Zhao Yingxin, Brasier Allan R
The University of Texas Medical Branch, 301 University Blvd, 77555, Galveston, TX, USA.
Adv Exp Med Biol. 2016;919:493-514. doi: 10.1007/978-3-319-41448-5_23.
The importance of biomarkers has long been recognized by the public, scientific community, and industry. Yet despite extensive efforts and funding investments in biomarker discovery, only 109 protein biomarkers in plasma or serum were approved by the US Food and Drug Administration throughout 2008 (Anderson NL. Clin Chem 56:177-185, 2010), and even fewer protein biomarkers are currently used routinely in the clinic. In recent years, the introduction of new protein biomarkers approved by the US Food and Drug Administration has fallen to an average of 1.5 per year (a median of only 1 per year) (Anderson NL. Clin Chem 56:177-185, 2010). The low efficiency of biomarker development is due to several reasons, including the poor quality of clinical samples, the gap between subjective clinical definition of a disease and objective protein measurements, and high false discovery rate of differentially expressed proteins identified in the initial discovery phase (Rifai N, Gillette MA, Carr SA. Nat Biotechnol 24:971-983, 2006). It has become clear that the vast majority of differentially expressed proteins identified in the discovery phase will ultimately fail as useful clinical biomarkers, and only few true positive candidates can move through the biomarker development pipeline. Isolation of true biomarkers from the large pool of differentially expressed proteins identified in the discovery phase becomes the greatest challenge and the bottleneck in most biomarker pipelines. To succeed, after the initial discovery study (see Chap. 20 ), the authenticity of biomarker candidates need to be tested in a pilot study with high throughput, high accuracy and reasonable cost. This essential process is addressed by qualification and verification phase of the biomarker development pipeline.
生物标志物的重要性早已得到公众、科学界和行业的认可。然而，尽管在生物标志物发现方面付出了巨大努力并投入了大量资金，但在2008年全年，美国食品药品监督管理局仅批准了109种血浆或血清中的蛋白质生物标志物（Anderson NL. Clin Chem 56:177 - 185, 2010），目前临床上常规使用的蛋白质生物标志物更少。近年来，美国食品药品监督管理局批准的新蛋白质生物标志物数量已降至平均每年1.5种（中位数仅为每年1种）（Anderson NL. Clin Chem 56:177 - 185, 2010）。生物标志物开发效率低下有多种原因，包括临床样本质量差、疾病的主观临床定义与客观蛋白质测量之间的差距，以及在初始发现阶段鉴定出的差异表达蛋白质的高假发现率（Rifai N, Gillette MA, Carr SA. Nat Biotechnol 24:971 - 983, 2006）。很明显，在发现阶段鉴定出的绝大多数差异表达蛋白质最终都无法成为有用的临床生物标志物，只有少数真正的阳性候选物能够进入生物标志物开发流程。从发现阶段鉴定出的大量差异表达蛋白质中分离出真正的生物标志物，成为了大多数生物标志物流程中最大的挑战和瓶颈。为了取得成功，在初始发现研究之后（见第20章），需要在一项高通量、高精度且成本合理的试点研究中测试生物标志物候选物的真实性。生物标志物开发流程的鉴定和验证阶段解决了这一关键过程。
