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系統識別號 U0026-0812200914165518
論文名稱(中文) 非單調假設下藥物劑量估計之研究 — alpha 分離程序的應用
論文名稱(英文) Estimation of Treatment Effects without Monotonicity Assumption in Dose-Finding Studies — The Application of alpha-Splitting Procedure
校院名稱 成功大學
系所名稱(中) 統計學系碩博士班
系所名稱(英) Department of Statistics
學年度 96
學期 2
出版年 97
研究生(中文) 張彥介
研究生(英文) Yen-Chieh Chang
電子信箱 r2695403@mail.ncku.edu.tw
學號 r2695403
學位類別 碩士
語文別 英文
論文頁數 67頁
口試委員 指導教授-杜宜軒
口試委員-黃錦輝
口試委員-嵇允嬋
中文關鍵字 alpha 分離  同時信賴界限  劑量反應研究  多重比較 
英文關鍵字 alpha-splitting  simultaneous confidence bounds  dose-finding study  multiple comparisons 
學科別分類
中文摘要 在藥物劑量反應研究裡,最重要的便是鑑別優於安慰劑的所有劑量以及估計所有有效劑量療效,其中對於所有有效劑量中又以劑量最小的劑量為主要研究目標之一,此劑量稱為最小有效劑量 (minimum effective dose, MED)。由於國際醫藥法規協合會 (ICH) E9 指導方針中建議在估計劑量療效最好採用區間估計,因此本研究亦以建構信賴界限為目標。一般而言,劑量反應會隨著劑量增加而越有效,但某些藥物當劑量達到某一臨界點時,其反應可能會有產生減少的情形,此一現象我們稱為此藥物劑量反應具有非單調性 (non-monotonicity) 。在現有對療效的區間估計方法中以 Stefansson, Kim, and Hsu (1988) 所提出方法在此非單調性的假設下表現最好,但此方法並未將療效程度的資訊納入信賴界限的估計中, 因此本文利用 Tu (2006) 所提出的 alpha 分離程序,將顯著水準分為檢定與估計兩部分,改善 Stefansson et al. 所提出的方法,期望提升對劑量療效的估計,並透過實例分析與模擬研究探討所提出的改進方法的表現。
英文摘要 During the process of drug development, dose-response studies are conducted to evaluate the treatment effects at various doses of the test drug. In such clinical trials, subjects or patients are randomly allocated to separate groups to receive either several increasing dose levels of the test drug or a placebo. The primary focus of dose-response studies is usually on identifying the minimal effective dose (MED) and on estimating the treatment effect at each dose level. Based on the suggestion of the International Conference on Harmonization (ICH) E9 guideline that the confidence interval is the preferable way to present the treatment effect, we propose a method to construct the simultaneous confidence intervals to estimate the treatment effects and to define the MED accordingly. As a rule of thumb, the relation between the dose level and corresponding response is assumed to be monotone. However, sometimes the response may drop when the test dose is beyond certain level. Such phenomenon is the so-called "dose-response with non-monotonicity". In this article, the authors apply the alpha-splitting approach (Tu, 2006) that divides the pre-specified significant level into testing and estimating parts to the method proposed by Stefansson, Kim, and Hsu (1988) with a view to obtaining more precise confidence bounds when the dose-response relation is non-monotone. Through simulations, our extended method further demonstrates the ability to construct more informative confidence intervals for the treatment effects whether the dose-response relation is monotone or non-monotone.
論文目次 1 INTRODUCTION 1
1.1 Overview......................................... 2
1.2 Methods of Multiple Comparisons with a Control... 3
2 METHODS 7
2.1 Preliminaries.................................... 7
2.2 Literature Review................................ 9
2.2.1 Single-Step Procedure......................... 10
2.2.2 Stepwise Procedure............................ 11
2.2.3 Other Methods................................. 14
2.3 SKH alpha-Splitting Approach.................... 15
2.3.1 alpha-Splitting Approach...................... 15
2.3.2 Conjecture of SKH alpha-splitting Method...... 17
3 SIMULATION STUDY 21
3.1 Simulation Setup................................ 21
3.2 Simulation Results.............................. 24
3.2.1 Confirmation of Coverage Rate................. 24
3.2.2 A Comparison of Methods....................... 25
4 DISCUSSION 33
4.1 Main Results.................................... 33
4.2 Future Works.................................... 34
REFERENCES 35
A PRELIMINARY PROOFS 39
B SIMULATION RESULTS OF COVERAGE RATE 43
C SIMULATION RESULTS OF COMPARISONS 46
C.1 Coverage Rate................................... 46
C.2 Familywise Error Rate........................... 49
C.3 Estimated Power................................. 51
C.4 Mean Square Error............................... 53
C.5 Simultaneous Confidence Limits.................. 55
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