Automated 3-D registration of MR and CT images of the head

This paper discusses the application of voxel similarity measures in the automated registration of clinically acquired MR and CT data of the head. We describe a novel single-start multi-resolution approach to the optimization of these measures, and the issues involved in applying this to data having a range of different fields of view and sampling resolution. We compare four proposed measures of voxel similarity using the same optimization scheme when presented with 10 pairs of images with a range of initial misregistrations. The registration estimates are compared with those provided by manual point-based registration and evaluated by visual inspection to give an assessment of the robustness and accuracy of the different measures. One full-volume CT image set is used to investigate the performance of each measure when used to align truncated images from different regions in the head. The soft tissue correlation and mutual information measures were found to provide the most robust measures of misregistration, providing results comparable to or better than those from manual point-based registration for all but the most truncated image volumes.     

Cool or Fool? The Association Between Drinker Prototypes and Alcohol Consumption Using Multiple Time-Point Diary Assessments in Adolescent Males

Objectives: There is still limited understanding of how different kinds of drinker prototypes are associated with adolescent drinking. This study uses the strengths of multiple time-point diary measures (enhanced validity of alcohol use measurement) to test the predictive value of abstainer, moderate and heavy drinker prototypes in social situations. We examined whether the favorability of these prototypes (i.e., “prototype evaluation”), the perceived similarity of these prototypes to one's self-image (i.e., “prototype similarity”) assessed at baseline, and their interaction predict alcohol use assessed in social situations. Methods: Drinker prototypes were assessed in a baseline sample of 599 adolescents. Subsequently, a sample of 77 alcohol-using 16 to 18-year-old males reported their Friday and Saturday evening drinking behavior the next day during eight weeks (resulting in 495 daily measures). Alcohol use was assessed in the company of peers. Results: The more adolescents perceived themselves as similar to heavy drinker prototypes the higher their alcohol consumption in social situations. The more adolescents held favorable abstainer prototypes, the lower their alcohol consumption. The interaction between prototype evaluation and similarity was not significant. Conclusions: By using a more reliable and valid method to assess adolescents' alcohol use, the present study showed that more “extreme” drinker prototypes (i.e., heavy drinker and abstainer prototypes) are most predictive of adolescent alcohol use in social situations. Increasing the perceived dissimilarity to heavy drinker prototypes and the favorability of abstainer prototypes may therefore be important targets in interventions aimed at reducing adolescents' alcohol consumption.     

过程分析比较5个不同厂家格列吡嗪片的体外溶出相似性

目的通过实时过程监测方法分析5个不同厂家格列吡嗪片在4种溶出介质中的溶出曲线,并采用f2因子对其进行相似性评价。方法不同pH值条件下,采用光纤药物溶出度实时测定仪在222nm处测定波长,测定光程为10mm,分别测定5个不同厂家格列吡嗪片的溶出曲线,通过相似因子f2法评价溶出曲线的相似性。结果不同厂家生产的药品在不同pH值条件下,溶出曲线差异较大。结论实验选用的方法简便、数据真实可靠,可用于区分体外溶出曲线的相似性,为制剂生物等效性实验提供参考数据。     

知柏地黄丸的UPLC指纹图谱研究

目的 建立知柏地黄丸UPLC指纹图谱的研究方法。方法 采用Waters Acquity BEH C₁₈色谱柱（2.1 mm×100 mm,1.7 μm）,流动相为乙腈-0.1%磷酸,梯度洗脱,检测波长236 nm,流速0.4 mL·min^-1,柱温40℃,以丹皮酚作为参照物。结果 在12 min内完成指纹图谱分析,标出12个共有峰,对6个色谱峰进行了归属,并进行了相似度评价。结论 UPLC简便可行,建立的指纹图谱可用于知柏地黄丸的质量控制。     

图像数据化软件在仿制药体外溶出曲线一致性评价中的应用

目的 利用图像数据化软件读取日本橙皮书中或FDA固体制剂溶出曲线数据库中溶出曲线数据,再用f₂相似因子计算公式计算,用于国产仿制药与原研药的体外溶出曲线一致性评价的预试验。方法 按软件使用说明,设置坐标原点和纵坐标、横坐标最大值。利用截图软件获取参比制剂的溶出曲线图,保存为图像文件。确定溶出曲线上需要获取数据的点,经软件分析即可获得各个点的累积溶出量。再用f₂相似因子计算公式计算,得到的f₂值用于仿制药与参比制剂溶出曲线一致性判断。结果 以盐酸雷尼替丁片为例,通过图像分析软件可以获得日本橙皮书溶出数据库中参比制剂的累积溶出量数据,用于仿制药与参比制剂体外溶出曲线一致性评价的预试验。结论 图像分析软件可以通过数据化处理,得到文献上参比制剂的溶出量数据,用于仿制药体外溶出曲线一致性的预试验。     

