A metabolomics-based laboratory developed test to improve the diagnostic precision of Polycystic Ovary Syndrome

摘要 多囊卵巢综合征（PCOS）是一种复杂的多因素内分泌疾病，其特征是 高雄激素血症、慢性无排卵和多囊卵巢。目前由鹿特丹 标准，它将这些基本表型的表现分为四种主要的表型，标记为A， B C和D。虽然这些表型可以定义疾病并在广义上为临床决策提供信息， 我们选择最佳精确治疗方法和适当队列进行临床试验的能力仍然有限 因为在表型中存在相当大的异质性，并且很少有数据可以用来定义它们， 精度以更高的精度定义PCOS表型，从而改善患者的预后， 将额外的循证诊断标准纳入当今的诊断指南。 在第一阶段SBIR中，我们将通过测试假设来解决更高精度的需求， 代谢组学数据结合临床症状可以更精确地定义PCOS表型 而不是仅仅临床症状。 代谢产物是代谢的小分子中间体和产物， 基因组、环境和生活方式因素汇聚在一起。鉴于它们在中心法则中的独特地位， 从生物学的角度来看，它们被认为是最接近个人实时健康状况的反映。代谢物 通过其丰度的变化反映疾病活动，这可以使用超高性能 液相色谱和串联质谱法（UHPLC-MS/MS）。当以非靶向方式使用时， UPLC-MS/MS可以测量给定生物样品中代谢物的整个集合（代谢物组）， 能够广泛筛选个体的生化特征，以确定致病代谢 干扰（疾病的代谢特征）。我们和其他人已经证明， 可以提供对疾病活动的深入的表型洞察。与Richard Legro博士合作， 宾夕法尼亚州立大学医学院Metabolon将利用其专有的UHPLC-MS/MS平台NGPTM， 询问PCOS表型A和表型B特有代谢特征，并利用高水平统计学 分析以确定代谢谱是否可以识别新的、临床相关的亚表型， 从而比单独的临床症状更精确地定义表型。 在成功的情况下，该项目的发现将证明后续研究的合理性，在该研究中，我们开发了一种诊断测试， 针对这些表型定义的代谢特征。第一阶段成功的最终结果将是 开发一种工具，使PCOS表型的定义比今天的诊断更精确 指南，这代表了改善临床决策的一步，临床中的患者分层 试验和总体患者结局。

Abstract Polycystic ovary syndrome (PCOS) is a complex, multifactorial endocrine disorder characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries. It is currently diagnosed by the Rotterdam criteria, which categorizes the presentation of these basic symptomologies into four main phenotypes labeled A, B, C, and D. While these phenotypes can define disease and inform clinical decision making in a broad sense, our ability to select the best precision treatments and appropriate cohorts for clinical trials remains limited because there is considerable heterogeneity within phenotypes and little data by which to define them with higher precision. Defining PCOS phenotypes with higher precision to thereby improve patient outcomes starts by incorporating additional, evidence-based diagnostic criteria into present day diagnostic guidelines. In this Phase I SBIR, we will address the need for greater precision by testing the hypothesis that using metabolomics data in conjunction with clinical symptoms can define PCOS phenotypes with higher precision than clinical symptoms alone. Metabolites are the small molecule intermediates and products of metabolism upon which the inputs from the genome, the environment, and lifestyle factors converge. Given their unique position in the central dogma of biology they are considered to be the closest reflection of an individual’s real-time health status. Metabolites reflect disease activity through changes in their abundance, which can be quantified using ultra-high performance liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS). When used in an untargeted manner, UPLC-MS/MS can measure the entire collection of metabolites in a given biological sample (the metabolome), enabling broad screening of an individual’s biochemical profile to identify disease-causing metabolic perturbations (metabolic signatures of disease). We and others have shown that metabolic signatures associated with PCOS can provide deep phenotypic insight into disease activity. In collaboration with Dr. Richard Legro at Penn State Medical School, Metabolon will leverage its proprietary UHPLC-MS/MS platform, NGPTM, to interrogate metabolic signatures unique to PCOS phenotype A and phenotype B and utilize high level statistical analyses to determine whether metabolic profiling can identify novel, clinically relevant sub-phenotypes and thereby define phenotypes more precisely than clinical symptoms alone. In success, the findings of this project will justify a follow-up study in which we develop a diagnostic test that targets these phenotype-defining metabolic signatures. The ultimate outcome of a successful Phase I will be the development of a tool that allows PCOS phenotypes to be defined more precisely than today’s diagnostic guidelines, which represents a step towards improving clinical decision making, patient stratification in clinical trials, and overall patient outcomes.