Fang Hong-Bin, Ross Douglas D, Sausville Edward, Tan Ming
Division of Biostatistics, University of Maryland, Marlene and Stewart Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA.
Stat Med. 2008 Jul 20;27(16):3071-83. doi: 10.1002/sim.3204.
Drug combination is a major treatment approach in cancer and antiviral therapies. A key issue is to find which combinations are additive, synergistic or antagonistic. In this paper, we develop statistical methods for experimental design and data analysis of combination studies of drugs that have log-linear dose-response curves. This class of dose response includes the Hill, sigmoid and simple exponential models. The experimental design (dose-finding and sample size determination) is derived by means of uniform measures that maximize the minimum power of the F-test to detect any departures from additive action and at the same time minimizes the maximum bias due to lack of fit among all potential departures of a given meaningful magnitude. Furthermore, we propose a model-free interaction index surface to capture the interaction of two drugs. The nonparametric function of the interaction index is estimated using the technique developed in thin plate splines. These methods are applicable to both in vivo and in vitro experiments. A study of two anticancer drugs, suberoylanilide hydroxamic acid (Vorinostat) and Etoposide applied sequentially against the cell line HL-60, is given to illustrate the proposed methods of experimental design and interaction analysis.
药物联合是癌症和抗病毒治疗中的主要治疗方法。一个关键问题是找出哪些联合用药具有相加、协同或拮抗作用。在本文中，我们针对具有对数线性剂量反应曲线的药物联合研究，开发了用于实验设计和数据分析的统计方法。这类剂量反应包括希尔模型、S型模型和简单指数模型。实验设计（剂量探索和样本量确定）是通过均匀度量得出的，该度量能使F检验检测到与相加作用的任何偏差的最小功效最大化，同时使给定有意义幅度的所有潜在偏差中由于拟合不足导致的最大偏差最小化。此外，我们提出了一个无模型的相互作用指数曲面来捕捉两种药物的相互作用。相互作用指数的非参数函数使用薄板样条中开发的技术进行估计。这些方法适用于体内和体外实验。给出了一项针对两种抗癌药物——辛二酰苯胺异羟肟酸（伏立诺他）和依托泊苷依次作用于HL - 60细胞系的研究，以说明所提出的实验设计和相互作用分析方法。
