Testing bioequivalence for multiple formulations with power and sample size calculations

Bioequivalence (BE) trials play an important role in drug development for demonstrating the BE between test and reference formulations. The key statistical analysis for BE trials is the use of two one‐sided tests (TOST), which is equivalent to showing that the 90% confidence interval of the relative bioavailability is within a given range. Power and sample size calculations for the comparison between one test formulation and the reference formulation has been intensively investigated, and tables and software are available for practical use. From a statistical and logistical perspective, it might be more efficient to test more than one formulation in a single trial. However, approaches for controlling the overall type I error may be required. We propose a method called multiplicity‐adjusted TOST (MATOST) combining multiple comparison adjustment approaches, such as Hochberg's or Dunnett's method, with TOST. Because power and sample size calculations become more complex and are difficult to solve analytically, efficient simulation‐based procedures for this purpose have been developed and implemented in an R package. Some numerical results for a range of scenarios are presented in the paper. We show that given the same overall type I error and power, a BE crossover trial designed to test multiple formulations simultaneously only requires a small increase in the total sample size compared with a simple 2 × 2 crossover design evaluating only one test formulation. Hence, we conclude that testing multiple formulations in a single study is generally an efficient approach. The R package MATOST is available at https://sites.google.com/site/matostbe/ . Copyright © 2012 John Wiley & Sons, Ltd.     

社会的标志—在语言消亡论者笔下的英国语言

虽然在语言问题上人们各持己见,但确有一些语言评论家,包括约翰·西蒙,埃德温·纽曼,威廉·萨菲尔和理查德·米切尔,认为英国语言正趋向消亡,因为他们的著作和文章在一般人的情感上引起了强烈的反响,有的遭到强烈之否定,有的则为强烈的肯定,然而,居于这之间的反应则很少见,他们正明显地触及深深存在于我们之中的东西,这就要求我们不要对那些病态的语言仅仅予以反驳或盲目地加以接受.当我们退一步认真并且客观地去看一看那些告诉我们英国语言已步入死亡边缘的论著,或者考虑一下那些有关语言变化的来龙去脉,我们就会发觉有趣的是其内在的矛盾性,并会直接卷入事实与信仰的冲突之中.最明显的是在那些大谈特谈英语会迅速消亡的人看来,     

根据差异量热比色法测定支链淀粉链的缔合

直链淀粉和类脂化合物是通过采用差异量热比色法（DSC），在过量的水中把玉蜀黍淀粉、豌豆、玉米、小麦、马铃薯、蜡质种玉米从20℃加热到180℃，然后冷却到4℃，最后再加热至180℃除去淀粉而形成的。直链淀粉和软化淀粉的冷却曲线显示了放热期（＜70℃）是由直链淀物链组成的原理．覆盖范围0～95％的直链淀粉和支链淀粉混合物类似于被加热和被冷却．直链糖链淀物链的缔合被支链淀粉所限制．     

Physician organizations. Part 1: A report from the trenches of a start-up PO

How has Community Health Partners, a physician organization based in Kansas City, turned the corner as it rolls into the second year of operation? The biggest indicator is that CHP hammered out the city's first professional risk contracts and the PO has grown from 23 to more than 50 physician member/owners. Looking back, there are at least 10 reasons why CHP made it this far. These are not reasons you learn about in medical school or an MBA program. There is no one-size-fits-all template for building POs. No fixed organizational chart. No neon signs pointing to the best capital partner. Part I explores five reasons for success, such as having a strong board and physician leadership, as well as educating participating physicians about capitation and affiliating with any hospital or payer that really knows how to partner with physicians. Part 2 will focus on five more lessons learned from the trenches of a start up PO.     

The role of public health in population health

The role of public health is central in population health. What distinguishes public health from clinical medicine is that it's focus is on the entire population--not the individual patient. To achieve the goal of population health, healthy communities, or Healthy People 2000 requires physician leadership in medicine and public health at all levels--local, state, and national. The challenge is formidable, but the goals are attainable through strategies that focus on the goal of the common good and through collaboration of public health, medicine, and the community.     

The shape of public health policy: the Australian experience

Public health policy is shaped by many factors. A brief historical reflection is given on policy development in Australia to illustrate the various influences on health policy. Medical technology; ethical trade-offs; environmental, social, and political imperatives; popular movements; and changing patterns of disease; as well as market forces have helped to shape Australian contemporary public health policy. These multiple and often competing forces, however, can work against individual consumer choice in health care decisions. This article demonstrates through the eyes of history the factors that shape public health policy. As Australia has a short history compared to most industrialized democratic societies and can be viewed as a microcosm, it is used as the exemplar.     

