A bootstrap method for uncertainty estimation in quality correlation algorithm for risk based tolerance synthesis

A risk based tolerance synthesis approach is based on ISO9001:2015 quality standard’s risk based thinking. It analyses in-process data to discover correlations among regions of input data scatter and desired or undesired process outputs. Recently, Ransing, Batbooti, Giannetti, and Ransing (2016) proposed a quality correlation algorithm (QCA) for risk based tolerance synthesis. The quality correlation algorithm is based on the principal component analysis (PCA) and a co-linearity index concept (Ransing, Giannetti, Ransing, & James 2013). The uncertainty in QCA results on mixed data sets is quantified and analysed in this paper.The uncertainty is quantified using a bootstrap sampling method with bias-corrected and accelerated confidence intervals. The co-linearity indices use the length and cosine angles of loading vectors in a p-dimensional space. The uncertainty for all p-loading vectors is shown in a single co-linearity index plot and is used to quantify the uncertainty in predicting optimal tolerance limits. The effects of re-sampling distributions are analysed. The QCA tolerance limits are revised after estimating the uncertainty in limits via bootstrap sampling. The proposed approach has been demonstrated by analysing in-process data from a previously published case study

Risk based uncertainty quantification to improve robustness of manufacturing operations

The cyber-physical systems of Industry 4.0 are expected to generate vast amount of in-process data and revolutionise the way data, knowledge and wisdom is captured and reused in manufacturing industries. The goal is to increase profits by dramatically reducing the occurrence of unexpected process results and waste. ISO9001:2015 defines risk as effect of uncertainty. In the 7Epsilon context, the risk is defined as effect of uncertainty on expected results. The paper proposes a novel algorithm to embed risk based thinking in quantifying uncertainty in manufacturing operations during the tolerance synthesis process. This method uses penalty functions to mathematically represent deviation from expected results and solves the tolerance synthesis problem by proposing a quantile regression tree approach. The latter involves non parametric estimation of conditional quantiles of a response variable from in-process data and allows process engineers to discover and visualise optimal ranges that are associated with quality improvements. In order to quantify uncertainty and predict process robustness, a probabilistic approach, based on the likelihood ratio test with bootstrapping, is proposed which uses smoothed probability estimation of conditional probabilities. The mathematical formulation presented in this paper will allow organisations to extend Six Sigma process improvement principles in the Industry 4.0 context and implement the 7 steps of 7Epsilon in order to satisfy the requirements of clauses 6.1 and 7.1.6 of the ISO9001:2015 and the aerospace AS9100:2016 quality standard

Manufacturing Process Causal Knowledge Discovery using a Modified Random Forest-based Predictive Model

A Modified Random Forest algorithm (MRF)-based predictive model is proposed for use in man-ufacturing processes to estimate the e˙ects of several potential interventions, such as (i) altering the operating ranges of selected continuous process parameters within specified tolerance limits,(ii) choosing particular categories of discrete process parameters, or (iii) choosing combinations of both types of process parameters. The model introduces a non-linear approach to defining the most critical process inputs by scoring the contribution made by each process input to the process output prediction power. It uses this contribution to discover optimal operating ranges for the continuous process parameters and/or optimal categories for discrete process parameters. The set of values used for the process inputs was generated from operating ranges identified using a novel Decision Path Search (DPS) algorithm and Bootstrap sampling.The odds ratio is the ratio between the occurrence probabilities of desired and undesired process output values. The e˙ect of potential interventions, or of proposed confirmation trials, are quantified as posterior odds and used to calculate conditional probability distributions. The advantages of this approach are discussed in comparison to fitting these probability distributions to Bayesian Networks (BN).The proposed explainable data-driven predictive model is scalable to a large number of process factors with non-linear dependence on one or more process responses. It allows the discovery of data-driven process improvement opportunities that involve minimal interaction with domain expertise. An iterative Random Forest algorithm is proposed to predict the missing values for the mixed dataset (continuous and categorical process parameters). It is shown that the algorithm is robust even at high proportions of missing values in the dataset.The number of observations available in manufacturing process datasets is generally low, e.g. of a similar order of magnitude to the number of process parameters. Hence, Neural Network (NN)-based deep learning methods are generally not applicable, as these techniques require 50-100 times more observations than input factors (process parameters).The results are verified on a number of benchmark examples with datasets published in the lit-erature. The results demonstrate that the proposed method outperforms the comparison approaches in term of accuracy and causality, with linearity assumed. Furthermore, the computational cost is both far better and very feasible for heterogeneous datasets

