Ransohoff David F
Department of Medicine, University of North Carolina at Chapel Hill, CB# 7080, 4103 Bioinformatics Building, Chapel Hill, NC 27599-7080, USA.
J Clin Epidemiol. 2007 Dec;60(12):1205-19. doi: 10.1016/j.jclinepi.2007.04.020. Epub 2007 Sep 24.
The search for molecular markers for cancer, using "discovery-based" techniques, has resulted in claims of a very high degree of discrimination both for cancer diagnosis (e.g., serum proteomics patterns) and prognosis (e.g., RNA expression genomic signatures). However, many promising initial results have been found to be unreliable or not reproducible, and the larger process of discovery can seem slow and inefficient. To improve the process to develop molecular markers, proposals to use "phases" and "guidelines" have been made, based on experience with the process of drug development and randomized controlled clinical trials. The objective is to help improve the reliability and efficiency of development of molecular markers for cancer diagnosis.
The literature was searched to identify important current problems (in serum proteomics for cancer diagnosis and RNA expression genomics for cancer prognosis) are identified, and the roles of tools ("phases," "guidelines," and "study design") to address those problems are considered. Based on lessons learned, approaches for the future are discussed, some of which may seem "radical" compared with drug development.
Phases identify and organize questions to be addressed by individual studies. Guidelines identify features of design and conduct to be reported so that each study's reliability can be judged. Study design involves the myriad details and choices involved in actual planning and conduct of a study. Study design is most important in the sense of determining whether a study is reliable or not. Studies that are unreliable, because of problems from chance and bias, constitute a major current problem leading to inflated expectations, wasted effort, and inefficiency in the larger process of development. By considering fundamental principles, it may be possible to identify approaches that are different than those used in drug development, while preserving reliability and efficiency.
Phases and guidelines have important roles, but issues in study design address the fundamental problems that compromise reliability and efficiency. Tools to study markers are underdeveloped and will evolve over time, perhaps to include seemingly radical approaches.
运用“基于发现”的技术寻找癌症分子标志物，已产生了关于癌症诊断（如血清蛋白质组学模式）和预后（如RNA表达基因组特征）具有高度区分度的说法。然而，许多有前景的初步结果被发现不可靠或不可重复，而且更大规模的发现过程似乎缓慢且低效。为改进开发分子标志物的过程，基于药物开发和随机对照临床试验过程的经验，有人提出使用“阶段”和“指南”的建议。目的是帮助提高用于癌症诊断的分子标志物开发的可靠性和效率。
检索文献以识别当前重要问题（癌症诊断的血清蛋白质组学和癌症预后的RNA表达基因组学方面的问题），并考虑用于解决这些问题的工具（“阶段”、“指南”和“研究设计”）的作用。基于吸取的经验教训，讨论了未来的方法，其中一些方法与药物开发相比可能显得“激进”。
阶段确定并组织各个研究要解决的问题。指南确定要报告的设计和实施特征，以便能够判断每项研究的可靠性。研究设计涉及实际规划和开展一项研究时涉及的无数细节和选择。从确定一项研究是否可靠的意义上讲，研究设计最为重要。由于机遇和偏差问题而不可靠的研究，是导致期望过高、精力浪费以及更大规模开发过程效率低下的一个主要当前问题。通过考虑基本原则，有可能识别出与药物开发中使用的方法不同的方法，同时保持可靠性和效率。
阶段和指南具有重要作用，但研究设计中的问题解决了损害可靠性和效率的根本问题。研究标志物的工具尚不完善，将随着时间的推移而发展，或许会包括看似激进的方法。
