The prediction of early preeclampsia: Results from a longitudinal proteomics study

ObjectivesTo identify maternal plasma protein markers for early preeclampsia (delivery Study designThis longitudinal case-control study included 90 patients with a normal pregnancy and 33 patients with early preeclampsia. Two to six maternal plasma samples were collected throughout gestation from each woman. The abundance of 1,125 proteins was measured using high-affinity aptamer-based proteomic assays, and data were modeled using linear mixed-effects models. After data transformation into multiples of the mean values for gestational age, parsimonious linear discriminant analysis risk models were fit for each gestational-age interval (8–16, 16.1–22, 22.1–28, 28.1–32 weeks). Proteomic profiles of early preeclampsia cases were also compared to those of a combined set of controls and late preeclampsia cases (n = 76) reported previously. Prediction performance was estimated via bootstrap.ResultsWe found that 1) multi-protein models at 16.1–22 weeks of gestation predicted early preeclampsia with a sensitivity of 71% at a false-positive rate (FPR) of 10%. High abundance of matrix metalloproteinase-7 and glycoprotein IIbIIIa complex were the most reliable predictors at this gestational age; 2) at 22.1–28 weeks of gestation, lower abundance of placental growth factor (PlGF) and vascular endothelial growth factor A, isoform 121 (VEGF-121), as well as elevated sialic acid binding immunoglobulin-like lectin 6 (siglec-6) and activin-A, were the best predictors of the subsequent development of early preeclampsia (81% sensitivity, FPR = 10%); 3) at 28.1–32 weeks of gestation, the sensitivity of multi-protein models was 85% (FPR = 10%) with the best predictors being activated leukocyte cell adhesion molecule, siglec-6, and VEGF-121; 4) the increase in siglec-6, activin-A, and VEGF-121 at 22.1–28 weeks of gestation differentiated women who subsequently developed early preeclampsia from those who had a normal pregnancy or developed late preeclampsia (sensitivity 77%, FPR = 10%); 5) the sensitivity of risk models was higher for early preeclampsia with placental MVM lesions than for the entire early preeclampsia group (90% versus 71% at 16.1–22 weeks; 87% versus 81% at 22.1–28 weeks; and 90% versus 85% at 28.1–32 weeks, all FPR = 10%); and 6) the sensitivity of prediction models was higher for severe early preeclampsia than for the entire early preeclampsia group (84% versus 71% at 16.1–22 weeks).ConclusionWe have presented herein a catalogue of proteome changes in maternal plasma proteome that precede the diagnosis of preeclampsia and can distinguish among early and late phenotypes. The sensitivity of maternal plasma protein models for early preeclampsia is higher in women with underlying vascular placental disease and in those with a severe phenotype.研究目标：本研究旨在识别早发型子痫前期（early preeclampsia）的母体血浆蛋白标志物。 研究设计：本项纵向病例对照研究共纳入90名正常妊娠者与33名早发型子痫前期患者。每名受试者在整个妊娠期内采集2~6份母体血浆样本。采用高亲和力适配子介导的蛋白质组学检测（high-affinity aptamer-based proteomic assays）对1125种蛋白质的丰度进行定量，并通过线性混合效应模型（linear mixed-effects models）开展数据建模。将数据转换为对应胎龄的均值倍数后，针对各胎龄区间（8~16、16.1~22、22.1~28、28.1~32孕周）构建简约线性判别分析（linear discriminant analysis）风险模型。同时将早发型子痫前期患者的蛋白质组谱与既往报道的对照组合并晚发型子痫前期患者（n=76）的蛋白质组谱进行对比。预测性能通过自助法（bootstrap）进行评估。 研究结果：本研究得到以下结论：1）孕16.1~22周时构建的多蛋白模型可预测早发型子痫前期，在假阳性率（false-positive rate, FPR）为10%的前提下灵敏度达71%；其中基质金属蛋白酶-7（matrix metalloproteinase-7）与糖蛋白IIbIIIa复合物（glycoprotein IIbIIIa complex）的高丰度是该胎龄阶段最可靠的预测因子；2）孕22.1~28周时，胎盘生长因子（placental growth factor, PlGF）与血管内皮生长因子A亚型121（vascular endothelial growth factor A isoform 121, VEGF-121）的低丰度，以及唾液酸结合免疫球蛋白样凝集素6（sialic acid-binding immunoglobulin-like lectin 6, SIGLEC-6）和激活素A（activin-A）的高丰度，是预测后续发生早发型子痫前期的最优指标（灵敏度81%，FPR=10%）；3）孕28.1~32周时，多蛋白模型的灵敏度为85%（FPR=10%），最佳预测因子为活化白细胞黏附分子、SIGLEC-6与VEGF-121；4）孕22.1~28周时SIGLEC-6、activin-A与VEGF-121的水平变化可区分后续发生早发型子痫前期的孕妇与正常妊娠或晚发型子痫前期孕妇（灵敏度77%，FPR=10%）；5）伴胎盘MVM病变的早发型子痫前期患者，其风险模型灵敏度高于全部早发型子痫前期队列（16.1~22周时为90% vs 71%；22.1~28周时为87% vs 81%；28.1~32周时为90% vs 85%，所有组FPR均为10%）；6）重度早发型子痫前期患者的预测模型灵敏度高于全部早发型子痫前期队列（16.1~22周时为84% vs 71%）。 研究结论：本研究揭示了子痫前期（preeclampsia）确诊前母体血浆蛋白质组的一系列变化特征，可用于区分早发型与晚发型子痫前期表型。针对早发型子痫前期的母体血浆蛋白预测模型，在合并胎盘血管病变的孕妇以及重度表型孕妇中具有更高的诊断灵敏度。