，其中5.7％的女性比人口平均水平高2倍以上，1.4％的女性风险高3倍以上。
■PRS测试将不同的BC风险水平分开，并且在临床实践中实施是可行的。