A novel imputation based predictive algorithm for reducing common cause variation from small and mixed datasets with missing values

Most process control algorithms need a predetermined target value as an input for a process variable so that the deviation is observed and minimized. In this paper, a novel machine learning algorithm is proposed that has an ability to not only suggest new target values for both categorical and continuous variables to minimize process output variation but also predict the extent to which the variation can be minimized.In foundry processes, an average rejection rate of 3%–5% within batches of castings produced is considered as acceptable and is considered as an effect of the common cause variation. As a result, the operating range for process input values is often not changed during the root cause analysis. The relevant available historical process data is normally limited with missing values and it combines both categorical and continuous variables (mixed dataset). However, technological advancements manufacturing processes provide opportunities to further refine process inputs in order to minimize undesired variation in process outputs.A new linear regression based algorithm is proposed to achieve lower prediction error in comparison to the commonly used linear factor analysis for mixed data (FAMD) method. This algorithm is further coupled with a novel missing data algorithm to predict the process response values corresponding to a given set of values for process inputs. This enabled the novel imputation based predictive algorithm to quantify the effect of a confirmation trial based on the proposed changes in the operating ranges of one or more process inputs. A set of values for optimal process inputs is generated from operating ranges discovered by a recently proposed quality correlation algorithm (QCA) using a Bootstrap sampling method. The odds ratio, which represents a ratio between the probability of occurrence of desired and undesired process output values, is used to quantify the effect of a confirmation trial.The limitations of the underlying PCA based linear model have been discussed and the future research areas have been identified

Sensitivitätsanalyse und robustes Prozessdesign pharmazeutischer Herstellungsprozesse

The existence of parameter uncertainties(PU) limits model-based process design techniques. It also hinders the modernization of pharmaceutical manufacturing processes, which is necessitated for intensified market competition and Quality by Design (QbD) principles. Thus, in this thesis, proper approaches are proposed for efficient and effective sensitivity analysis and robust design of pharmaceutical processes. Moreover, the point estimate method (PEM) and polynomial chaos expansion (PCE) are further implemented for uncertainty propagation and quantification (UQ) in the proposed approaches. Global sensitivity analysis (GSA) provides quantitative measures on the influence of PU on process outputs over the entire parameter domain. Two GSA techniques are presented in detail and computed with the PCE. The results from case studies show that GSA is able to quantify the heterogeneity of the information in PU and model structure and parameter dependencies affects significantly the final GSA result as well as output variation. Frameworks for robust process design are introduced to alleviate the adverse effect of PU on process performance. The first robust design framework is developed based on the PEM. The proposed approach has high computational efficiency and is able to take parameter dependencies into account. Then, a novel approach, in which the Gaussian mixture distribution (GMD) concept is combined with PEM, is proposed to handle non-Gaussian distribution. The resulting GMD-PEM concept provides a better trade-off between process efficiency and probability of constraint violations than other approaches. The second robust design framework is based on the iterative back-off strategy and PCE. It provides designs with the desired robustness, while the associated computational expense is independent from the optimization problem. The decoupling of optimization and UQ provides the possibility of implementing robust process design to more complex pharmaceutical manufacturing processes with large number of PU. In this thesis, the case studies include unit operations for (bio)chemical synthesis, separation (crystallization) and formulation (freeze-drying), which cover the complete production chain of pharmaceutical manufacturing. Results from the case studies reveal the significant impact of PU on process design. Also they show the efficiency and effectiveness of the proposed frameworks regarding process performance and robustness in the context of QbD.Die pharmazeutische Industrie muss sowohl den gestiegenen Wettbewerbsdruck standhalten als auch die von Regulierungsbehörden geforderte QbD-Initiative (Quality by Design) umsetzen. Modellgestützte Verfahren können einen signifikanten Beitrag leisten, aber Parameterunsicherheiten (PU) erschweren jedoch eine zuverlässige modellgestützte Prozessauslegung. Das Ziel dieser Arbeit ist daher die Erforschung von effizienten Approaches zur Sensitivitätsanalyse und robusten Prozessdesign der pharmazeutische Industrie. Methoden, Point Estimate Method (PEM) und Polynomial Chaos Expansion (PCE), wurde implementiert, um effizient Unsicherheitenquantifizierung (UQ) zu erlauben. Der globalen Sensitivitätsanalyse (GSA) ist eine systematische Quantifizierung von Parameterschwankungen auf die Simulationsergebnisse. Zwei GSA Techniken werden im Detail vorgestellt und an Beispielen demonstriert. Die Ergebnisse zeigen sowohl den Mehrwert der GSA im Kontext des robusten Prozessdesigns als auch die Relevanz zur korrekten Berücksichtigung von Parameterkorrelationen bei der GSA. Um den schädlichen Einfluss von PU auf die modellgestützte Prozessauslegung zusätzlich zu minimieren, wurden weitere Konzepte aus der robusten Optimierung untersucht. Zunächst wurde das erste Konzept basierend auf der PEM entwickelt. Das erste Konzept zeigt einen deutlich reduzierte Rechenaufwand und kann auch die Parameterkorrelationen entsprechend in der robusten Prozessauslegung berücksichtigen. In einem zweiten Schritt wurde ein neuer Ansatz, der die Gauß-Mischverteilung mit der PEM kombiniert, hierzu für nicht normalverteilte PU erfolgreich implementiert. Weiterhin wurde eine iterative Back-off-Strategie erforscht, die auch die PU entsprechend berücksichtigt aber leichte Rechenaufwand zeigt. Durch die Entkoppelung von UQ und Optimierung können wesentlich komplexere pharmazeutische Herstellungsprozesse mit einer hohen Anzahl an PU implementiert werden. Die in dieser Arbeit untersuchten verfahrenstechnische Grundoperationen decken somit einen Großteil der gesamten Produktionskette der pharmazeutischen Herstellung ab. Die Ergebnisse der untersuchten Beispiele zeigen deutlich den Einfluss von PU auf das modellgestützte Prozessdesign auf. Mithilfe der vorgeschlagenen Approaches können die PU effektiv und effizient bei einer optimalen Balance von Rechenaufwand und der geforderten Zuverlässigkeit ganz im QbD-Sinne berücksichtigt werden

