Ioannidis John P A, Bossuyt Patrick M M
Departments of Medicine, Health Research and Policy, and Statistics, and the Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA;
Department of Clinical Epidemiology, Biostatistics & Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Clin Chem. 2017 May;63(5):963-972. doi: 10.1373/clinchem.2016.254649. Epub 2017 Mar 7.
The large, expanding literature on biomarkers is characterized by almost ubiquitous significant results, with claims about the potential importance, but few of these discovered biomarkers are used in routine clinical care.
The pipeline of biomarker development includes several specific stages: discovery, validation, clinical translation, evaluation, implementation (and, in the case of nonutility, deimplementation). Each of these stages can be plagued by problems that cause failures of the overall pipeline. Some problems are nonspecific challenges for all biomedical investigation, while others are specific to the peculiarities of biomarker research. Discovery suffers from poor methods and incomplete and selective reporting. External independent validation is limited. Selection for clinical translation is often shaped by nonrational choices. Evaluation is sparse and the clinical utility of many biomarkers remains unknown. The regulatory environment for biomarkers remains weak and guidelines can reach biased or divergent recommendations. Removing inefficient or even harmful biomarkers that have been entrenched in clinical care can meet with major resistance.
The current biomarker pipeline is too prone to failures. Consideration of clinical needs should become a starting point for the development of biomarkers. Improvements can include the use of more stringent methodology, better reporting, larger collaborative studies, careful external independent validation, preregistration, rigorous systematic reviews and umbrella reviews, pivotal randomized trials, and implementation and deimplementation studies. Incentives should be aligned toward delivering useful biomarkers.
关于生物标志物的大量且不断扩充的文献几乎普遍呈现出显著结果，宣称具有潜在重要性，但这些发现的生物标志物中很少用于常规临床护理。
生物标志物开发流程包括几个特定阶段：发现、验证、临床转化、评估、实施（以及在无用的情况下，停用）。这些阶段中的每一个都可能受到导致整个流程失败的问题困扰。一些问题是所有生物医学研究的非特定挑战，而其他问题则是生物标志物研究特性所特有的。发现阶段存在方法欠佳以及报告不完整和有选择性的问题。外部独立验证有限。临床转化的选择往往受不合理选择的影响。评估稀少，许多生物标志物的临床效用仍然未知。生物标志物的监管环境仍然薄弱，指南可能会得出有偏差或不同的建议。去除已在临床护理中根深蒂固的低效甚至有害的生物标志物可能会遇到重大阻力。
当前的生物标志物开发流程太容易失败。临床需求的考量应成为生物标志物开发的起点。改进措施可包括使用更严格的方法、更好的报告、更大规模的合作研究、仔细的外部独立验证、预注册、严格的系统评价和汇总评价、关键随机试验以及实施和停用研究。应调整激励措施以提供有用的生物标志物。
