Development of a serum biosignature for ectopic pregnancy.

描述（由申请人提供）：这是一个高生产力、多学科、多中心项目的修订申请，评估有异位妊娠（EP）和早期妊娠失败风险的妇女的诊断。妊娠早期失败是妊娠中最常见的并发症，据估计临床上确认的妊娠中有25%以流产告终，1-2%被诊断为异位妊娠（EP）。EP是与妊娠有关的主要死亡原因，也是孕产妇发病的主要原因。当超声不可见妊娠时，区分健康的宫内妊娠（IUP）与流产或EP是一个关键的临床挑战，因为没有其他明确的、无创的诊断测试。目前的诊断方案可能导致预期宫内排卵的中断和/或与宫内排卵破裂相关的发病率。我们已经证明，当联合使用时，一些假定的EP生物标志物可以区分IUP和EP。使用无偏倚的蛋白质组学分析方法，我们还建立了新的生物标志物，其中一个我们已经验证了：ADAM-12。该项目的目标是扩大生物标志物的使用，以开发区分EP，持续IUP和流产的生物标记。具体目的和方法：我们计划开发一种多标记生物特征谱来帮助EP的诊断。我们假设少量的标记，结合使用，将能够区分EP和IUP（正在进行的IUP和流产的组合）和/或可以用来区分不可活妊娠（EP和流产的组合）和正在进行的IUP。在具体目标1中，我们将开发、完善和验证一种血清（多标记物）测试，以根据推测的早期植入和生存能力标记来识别EP。在Specific Aim 2中，我们将验证新发现的EP生物标记物的潜力，以添加（或取代）我们当前的多重标记物面板。在具体目标3中，我们将进行一项无偏倚的三方蛋白质组学发现研究，以确定区分EP， IUP和流产的新的低丰度生物标志物候选物。摘要：该提案提供了一个独特的机会，将流行病学和基础科学方法结合起来，以了解和改进我们诊断和治疗具有重要公共卫生后果的生殖障碍的能力的重要限制。利用对大量地理、种族和民族不同的EP风险女性的访问，我们计划使用表型良好的生物标本进行一系列多中心病例对照研究，并最终进行前瞻性队列研究，以评估在预期患者群体中的实际使用情况。无创诊断方法的发展，如血清试验诊断EP和/或流产的准确性高，将有巨大的临床影响。

DESCRIPTION (provided by applicant): This is a revised application from a highly productive, multidisciplinary, multicenter project evaluating the diagnosis of women at risk for ectopic pregnancy (EP) and early pregnancy failure. Early pregnancy failure is the most common complication in pregnancy with an estimated 25% of clinically recognized pregnancies ending in miscarriage, and 1-2% are diagnosed as ectopic pregnancy (EP). EP is the leading pregnancy-related cause of death and a major contributor to maternal morbidity. When the gestation is not visible with ultrasound, distinguishing a healthy ongoing intrauterine gestation (IUP) from a miscarriage or an EP poses a critical clinical challenge as there is no other definitive, noninvasive diagnostic test. Current diagnostic protocols can result in the interruption of a desired IUP and/or morbidity associated with rupture of an EP. We have demonstrated that a number of putative biomarkers of EP can distinguish IUP from EP when used in combination. Using an unbiased proteomic analysis approach we have also established new biomarkers, one which we have already validated: ADAM-12. The goal of this project is to expand the use of biomarkers to develop a biosignature distinguishing EP, ongoing IUP and miscarriage. Specific Aims and Methods: We plan to develop a multiple marker bio-signature profile to aid in the diagnosis of EP. We hypothesize that a small number of markers, used in combination, will be able to distinguish an EP from IUP (combination of ongoing IUP and miscarriage) and/or can be used to distinguish a nonviable gestation (combination of EP and miscarriage) from an ongoing IUP. In Specific aim 1 we will develop, refine and validate a serum (multiple marker) test to identify EP based on putative markers of early implantation and viability. In Specific Aim 2 we will validate the potential of newly discovered biomarkers of EP to add to (or replace) those in our current multiple marker panel. In Specific aim 3 we will conduct an unbiased three-way proteomic discovery study that will identify new, lower abundance biomarker candidates that distinguish between EP, IUP and miscarriage. Summary: This proposal represents a unique opportunity to combine epidemiologic and basic science methodologies to understand and improve upon important limitations in our ability to diagnose and treat a reproductive disorder with important public health consequences. Utilizing access to a large number of geographically, racially and ethnically diverse women at risk for EP, we plan to conduct a series of multicenter case control studies using well phenotyped bio-specimens, and ultimately conduct a prospective cohort study to assess actual use in the intended patient population. The development of non invasive methods of diagnosis, such as a serum test to diagnose an EP and/or miscarriage with high accuracy, would have tremendous clinical impact.