Statistical Validation of Reproducibility of HPLC Peptide Mapping for the Identity of an Investigational Drug Compound Based on Principal Component Analysis

Peptide mapping is a key analytical method for studying the primary structure of proteins. The sensitivity of the peptide map to even the smallest change in the covalent structure of the protein makes it a valuable “fingerprint” for identity testing and process monitoring. We recently conducted a full method validation study of an optimized reverse-phase high-performance liquid chromatography (RP-HPLC) tryptic map of a therapeutic anti-CD4 monoclonal antibody. We have used this method routinely for over a year to test production lots for clinical trials and to support bioprocess development. One of the difficulties in the validation of the peptide mapping method is the lack of proper quantitative measures of its reproducibility. A reproducibility study may include method and system precision study, ruggedness study, and robustness study. In this paper, we discuss the use of principal component analysis (PCA) to quantitate peptide maps properly using its projected scores on the reduced dimensions. This approach allowed us not only to summarize the reproducibility study properly, but also to use the method as a diagnostic tool to investigate any troubles in the reproducibility validation process.     

Analysing the effects of Lean manufacturing using a value stream mapping-based simulation generator

Value stream mapping (VSM) has become a popular implementation method for Lean manufacturing in recent years. However, its limitations such as being time-consuming, its inability to detail dynamic behaviour of production processes and to encompass their complexity, have spurred us to turn to simulation. This paper introduces two new elements to the value stream mapping method. First, it describes how the value stream mapping paradigm (VSMP) can be adapted for use in simulation, introducing specially designed VSM objects. Secondly, based on the VSMP and these objects, it presents a formal modelling method and its related database structure, that drives a generator which automatically yields a simulation model of the value stream map. In this way, a model generator, using the set of objects and the model database, can generate simulation models of Current and Future VSM scenarios quickly and automatically. Additionally, algorithms for converting raw ERP data and information from a VSM drawing into tables of the structured database are developed. Finally, the formal modelling method is applied to a real company case. A Current State model of the manufacturing system and three scenarios of Future States are generated to see the effects of Lean when transforming part of the system from push to pull.     

Ruggedness Study of HPLC Peptide Mapping for the Identity of a Drug Compound: A Chemometrics Approach

A statistically more reliable approach than the traditional visual inspection of peptide maps to identify a drug compound is to generate a set of reference standards from a designed experiment that incorporates many possible factors that affect variation of peptide mapping. In fact, the experiment can be done for a ruggedness study as part of a high-performance liquid chromatography (HPLC) method validation. Once the ruggedness is proved with the study, those articles in the experiment may form a set of reference standards, and future articles can be compared to the set later to prove identity. A quantitative analysis of the ruggedness study can be done using a chemometrics approach, principal component analysis (PCA). The analysis is used to reduce the many channels of peptide maps to a few manageable dimensions. The scores projected onto the reduced dimensions are used to test factor effects of the ruggedness study. As a by-product, the analysis provides visual inspection of the set of articles in the experiment for any outliers and anomalies.     

Ruggedness study of HPLC peptide mapping for the identity of a drug compound: a chemometrics approach

A statistically more reliable approach than the traditional visual inspection of peptide maps to identify a drug compound is to generate a set of reference standards from a designed experiment that incorporates many possible factors that affect variation of peptide mapping. In fact, the experiment can be done for a ruggedness study as part of a high-performance liquid chromatography (HPLC) method validation. Once the ruggedness is proved with the study, those articles in the experiment may form a set of reference standards, and future articles can be compared to the set later to prove identity. A quantitative analysis of the ruggedness study can be done using a chemometrics approach, principal component analysis (PCA). The analysis is used to reduce the many channels of peptide maps to a few manageable dimensions. The scores projected onto the reduced dimensions are used to test factor effects of the ruggedness study. As a by-product, the analysis provides visual inspection of the set of articles in the experiment for any outliers and anomalies.     

