Dite Gillian S, Spaeth Erika, Wong Chi Kuen, Murphy Nicholas M, Allman Richard
Genetic Technologies Limited, Fitzroy, Victoria, Australia.
Phenogen Sciences Inc, Charlotte, North Carolina.
Gastro Hep Adv. 2023 Jun 12;2(7):979-989. doi: 10.1016/j.gastha.2023.05.008. eCollection 2023.
Pancreatic cancer has the poorest 5-year survival rate of any major solid tumor, but when diagnosed at an early stage, survival rates improve. Population screening is impractical because pancreatic cancer is rare with a lifetime risk of 1.7%, but accurate risk stratification in the general population could enable health care providers to focus early detection strategies to at-risk individuals. Here, we validate a combined risk prediction model that integrates a polygenic risk score and a clinical risk model.
Using the UK Biobank, we conducted a prospective cohort study assessing 10-year pancreatic cancer risks based on a polygenic risk score, a clinical risk score, and a combined risk score. We assessed the association, discrimination, calibration, cumulative hazards, and standardized incidence ratios compared to population incidence rates for the risk scores. We also conducted net reclassification analyses.
While all of the risk scores discriminated well between affected and unaffected participants, the combined risk score - with a Harrell's C-index of 0.714 (95% confidence interval [CI] = 0.698, 0.730) - discriminated better than both the polygenic risk score ( = .001) and the clinical risk score ( = .02). In terms of calibration, there was no problem with dispersion for the combined risk score (β = 0.952, 95% CI = 0.865-1.039, = .3) and overall there was a small overestimation of risk (α = -0.089, 95% CI = -0.156 to -0.021, = .009). Participants in the top decile of 10-year risk were at 1.413 (95% CI = 1.242-1.607) times population risk.
The combined risk score was able to identify individuals at substantially increased risk of pancreatic cancer and to whom targeted screening could be useful.
胰腺癌是所有主要实体瘤中5年生存率最低的，但早期诊断时生存率会提高。由于胰腺癌发病率低，终生风险为1.7%，因此人群筛查不切实际，但对普通人群进行准确的风险分层可使医疗保健提供者将早期检测策略聚焦于高危个体。在此，我们验证了一种整合多基因风险评分和临床风险模型的联合风险预测模型。
利用英国生物银行，我们进行了一项前瞻性队列研究，基于多基因风险评分、临床风险评分和联合风险评分评估10年胰腺癌风险。我们评估了风险评分与人群发病率相比的关联性、区分度、校准度、累积风险和标准化发病率比。我们还进行了净重新分类分析。
虽然所有风险评分在患癌和未患癌参与者之间都有较好的区分度，但联合风险评分（Harrell氏C指数为0.714，95%置信区间[CI]=0.698,0.730）的区分度优于多基因风险评分（P=0.001）和临床风险评分（P=0.02）。在校准方面，联合风险评分的离散度没有问题（β=0.952，95%CI=0.865-1.039，P=0.3），总体而言风险有轻微高估（α=-0.089，95%CI=-0.156至-0.021，P=0.009）。10年风险处于最高十分位数的参与者的风险是人群风险的1.413倍（95%CI=1.242-1.607）。
联合风险评分能够识别胰腺癌风险大幅增加的个体，对这些个体进行靶向筛查可能会有帮助。
