Validation of a second-generation multivariate index assay for malignancy risk of adnexal masses
Validation of a second-generation multivariate index assay for malignancy risk of adnexal masses
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DOI：
10.1016/j.ajog.2016.03.003
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发表时间：
2016-07-01
影响因子：
9.8
通讯作者：
Wolf, Judith
中科院分区：
文献类型：
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作者：
Coleman, Robert L.;Herzog, Thomas J.;Wolf, Judith
背景：患有疑似卵巢恶性肿瘤的附件肿块的女性可能会受益于妇科肿瘤科医生的咨询，但确保转诊的影像学和生物标志物工具的敏感性较低，并且可能会在关键阶段漏掉癌症。 目的：多变量指数测定 (MIA) 旨在提高接受盆腔肿块手术的女性中卵巢癌的检出率。为了提高对良性肿块的预测，我们对第二代 MIA (MIA2G) 进行了重新设计和验证。研究设计：MIA2G 是使用来自先前发表的前瞻性多站点登记的血清样本开发的，这些患者接受了附件肿块切除手术。然后使用来自 OVA500 试验（第二个附件手术患者前瞻性队列）的血清样本来确定临床有效性。根据 OVA500 试验的最终病理学结果，MIA2G 测试的预期使用人群具有高风险，观察到的癌症患病率为 18.7% (92/493)。由外部临床实验室对编码样本进行 MIA2G 生物标志物分析。然后计算 MIA2G 结果并将其提交给临床统计合同组织，以进行解码并与每个受试者的 MIA 结果进行比较。计算敏感性、特异性、阳性预测值 (PPV) 和阴性预测值 (NPV) 等指标，并按绝经状态、分期和组织学亚型进行分层。 结果：MIA2G 中纳入了 3 个 MIA 标记物（癌抗原 125、转铁蛋白和载脂蛋白 A-1）和 2 个新生物标记物（卵泡刺激素和人附睾蛋白 4）。无论患者的绝经状态如何，单一截止点都会区分恶性肿瘤的高风险和低风险，从而消除了混淆或错误的可能性。 MIA2G 特异性（69%，277/401 [n/N]；95% 置信区间 [CI]，64.4-73.4%）和 PPV（40%，84/208；95% CI，33.9-47.2%）比 MIA（特异性，54%，215/401；95% CI，在此队列中，PPV 分别为 48.7-58.4%，PPV，31%，85/271；95% CI，26.1-37.1%。两次测试之间的灵敏度和 NPV 没有显着差异。与医生评估相结合时，MIA2G 正确识别了仅由医生评估漏掉的 75% 的恶性肿瘤。结论：与 MIA 相比，MIA2G 特异性和 PPV 显着提高，而敏感性和 NPV 没有变化。与 MIA 相比，第二代测试显着提高了分类的预测效率，同时又不牺牲对有效性至关重要的高灵敏度和 NPV。
BACKGROUND: Women with adnexal mass suspected of ovarian malignancy are likely to benefit from consultation with a gynecologic oncologist, but imaging and biomarker tools to ensure this referral show low sensitivity and may miss cancer at critical stages.OBJECTIVE: The multivariate index assay (MIA) was designed to improve the detection of ovarian cancer among women undergoing surgery for a pelvic mass. To improve the prediction of benign masses, we undertook the redesign and validation of a second-generation MIA (MIA2G).STUDY DESIGN: MIA2G was developed using banked serum samples from a previously published prospective, multisite registry of patients who underwent surgery to remove an adnexal mass. Clinical validity was then established using banked serum samples from the OVA500 trial, a second prospective cohort of adnexal surgery patients. Based on the final pathology results of the OVA500 trial, this intended-use population for MIA2G testing was high risk, with an observed cancer prevalence of 18.7% (92/493). Coded samples were assayed for MIA2G biomarkers by an external clinical laboratory. Then MIA2G results were calculated and submitted to a clinical statistics contract organization for decoding and comparison to MIA results for each subject. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, among other measures, and stratified by menopausal status, stage, and histologic subtype.RESULTS: Three MIA markers (cancer antigen 125, transferrin, and apolipoprotein A-1) and 2 new biomarkers (follicle-stimulating hormone and human epididymis protein 4) were included in MIA2G. A single cut-off separated high and low risk of malignancy regardless of patient menopausal status, eliminating potential for confusion or error. MIA2G specificity (69%, 277/401 [n/N]; 95% confidence interval [CI], 64.4-73.4%) and PPV (40%, 84/208; 95% CI, 33.9-47.2%) were significantly improved over MIA (specificity, 54%, 215/401; 95% CI, 48.7-58.4%, and PPV, 31%, 85/271; 95% CI, 26.1-37.1%, respectively) in this cohort. Sensitivity and NPV were not significantly different between the 2 tests. When combined with physician assessment, MIA2G correctly identified 75% of the malignancies missed by physician assessment alone.CONCLUSION: MIA2G specificity and PPV were significantly improved compared with MIA, while sensitivity and NPV were unchanged. The second-generation test significantly improved the predicted efficiency of triage vs MIA without sacrificing high sensitivity and NPV, which are essential for effectiveness.