Multiparametric Magnetic Resonance Imaging Artificial Intelligence Pipeline for Oropharyngeal Cancer Radiotherapy Treatment Guidance

Oropharyngeal cancer (OPC) is a widespread disease and one of the few domestic cancers that is rising in incidence. Radiographic images are crucial for assessment of OPC and aid in radiotherapy (RT) treatment. However, RT planning with conventional imaging approaches requires operator-dependent tumor segmentation, which is the primary source of treatment error. Further, OPC expresses differential tumor/node mid-RT response (rapid response) rates, resulting in significant differences between planned and delivered RT dose. Finally, clinical outcomes for OPC patients can also be variable, which warrants the investigation of prognostic models. Multiparametric MRI (mpMRI) techniques that incorporate simultaneous anatomical and functional information coupled to artificial intelligence (AI) approaches could improve clinical decision support for OPC by providing immediately actionable clinical rationale for adaptive RT planning. If tumors could be reproducibly segmented, rapid response could be classified, and prognosis could be reliably determined, overall patient outcomes would be optimized to improve the therapeutic index as a function of more risk-adapted RT volumes. Consequently, there is an unmet need for automated and reproducible imaging which can simultaneously segment tumors and provide predictive value for actionable RT adaptation. This dissertation primarily seeks to explore and optimize image processing, tumor segmentation, and patient outcomes in OPC through a combination of advanced imaging techniques and AI algorithms. In the first specific aim of this dissertation, we develop and evaluate mpMRI pre-processing techniques for use in downstream segmentation, response prediction, and outcome prediction pipelines. Various MRI intensity standardization and registration approaches were systematically compared and benchmarked. Moreover, synthetic image algorithms were developed to decrease MRI scan time in an effort to optimize our AI pipelines. We demonstrated that proper intensity standardization and image registration can improve mpMRI quality for use in AI algorithms, and developed a novel method to decrease mpMRI acquisition time. Subsequently, in the second specific aim of this dissertation, we investigated underlying questions regarding the implementation of RT-related auto-segmentation. Firstly, we quantified interobserver variability for an unprecedented large number of observers for various radiotherapy structures in several disease sites (with a particular emphasis on OPC) using a novel crowdsourcing platform. We then trained an AI algorithm on a series of extant matched mpMRI datasets to segment OPC primary tumors. Moreover, we validated and compared our best model\u27s performance to clinical expert observers. We demonstrated that AI-based mpMRI OPC tumor auto-segmentation offers decreased variability and comparable accuracy to clinical experts, and certain mpMRI input channel combinations could further improve performance. Finally, in the third specific aim of this dissertation, we predicted OPC primary tumor mid-therapy (rapid) treatment response and prognostic outcomes. Using co-registered pre-therapy and mid-therapy primary tumor manual segmentations of OPC patients, we generated and characterized treatment sensitive and treatment resistant pre-RT sub-volumes. These sub-volumes were used to train an AI algorithm to predict individual voxel-wise treatment resistance. Additionally, we developed an AI algorithm to predict OPC patient progression free survival using pre-therapy imaging from an international data science competition (ranking 1st place), and then translated these approaches to mpMRI data. We demonstrated AI models could be used to predict rapid response and prognostic outcomes using pre-therapy imaging, which could help guide treatment adaptation, though further work is needed. In summary, the completion of these aims facilitates the development of an image-guided fully automated OPC clinical decision support tool. The resultant deliverables from this project will positively impact patients by enabling optimized therapeutic interventions in OPC. Future work should consider investigating additional imaging timepoints, imaging modalities, uncertainty quantification, perceptual and ethical considerations, and prospective studies for eventual clinical implementation. A dynamic version of this dissertation is publicly available and assigned a digital object identifier through Figshare (doi: 10.6084/m9.figshare.22141871)