药物重定位候选药物筛选路径

相对传统新药研发模式,药物重定位策略发现药物新用途具有显著的成本效益优势,能加快药物上市步伐,满足恶性肿瘤、罕见病、个性化医疗等特定领域药物临床用药需求,因而被各界关注。本文主要介绍了药物重定位的一般流程与候选药物筛选路径,如从非理性设计方法向基于相似性、基于结构虚拟筛选、推理与机器学习等理性设计方法发现重定位药物的系统性转变。     

Sample size requirement in analytical studies for similarity assessment

ABSTRACT

For the assessment of biosimilar products, the FDA recommends a stepwise approach for obtaining the totality-of-the-evidence for assessing biosimilarity between a proposed biosimilar product and its corresponding innovative biologic product. The stepwise approach starts with analytical studies for assessing similarity in critical quality attributes (CQAs), which are relevant to clinical outcomes at various stages of the manufacturing process. For CQAs that are the most relevant to clinical outcomes, the FDA requires an equivalence test be performed for similarity assessment based on an equivalence acceptance criterion (EAC) that is obtained using a single test value of some selected reference lots. In practice, we often have extremely imbalanced numbers of reference and test lots available for the establishment of EAC. In this case, to assist the sponsors, the FDA proposed an idea for determining the number of reference lots and the number of test lots required in order not to have imbalanced sample sizes when establishing EAC for the equivalence test based on extensive simulation studies. Along this line, this article not only provides statistical justification of Dong, Tsong, and Weng’s proposal, but also proposes an alternative method for sample size requirement for the Tier 1 equivalence test.     

Exact test-based approach for equivalence test with parameter margin

ABSTRACT

The equivalence test has a wide range of applications in pharmaceutical statistics which we need to test for the similarity between two groups. In recent years, the equivalence test has been used in assessing the analytical similarity between a proposed biosimilar product and a reference product. More specifically, the mean values of the two products for a given quality attribute are compared against an equivalence margin in the form of ±f × σ_R, where ± f × σ R is a function of the reference variability. In practice, this margin is unknown and is estimated from the sample as ±f × S_R. If we use this estimated margin with the classic t-test statistic on the equivalence test for the means, both Type I and Type II error rates may inflate. To resolve this issue, we develop an exact-based test method and compare this method with other proposed methods, such as the Wald test, the constrained Wald test, and the Generalized Pivotal Quantity (GPQ) in terms of Type I error rate and power. Application of those methods on data analysis is also provided in this paper. This work focuses on the development and discussion of the general statistical methodology and is not limited to the application of analytical similarity.     

Development of statistical methods for analytical similarity assessment

ABSTRACT

To evaluate the analytical similarity between the proposed biosimilar product and the US-licensed reference product, a working group at Food and Drug Administration (FDA) developed a tiered approach. This proposed tiered approach starts with a criticality determination of quality attributes (QAs) based on risk ranking of their potential impact on product quality and the clinical outcomes. Those QAs characterize biological products in terms of structural, physicochemical, and functional properties. Correspondingly, we propose three tiers of statistical approaches based on the levels of stringency in requirements. The three tiers of statistical approaches will be applied to QAs based on the criticality ranking and other factors. In this article, we discuss the statistical methods applicable to the three tiers of QA. We further provide more details for the proposed equivalence test as the Tier 1 approach. We also provide some discussion on the statistical challenges of the proposed equivalence test in the context of analytical similarity assessment.     

银杏内酯组分释药单元体外释药行为评价研究

中药组分多元释药系统是多组分、多成分制剂体系,如何评价其多元化的释药行为一直都是中药制剂现代化面临的考验。该文通过对银杏内酯组分释药单元中各代表性成分释药的研究、释药行为相似度分析以及采用权重系数法对多成分的释药曲线进行整合,希望可以为中药组分制剂的释药评价提供思路与方法。