557 research outputs found

    Machine learning in bioprocess development: From promise to practice

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    Fostered by novel analytical techniques, digitalization and automation, modern bioprocess development provides high amounts of heterogeneous experimental data, containing valuable process information. In this context, data-driven methods like machine learning (ML) approaches have a high potential to rationally explore large design spaces while exploiting experimental facilities most efficiently. The aim of this review is to demonstrate how ML methods have been applied so far in bioprocess development, especially in strain engineering and selection, bioprocess optimization, scale-up, monitoring and control of bioprocesses. For each topic, we will highlight successful application cases, current challenges and point out domains that can potentially benefit from technology transfer and further progress in the field of ML

    Decoding Complexity in Metabolic Networks using Integrated Mechanistic and Machine Learning Approaches

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    How can we get living cells to do what we want? What do they actually ‘want’? What ‘rules’ do they observe? How can we better understand and manipulate them? Answers to fundamental research questions like these are critical to overcoming bottlenecks in metabolic engineering and optimizing heterologous pathways for synthetic biology applications. Unfortunately, biological systems are too complex to be completely described by physicochemical modeling alone. In this research, I developed and applied integrated mechanistic and data-driven frameworks to help uncover the mysteries of cellular regulation and control. These tools provide a computational framework for seeking answers to pertinent biological questions. Four major tasks were accomplished. First, I developed innovative tools for key areas in the genome-to-phenome mapping pipeline. An efficient gap filling algorithm (called BoostGAPFILL) that integrates mechanistic and machine learning techniques was developed for the refinement of genome-scale metabolic network reconstructions. Genome-scale metabolic network reconstructions are finding ever increasing applications in metabolic engineering for industrial, medical and environmental purposes. Second, I designed a thermodynamics-based framework (called REMEP) for mutant phenotype prediction (integrating metabolomics, fluxomics and thermodynamics data). These tools will go a long way in improving the fidelity of model predictions of microbial cell factories. Third, I designed a data-driven framework for characterizing and predicting the effectiveness of metabolic engineering strategies. This involved building a knowledgebase of historical microbial cell factory performance from published literature. Advanced machine learning concepts, such as ensemble learning and data augmentation, were employed in combination with standard mechanistic models to develop a predictive platform for important industrial biotechnology metrics such as yield, titer, and productivity. Fourth, my modeling tools and skills have been used for case studies on fungal lipid metabolism analyses, E. coli resource allocation balances, reconstruction of the genome-scale metabolic network for a non-model species, R. opacus, as well as the rapid prediction of bacterial heterotrophic fluxomics. In the long run, this integrated modeling approach will significantly shorten the “design-build-test-learn” cycle of metabolic engineering, as well as provide a platform for biological discovery

    Process analytical technology in food biotechnology

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    Biotechnology is an area where precision and reproducibility are vital. This is due to the fact that products are often in form of food, pharmaceutical or cosmetic products and therefore very close to the human being. To avoid human error during the production or the evaluation of the quality of a product and to increase the optimal utilization of raw materials, a very high amount of automation is desired. Tools in the food and chemical industry that aim to reach this degree of higher automation are summarized in an initiative called Process Analytical Technology (PAT). Within the scope of the PAT, is to provide new measurement technologies for the purpose of closed loop control in biotechnological processes. These processes are the most demanding processes in regards of control issues due to their very often biological rate-determining component. Most important for an automation attempt is deep process knowledge, which can only be achieved via appropriate measurements. These measurements can either be carried out directly, measuring a crucial physical value, or if not accessible either due to the lack of technology or a complicated sample state, via a soft-sensor.Even after several years the ideal aim of the PAT initiative is not fully implemented in the industry and in many production processes. On the one hand a lot effort still needs to be put into the development of more general algorithms which are more easy to implement and especially more reliable. On the other hand, not all the available advances in this field are employed yet. The potential users seem to stick to approved methods and show certain reservations towards new technologies.Die Biotechnologie ist ein Wissenschaftsbereich, in dem hohe Genauigkeit und Wiederholbarkeit eine wichtige Rolle spielen. Dies ist der Tatsache geschuldet, dass die hergestellten Produkte sehr oft den Bereichen Nahrungsmitteln, Pharmazeutika oder Kosmetik angehöhren und daher besonders den Menschen beeinflussen. Um den menschlichen Fehler bei der Produktion zu vermeiden, die Qualität eines Produktes zu sichern und die optimale Verwertung der Rohmaterialen zu gewährleisten, wird ein besonders hohes Maß an Automation angestrebt. Die Werkzeuge, die in der Nahrungsmittel- und chemischen Industrie hierfür zum Einsatz kommen, werden in der Process Analytical Technology (PAT) Initiative zusammengefasst. Ziel der PAT ist die Entwicklung zuverlässiger neuer Methoden, um Prozesse zu beschreiben und eine automatische Regelungsstrategie zu realisieren. Biotechnologische Prozesse gehören hierbei zu den aufwändigsten Regelungsaufgaben, da in den meisten Fällen eine biologische Komponente der entscheidende Faktor ist. Entscheidend für eine erfolgreiche Regelungsstrategie ist ein hohes Maß an Prozessverständnis. Dieses kann entweder durch eine direkte Messung der entscheidenden physikalischen, chemischen oder biologischen Größen gewonnen werden oder durch einen SoftSensor. Zusammengefasst zeigt sich, dass das finale Ziel der PAT Initiative auch nach einigen Jahren des Propagierens weder komplett in der Industrie noch bei vielen Produktionsprozessen angekommen ist. Auf der einen Seite liegt dies mit Sicherheit an der Tatsache, dass noch viel Arbeit in die Generalisierung von Algorithmen gesteckt werden muss. Diese müsse einfacher zu implementieren und vor allem noch zuverlässiger in der Funktionsweise sein. Auf der anderen Seite wurden jedoch auch Algorithmen, Regelungsstrategien und eigne Ansätze für einen neuartigen Sensor sowie einen Soft-Sensors vorgestellt, die großes Potential zeigen. Nicht zuletzt müssen die möglichen Anwender neue Strategien einsetzen und Vorbehalte gegenüber unbekannten Technologien ablegen

