Development of a serum biosignature for ectopic pregnancy.

描述（由申请人提供）：这是一个高生产率、多学科、多中心项目的修订申请，该项目评价了异位妊娠（EP）和早孕失败风险女性的诊断。 早期妊娠失败是妊娠中最常见的并发症，估计25%的临床公认妊娠以流产结束，1-2%被诊断为异位妊娠（EP）。 EP是导致妊娠相关死亡的主要原因，也是孕产妇发病的主要原因。当妊娠在超声下不可见时，区分健康的持续宫内妊娠（IUP）与流产或EP构成了关键的临床挑战，因为没有其他明确的非侵入性诊断测试。目前的诊断方案可能导致所需IUP中断和/或与EP破裂相关的发病率。我们已经证明，当联合使用时，许多EP的推定生物标志物可以区分IUP和EP。 使用无偏见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：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和流产的生物特征。 具体目标和方法：我们计划开发一种多标记物生物特征谱，以帮助诊断EP。 我们假设，少量的标记物，联合使用，将能够区分EP从IUP（正在进行的IUP和流产的组合）和/或可以用来区分不可行的妊娠（EP和流产的组合）从正在进行的IUP。在具体目标1中，我们将开发、完善和验证血清（多标记物）检测，以根据早期植入和存活的推定标记物识别EP。 在具体目标2中，我们将验证新发现的EP生物标志物添加到（或取代）我们目前的多标志物组中的潜力。在具体目标3中，我们将进行一项无偏见的三向蛋白质组发现研究，该研究将鉴定新的、丰度较低的生物标志物候选物，以区分EP、IUP和流产。 总结：这一建议代表了一个独特的机会，联合收割机结合流行病学和基础科学的方法，以了解和改善我们的能力，诊断和治疗生殖疾病的重要限制与重要的公共卫生后果。我们计划利用大量具有EP风险的地理、种族和人种多样性女性，使用良好表型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，以评估预期患者人群的实际使用情况。 非侵入性诊断方法的发展，例如以高准确度诊断EP和/或流产的血清测试，将具有巨大的临床影响。

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.