轮式机器人环境建图计量评价方法研究

针对移动机器人环境建图计量评价指标缺失和评价技术不完善的问题,本文以轮式机器人和FastSlam建图算法为研究对象,通过构造实物场景和标准数字地图,提取准确、有效、可靠的环境地图评价指标,全方位对激光雷达和其建图结果进行计量评价。本方法提出全局特征参数和局部特征参数等多种评价指标,为移动机器人环境建图质量和环境建图算法优越性的合理评价提供支撑。     

An inverse problem approach to stiffness mapping for early detection of breast cancer: tissue phantom experiments

Early detection of breast cancer will continue to be crucial in improving patient survival rates. Our ultimate goal is to develop an electro-mechanical device to automate and refine the manual breast exam process, and use inverse techniques to generate a tissue stiffness map of the breast tissue. We have previously presented computational simulations of the stiffness mapping approach, which employs static indentations of the tissue and measurements of surface displacements. In this paper, we report on experimental validation of the technique with tissue phantom experiments. We tested 12 tissue phantom samples without simulated tumours and 14 tissue phantom samples with simulated tumours. Our stiffness mapping approach correctly identified all 26 samples.     

Reproducibility assessment of relative quantitation strategies for LC-MS based proteomics

The reproducibility of a given method for relative quantitation governs the reliability of liquid chromatography-mass spectrometry (LC-MS) based differential analysis in proteomic studies. Understanding the noise level introduced from biological, chemical, and instrumental sources not only helps to determine the experimental design but also aids in assessing the reliability of expression ratios used for quantitation. Here we present a reproducibility assessment method for relative quantitation based on the intensity ratio distribution of common features in LC-MS replicates. This method applies to both decoupled (label-free quantitation) and coupled (label-dependent quantitation) methods. Aligning the features of LC-MS maps directly for the decoupled method or by matching an LC-MS map and its virtual map for the coupled method results in a list of common features for replicate samples. We find that the ratio distribution of the common features successfully indicates the reproducibility of each experiment prior to MS/MS peptide sequencing in three different quantitation strategies: decoupled, coupled isotope-coded affinity tag, and coupled stable isotope labeling of amino acids in cell culture experiments.     

The Virtual Integrated Design Method

Quality function deployment proposes to take into account the “voice of the customer,” through a list of customer needs, which are (qualitatively) mapped to technical requirements in House One. But customers do not perceive products in this space and do not make purchase decisions in this space. Marketing specialists use statistical models to map between a simpler space of customer perceptions and the long and detailed list of needs. For automobiles, for example, the main axes in perceptual space might be categories such as luxury, performance, sport, and utility. A product's position on these few axes determines the detailed customer requirements consistent with the automobile's position such as interior volume, gauges and accessories, seating type, fuel economy, door height, horsepower, interior noise level, seating capacity, paint colors, trim, and so forth. Statistical models such as factor analysis and principal components analysis are used to describe the mapping between these spaces, which we call House Zero. Furthermore, utility functions used to determine market share are auxiliary functions that are often based in perceptual space. Conjoint analysis is often used to capture the product preference and potential market share. This research draws from the formal mapping concepts developed by Nam Suh and the qualitative maps of quality function deployment, to present unified information and mapping paradigm for concurrent product/process design. We call this approach the virtual integrated design method that is tested upon data from a business design problem.     

NM2:噪声地图和监测

噪声地图被公认是城市规划和管理的得力工具.不过它的可靠性和大众对它的信心在很大程度上取决于噪声地图是否可以通过利用噪声监测数据来校正和更新.此外,噪声地图应能反映因不断变化的交通情况而产生的噪声水平.通过回顾噪声地图在世界上在制作和应用上面对的问题,讨论其拥有噪卢监测功能的必要性,与作为协助决策者和广大群众做出合适决定...     

On Nonparametric Image Registration

Image registration (IR) aims to map one image to another of a same scene. It is a fundamental task in many imaging applications. Most existing IR methods assume that the mapping transformation has a parametric form or satisfies certain regularity conditions (e.g., it is a smooth function with continuous first or higher order derivatives). They often estimate the mapping transformation globally by solving a global minimization/maximization problem. Such global smoothing methods usually cannot preserve singularities (e.g., discontinuities) and other features of the mapping transformation well. Further, the ill-posed nature of the IR problem, namely, the mapping transformation is not well defined at certain places, including the place where the true image intensity surface is straight, is not handled properly by such methods. In this article, we suggest solving the IR problem locally, by first studying the local properties of a mapping transformation. To this end, some concepts for describing such local properties are suggested, and a local smoothing method for estimating the mapping transformation is proposed. Because of the flexibility of local smoothing, our method does not require any parametric form or other global regularity conditions on the mapping transformation. Both theoretical and numerical studies show that it is effective in various applications. Supplementary materials are available online.     