    Novel strategies for process control based on hybrid semi-parametric mathematical systems

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    Tese de doutoramento. Engenharia Química. Universidade do Porto. Faculdade de Engenharia. 201

    Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing

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    Biopharmaceutical and pharmaceutical manufacturing are strongly influenced by the process analytical technology initiative (PAT) and quality by design (QbD) methodologies, which are designed to enhance the understanding of more integrated processes. The major aim of this effort can be summarized as developing a mechanistic understanding of a wide range of process steps, including the development of technologies to perform online measurements and real-time control and optimization. Furthermore, minimization of the number of empirical experiments and the model-assisted exploration of the process design space are targeted. Even if tremendous progress has been achieved so far, there is still work to be carried out in order to realize the full potential of the process systems engineering toolbox. Within this reprint, an overview of cutting-edge developments of process systems engineering for biopharmaceutical and pharmaceutical manufacturing processes is given, including model-based process design, Digital Twins, computer-aided process understanding, process development and optimization, and monitoring and control of bioprocesses. The biopharmaceutical processes addressed focus on the manufacturing of biopharmaceuticals, mainly by Chinese hamster ovary (CHO) cells, as well as adeno-associated virus production and generation of cell spheroids for cell therapies

    Innovative Surveillance and Process Control in Water Resource Recovery Facilities