Prediction based classification for longitudinal biomarkers

Assessment of circulating CD4 count change over time in HIV-infected subjects on antiretroviral therapy (ART) is a central component of disease monitoring. The increasing number of HIV-infected subjects starting therapy and the limited capacity to support CD4 count testing within resource-limited settings have fueled interest in identifying correlates of CD4 count change such as total lymphocyte count, among others. The application of modeling techniques will be essential to this endeavor due to the typically non-linear CD4 trajectory over time and the multiple input variables necessary for capturing CD4 variability. We propose a prediction based classification approach that involves first stage modeling and subsequent classification based on clinically meaningful thresholds. This approach draws on existing analytical methods described in the receiver operating characteristic curve literature while presenting an extension for handling a continuous outcome. Application of this method to an independent test sample results in greater than 98% positive predictive value for CD4 count change. The prediction algorithm is derived based on a cohort of n = 270 HIV-1 infected individuals from the Royal Free Hospital, London who were followed for up to three years from initiation of ART. A test sample comprised of n = 72 individuals from Philadelphia and followed for a similar length of time is used for validation. Results suggest that this approach may be a useful tool for prioritizing limited laboratory resources for CD4 testing after subjects start antiretroviral therapy.     

对关于统计推断性质的十四个难以理解和有待澄清的问题的思考（下）

十四、概率上限和概率下限在理论和实际中有什么作用?　　由于具体的或认识上的概率的上、下限产生于不同的环境,短语概率“上限”和概率“下限”可以从不同的角度来解释。在格罗宁根,从20世纪70年代中期以来,就有一种对后验概率构造置信区间的传统[126,4]。在罗吉斯蒂回归中,即使对比例风险回归模型,也可得到类似的结果,见[70,17]。标准误和置信限加深了评估中涉及的统计不确定性的印象。除了这些统计不确定性外,还存在系统误差引起的不确定性:参数模型在某种程度上总是错误的。因此将精力集中在这些统计不确定性上多少是一种误导。然而在…     

Operational challenges in adaptive design implementation

Implementation of adaptive clinical trial designs raises challenges with regard to the processes by which accruing trial data is analyzed, reviewed, and acted upon. In line with current monitoring conventions, it should be viewed that inappropriate knowledge of interim results can raise concerns regarding maintaining trial integrity and interpretability of results. Here we discuss issues related to these processes in adaptive trials, and point out distinctions versus other more familiar monitoring situations. One topic involves the composition of the group of individuals who will have access to interim results in order to recommend adaptations. We discuss operational models for data review by this group; one question addressed is whether in adaptive trials a role in this process for a representative of the study sponsor could at times be warranted, and might be justified if adequate protections are in place. Another issue involves whether adaptations made based upon interim data can convey to observers an amount of information about the results, which could rise to a level of concern. We consider whether different types of adaptations might be more or less problematic with regard to this issue, and recommend steps that might be considered to mitigate this concern.     

多效唑对亚热带低寒带桃“Flordaprince”物候循环的影响

Allan，p，George，A．P，Nissen，R．J，Rasmussen，T．S．和Morley－Bunker，M．J，1993。多效吐对亚热带澳大利亚的低寒带桃“Flordaprince”物候循环的影响。园艺科学，53：73-84。将低寒带桃“Flordaprince”种植在亚热带澳大利亚，用多效吐处理两次以矮化树体，或使用氮处理来强化树体。疏花之后，调整并统一单株果实数，使每棵树的果实具有充分空间。多效唑能显著地抑制竞争性的春梢生长，引起果实提早成熟，并使产量增加，果实增大，品质提高。多效吐减少根的春季生长，而导致秋季根的大量生长。在乔化树中，果实生长的第二阶段稍长，使得种子和胚的生长推迟，胚中干物质较多。淀粉储藏量以根中为最大，其次是根干、枝和叶。在硬核期和果实成熟阶段，淀粉储藏量降到最低水平，但在枝梢伸长生长结束之后，又会升高，到落叶时，再次达到峰值。叶分析显示，整个季节中N、P和K的浓度降低，而Ca和Mg的浓度升高。多效唑处理树中，K的水平显著低于乔化树，而Ca、Mg水平显著高于乔化树。