Computer-aided clustering of citation networks as a tool of mapping of research trends in biomedicine

The use of the cluster analysis in scientometrics is dealt with. The ways of developing citation networks and mapping research field with the help of this method are also presented. The methodology of computer-aided cluster analysis of citation is described, which allows to map the structure of a research field and to identify main tendencies of its development.     

A topological model of limitations in design for manufacturing

Design for manufacturing (DFM) is a methodology that requires the use of specific manufacturing information at all stages of design. The method relies on a collection of informal and often controversial principles that seem to have eluded the benefits of formal analysis. The transition from design to manufacturing can be modeled as a mathematical mapping, and it has been previously shown how the discontinuity of this mapping formally captures the folklore that small design changes can lead to significantly increased manufacturing cost. We study the properties of the transition map in the presence of design and manufacturing variations, and show that its continuity is closely related to the structure of design and manufacturing topological spaces. The main result of this paper establishes conditions on these spaces under which design for manufacturing cannot be described by any continuous transition map. In practical terms, our study reveals the limitations of many DFM systems and approaches in their ability to relate design and manufacturing knowledge, and explains these limitations in terms of a basic incompatibility between the underlying design and manufacturing representations. We discuss how our model applies to DFM relative to traditional manufacturing methods (such as casting and stamping) and we speculate what changes might occur for alternative manufacturing technologies (such as electrical discharge machining (EDM), stereolithography, laser machining, and particle deposition).     

Analysis of space mapping algorithms for application to partitioned fluid–structure interaction problems

Fluid–structure interactions (FSI) play a crucial role in many engineering fields. However, the computational cost associated with high‐fidelity aeroelastic models currently precludes their direct use in industry, especially for strong interactions. The strongly coupled segregated problem—that results from domain partitioning—can be interpreted as an optimization problem of a fluid–structure interface residual. Multi‐fidelity optimization techniques can therefore directly be applied to this problem in order to obtain the solution efficiently. In previous work, it is already shown that aggressive space mapping (ASM) can be used in this context. In this contribution, we extend the research towards the use of space mapping for FSI simulations. We investigate the performance of two other approaches, generalized space mapping and output space mapping, by application to both compressible and incompressible 2D problems. Moreover, an analysis of the influence of the applied low‐fidelity model on the achievable speedup is presented. The results indicate that output space mapping is a viable alternative to ASM when applied in the context of solver coupling for partitioned FSI, showing similar performance as ASM and resulting in reductions in computational cost up to 50% with respect to the reference quasi‐Newton method. Copyright © 2015 John Wiley & Sons, Ltd.     

三角网格模型上的四边形曲线网生成新方法

四边形网格划分是组合曲面建模技术的首要条件。针对海量流形三角网格数据,提出了基于网格简化技术与调和映射算法的四边形网格生成新方法--映射法。该方法采用基于顶点删除的网格简化技术对三角网格模型进行简化,进而借助调和映射算法将简化网格映射到二维平面上进行四边形划分,并将所获得的平面四边形节点数据逆映射回物理域,采用短程线边界形式最终得到适于组合曲面建模的空间四边形拓扑。该方法简单、实用,运行速度较快,实际的算例也验证了方法的有效性与可行性。     

A non‐stationary covariance‐based Kriging method for metamodelling in engineering design

Metamodels are widely used to facilitate the analysis and optimization of engineering systems that involve computationally expensive simulations. Kriging is a metamodelling technique that is well known for its ability to build surrogate models of responses with non‐linear behaviour. However, the assumption of a stationary covariance structure underlying Kriging does not hold in situations where the level of smoothness of a response varies significantly. Although non‐stationary Gaussian process models have been studied for years in statistics and geostatistics communities, this has largely been for physical experimental data in relatively low dimensions. In this paper, the non‐stationary covariance structure is incorporated into Kriging modelling for computer simulations. To represent the non‐stationary covariance structure, we adopt a non‐linear mapping approach based on parameterized density functions. To avoid over‐parameterizing for the high dimension problems typical of engineering design, we propose a modified version of the non‐linear map approach, with a sparser, yet flexible, parameterization. The effectiveness of the proposed method is demonstrated through both mathematical and engineering examples. The robustness of the method is verified by testing multiple functions under various sampling settings. We also demonstrate that our method is effective in quantifying prediction uncertainty associated with the use of metamodels. Copyright © 2006 John Wiley & Sons, Ltd.     