Machine Learning with Metaheuristic Algorithms for Sustainable Water Resources Management

The main aim of this book is to present various implementations of ML methods and metaheuristic algorithms to improve modelling and prediction hydrological and water resources phenomena having vital importance in water resource management

Circuit Design

Circuit Design = Science + Art! Designers need a skilled "gut feeling" about circuits and related analytical techniques, plus creativity, to solve all problems and to adhere to the specifications, the written and the unwritten ones. You must anticipate a large number of influences, like temperature effects, supply voltages changes, offset voltages, layout parasitics, and numerous kinds of technology variations to end up with a circuit that works. This is challenging for analog, custom-digital, mixed-signal or RF circuits, and often researching new design methods in relevant journals, conference proceedings and design tools unfortunately gives the impression that just a "wild bunch" of "advanced techniques" exist. On the other hand, state-of-the-art tools nowadays indeed offer a good cockpit to steer the design flow, which include clever statistical methods and optimization techniques.Actually, this almost presents a second breakthrough, like the introduction of circuit simulators 40 years ago! Users can now conveniently analyse all the problems (discover, quantify, verify), and even exploit them, for example for optimization purposes. Most designers are caught up on everyday problems, so we fit that "wild bunch" into a systematic approach for variation-aware design, a designer's field guide and more. That is where this book can help! Circuit Design: Anticipate, Analyze, Exploit Variations starts with best-practise manual methods and links them tightly to up-to-date automation algorithms. We provide many tractable examples and explain key techniques you have to know. We then enable you to select and setup suitable methods for each design task - knowing their prerequisites, advantages and, as too often overlooked, their limitations as well. The good thing with computers is that you yourself can often verify amazing things with little effort, and you can use software not only to your direct advantage in solving a specific problem, but also for becoming a better skilled, more experienced engineer. Unfortunately, EDA design environments are not good at all to learn about advanced numerics. So with this book we also provide two apps for learning about statistic and optimization directly with circuit-related examples, and in real-time so without the long simulation times. This helps to develop a healthy statistical gut feeling for circuit design. The book is written for engineers, students in engineering and CAD / methodology experts. Readers should have some background in standard design techniques like entering a design in a schematic capture and simulating it, and also know about major technology aspects