A systematic approach to preliminary polymer process development: modeling and design

A general and complete methodology is presented to facilitate systematic modeling and design of polymer processes during the early development period. To capture and handle the subjective type of uncertainty, embedded in the preliminary process development, fuzzy theories are used as a basis to model and design the process in the presence of ambiguity and vagueness. Physical membership functions are developed for mapping the relation between process variables and the associated fuzzy uncertainties. Based on the qualitative results generated using our previously proposed “linguistic based preliminary design method,” the process modeling can be followed even in the absence of any process governing equations. The modeling is carried out by establishing an appropriate fuzzy reasoning system which provides a specific functional mapping that relates input process variables to one (or more than one) output performance parameter(s). A reduced yet feasible domain is generated by our qualitative design scheme to constrain the process variables. Now, any optimization routine can then be employed to search for a proper process design. We demonstrate the effectiveness of the proposed methodology by its application to a typical compression molding process.     

Development and validation of “grey-box” models for refrigeration applications: A review of key concepts

“Grey-box” modelling combines the use of first-principle based “white-box” models and empirical “black-box” models, offering particular benefits when: (a) there is a lack of fundamental theory to describe the system or process modelled; (b) there is a scarcity of suitable experimental data for validation or (c) there is a need to decrease the complexity of the model. The grey-box approach has been used, for example, to create mathematical models to predict the shelf life of chilled products or the thermal behaviour of imperfectly mixed fluids, or to create models that combine artificial neural networks and dynamic differential equations for control-related applications. This paper discusses the main characteristics of white-box, black-box and their integration into grey-box models, the requirements and sourcing of accurate data for model development and important validation concepts and measures.     

Paper Organizers International: A Fictitious Six Sigma Green Belt Case Study. I

“Six Sigma” management is in vogue in many of the world's largest and most successful corporations. However, for all of its popularity, there is much confusion as to the exact structure of a Six Sigma project. The purpose of this article is to present the first part of a detailed, step-by-step case study of a simple Six Sigma Green Belt project. This part of the case study presents the Define and Measure phases of the define-measure-analyze-improve-control (DMAIC) method for improving a process.     

傅里叶变换轮廓术中三维坐标同时校准方法

在相位测量型光学三维面形测量中,最终都要将相位信息转换成被测物体的高度分布信息,这个过程往往是通过对已知世界空间坐标的特征点事先标定,获得测量系统的内外特征参数后,完成被测物体的三维坐标转换.因此,标定是三维面形测量的关键环节.本文基于双向二次相位-高度映射方法和摄像机针孔模型线性无畸变标定技术,充分利用傅里叶变换的频谱方向特性,提出了对含有特征点的二维标定物表面变形条纹的频谱进行方向滤波操作,同时获取测量系统XYZ三个方向上的标定数据,对测量系统进行立体校准的系统标定方法.结合旋转风扇叶片形变的测量系统,给出了该方法的标定结果:在XY面内(230mm×230mm)的标准偏差小于0.27mm;在Z方向上小于0.022mm,位移测量灵敏度优于0.05mm.该方法为测量系统的实用化奠定了基础.     

Validation of solid dosage forms the FDA view

In May 1987 the United States Food and Drug Administration published the final version of a guideline for process validation for pharmaceutical manufacturing. The document incorporated the comments from the pharmaceutical industry gathered after the publication of three draft versions in 1983, 1984 and 1986.

The presentation will cover the current definition of process validation as well as terms such as “worse case” and “installation qualification”.

The stages of process validation will be discussed including the written plan (protocol): records to be maintained; suitability of raw materials; equipment performance qualification; the number of runs required; and acceptance criteria.

Specifics for solid dosage forms will be presented along with details on batch record in instructions and establishment of acceptable range limits.

Circumstances and requirements for revalidation will be discussed as well as the validation of current finished dosage forms by retrospective validation.