Prediction intervals based on historical control data obtained from bioassays

Die Berechnung von Vorhersageintervallen auf derGrundlage von historischen Kontrolldaten aus Bioassays ist in vielen Bereichen der biologischen Forschung von Interesse. Bei pharmazeutischen und präklinischen Anwendungen, wie z. B. Immonogenitätstests, ist die Berechnung von Vorhersageintervallen (oder oberen Vorhersagegrenzen), die zwischen anti-drug Antikörper positiven Patienten und anti-drug Antikörper negativen Patienten unterscheiden, von Interesse. In der (Öko-)Toxikologie werden verschiedene Bioassays angewendet, um die toxikologischen Eigenschaften einer bestimmten chemischen Verbindung anModellorganismen zu untersuchen (z. B. ihre Karzinogenität oder ihre Auswirkungen auf aquatische Nahrungsketten). In diesem Forschungsbereich ist es von Interesse zu überprüfen, ob das Ergebnis der aktuellen unbehandelten Kontrolle (oder der gesamten aktuellen Studie) mit den historischen Informationen übereinstimmt. Zu diesem Zweck können Vorhersageintervalle auf der Grundlage von historischen Kontrolldaten berechnet werden. Wenn die aktuellen Beobachtungen im Vorhersageintervall liegen, kann davon ausgegangen werden, dass sie mit den historischen Informationen übereinstimmen. Das erste Kapitel dieser Arbeit gibt einen detaillierten Überblick über die Verwendung von historischen Kontrolldaten im Rahmen von biologischen Versuchen. Darüber hinaus wird ein Überblick über die Datenstruktur (dichotome Daten, Zähldaten, kontinuierliche Daten) und die Modelle, auf denen die vorgeschlagenen Vorhersageintervalle basieren, gegeben. Im Zusammenhang mit dichotomen Daten oder Zähldaten wird besonderes Augenmerk auf Überdispersion gelegt, die in Daten mit biologischem Hintergrund häufig vorkommt, in der Literatur zu Vorhersageintervallen jedoch meist nicht berücksichtigt wird. Daher wurden Vorhersageintervalle für eine zukünftige Beobachtung vorgeschlagen, die auf überdispersen Binomialdaten beruhen. Die Überdeckungswahrscheinlichkeiten dieser Intervalle wurden auf der Grundlage von Monte-Carlo-Simulationen bewertet und lagen wesentlich näher am nominellen Level als die in der Literatur gefundenen Vorhersageintervalle, die keineÜberdispersion berücksichtigen (siehe Abschnitte 2.1 und 2.2). In mehreren Anwendungen ist die abhängige Variable kontinuierlich und wird als normalverteilt angenommen. Dennoch können die Daten durch verschiedene Zufallsfaktoren (zum Beispiel unterschiedliche Labore die Proben von mehreren Patienten analysieren) beeinflusst werden. In diesem Fall können die Daten durch lineareModelle mit zufälligen Effekten modelliert werden, bei denen Parameterschätzer mittels Restricted- Maximum-Likelihood Verfahren geschätztwerden. Für dieses Szenariowerden in Abschnitt 2.3 zwei Vorhersageintervalle vorgeschlagen. Eines dieser vorgeschlagenen Intervalle basiert auf einem Bootstrap- Kalibrierungsverfahren, das es auch in Fällen anwendbar macht, in denen ein Vorhersageintervall für mehr als eine zukünftige Beobachtung benötigt wird. Abschnitt 2.4 beschreibt das R-Paket predint, in dem das in Abschnitt 2.3 beschriebene bootstrap-kalibrierte Vorhersageintervall (sowie untere und obere Vorhersagegrenzen) implementiert ist. Darüber hinaus sind Vorhersageintervalle für mindestens eine zukünftige Beobachtung für überdisperse Binomial- oder Zähldaten implementiert. Der Kern dieser Arbeit besteht in der Berechnung von Vorhersageintervallen für eine oder mehrere zukünftige Beobachtungen, die auf überdispersen Binomialdaten, überdispersen Zähldaten oder linearen Modellen mit zufälligen Effekten basieren. Nach Kenntnis des Autors ist dies das erste Mal, dass Vorhersageintervalle, die Überdispersion berücksichtigen, vorgeschlagen werden. Darüber hinaus ist "predint" das erste über CRAN verfügbare R-Paket, das Funktionen für die Anwendung von Vorhersageintervallen für die genanntenModelle bereitstellt. Somit ist die in dieser Arbeit vorgeschlageneMethodik öffentlich zugänglich und kann von anderen Forschenden leicht angewendet werden