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    Water Resource Recovery Facilities (WRRF), previously known as Wastewater Treatment Plants (WWTP), are getting increasingly complex, with the incorporation of sludge processing and resource recovery technologies. Along with maintaining a stringent effluent water quality standard, the focus is gradually shifting towards energy-efficient operations and recovery of resources. The new objectives of the WRRF demand an economically optimal operation of processes that are subjected to extreme variations in flowrate and composition at the influent. The application of online monitoring, process control, and automation in WRRF has already shown a steady increase in the past decade. However, the advanced model-based optimal control strategies, implemented in most process industries, are less common in WRRF. The complex nature of biological processes, the unavailability of simplified process models, and a lack of cost-effective surveillance infrastructure have often hindered the implementation of advanced control strategies in WRRF. The ambition of this research is to implement and validate cost-efficient monitoring alternatives and advanced control strategies for WRRF by fully utilizing the powerful Internet of Things (IoT) and data science tools. The first step towards implementing an advanced control strategy is to ensure the availability of surveillance infrastructure for monitoring nutrient compositions in WRRF processes. In Paper A, a soft sensor, based on Extended Kalman Filter, is developed for estimating water-quality parameters in a Sequential Batch MBBR process using reliable and inexpensive online sensors. The model used in the soft sensor combines the mechanistic understanding of the nutrient removal process with a statistical correlation between nutrient composition and easy-to-measure parameters. Paper B demonstrates the universality of the soft sensor through validation tests conducted in a Continuous Multistage MBBR pilot plant. The drift in soft-sensor estimation caused by a mismatch between the mathematical model and process behavior is studied in Paper B. The robustness of the soft sensor is assessed by observing estimated nutrient composition values for a period of three months. A systematic method to calibrate the measurement model and update model parameters using data from periodic lab measurements are discussed in Paper B. The term SCADA has been ubiquitous while mentioning online monitoring and control strategy deployment in WRRFs. The present digital world of affordable communication hardware, compact single board processors, and high computational power presents several options for remote monitoring and deployment of soft sensors. In Paper C, a cost-effective IoT strategy is developed by using an open-source programming language and inexpensive hardware. The functionalities of the IoT infrastructure are demonstrated by using it to deploy a soft sensor script in the ContinuousMultistage MBBR pilot plant. A cost-comparison between the commercially available alternatives presented in Paper A and the open-source IoT strategy in Paper B and Paper C highlights the benefits of the new monitoring infrastructure. Lack of reliable control models have often been the cause for the poor performance of advanced control strategies, such as Model Predictive Controls (MPC) when implemented to complex biological nutrient removal processes. Paper D attempts to overcome the inadequacies of the linear prediction model by combining a recursive model parameter estimator with the linear MPC. The new MPC variant, called the adaptive MPC (AMPC), reduces the dependency of MPC on the accuracy of its prediction model. The performance of the AMPC is compared with that of a linear MPC, nonlinear MPC, and the traditional proportional-integral cascade control through simulator-based evaluations conducted on the Benchmark Simulator platform(BSM2). The advantages of AMPC compared to its counterparts, in terms of reducing the aeration energy, curtailing the number of effluent ammonia violations, and the use of computational resources, are highlighted in Paper D. The complex interdependencies between different processes in a WRRF pose a significant challenge in defining constant reference points for WRRFs operations. A strategy that decides control outputs based on economic parameters rather than maintaining a fixed reference set-point is introduced in Paper E. The model-based control strategy presented in Paper D is further improved by including economic parameters in the MPC’s objective function. The control strategy known as Economic MPC (EMPC) is implemented for optimal dosage of magnesium hydroxide in a struvite recovery unit installed in a WRRF. A comparative study performed on the BSM2 platform demonstrates a significant improvement in overall profitability for the EMPC when compared to a constant or a feed-forward flow proportional control strategy. The resilience of the EMPC strategy to variations in the market price of struvite is also presented in Paper E. A combination of cost-effective monitoring infrastructure and advanced control strategies using advanced IoTs and data science tools have been documented to overcome some of the critical problems encountered in WRRFs. The overall improvement in process efficiency, reduction in operating costs, an increase in resource recovery, and a substantial reduction in the price of online monitoring infrastructure contribute to the overall aim of transitioning WRRFs to a self-sustaining facility capable of generating value-added products.Water Resource Recovery Facilities (WRRF), tidligere kjent som avløpsrenseanlegg (WWTP), blir stadig mer komplekse ettersom flere prosess steg tillegges anleggene i form av slambehandling og ressursgjenvinningsteknologi. Foruten hovedmålet om å imøtekomme strenge avløpsvannskvalitetskrav, har anleggenes fokus gradvis skiftet mot energieffektiv drift og gjenvinning av ressurser. Slike nye mål krever økonomisk optimal drift av prosesser som er utsatt for ekstreme variasjoner i volum og sammensetning av tilløp. Bruk av online overvåking, prosesskontroll og automatisering i WRRF har jevnt økt det siste tiåret. Likevel er avanserte modellbaserte kontrollstrategier for optimalisering ikke vanlig i WRRF, i motsetning til de fleste prosessindustrier. Komplekse forhold i biologiske prosesser, mangel på tilgang til pålitelige prosessmodeller og mangel på kostnadseffektiv overvåkingsinfrastruktur har ofte hindret implementeringen av avanserte kontrollstrategier i WRRF. Ambisjonen med denne avhandlingen er å implementere og validere kostnadseffektive overvåkingsalternativer og avanserte kontrollstrategier somutnytter kraftige Internet of Things (IoT) og datavitenskapelige verktøy i WRRF sammenheng. Det første steget mot implementering av en avansert kontrollstrategi er å sørge for tilgjengelighet av overvåkingsinfrastruktur for måling av næringsstoffer i WRRF-prosesser. Paper A demonstrerer en virtuell sensor basert på et utvidet Kalman filter, utviklet for å estimere vannkvalitetsparametere i en sekvensiell batch MBBR prosess ved hjelp av pålitelige og rimelige online sensorer. Modellen som brukes i den virtuelle sensoren kombinerer en mekanistisk forståelse av prosessen for fjerning av næringsstoffer fra avløpsvann med et statistisk sammenheng mellom næringsstoffsammensetning i avløpsvann og parametere som er enkle å måle. Paper B demonstrerer det universale bruksaspektet til den virtuelle sensoren gjennom valideringstester utført i et kontinuerlig flertrinns MBBR pilotanlegg. Feilene i sensorens estimering forårsaket av uoverensstemmelse mellom den matematiske modellen og prosesseatferden er undersøkt i Paper B. Robustheten til den virtuelle sensoren ble vurdert ved å observere estimerte næringssammensetningsverdier i en periode på tre måneder. En systematisk metode for å kalibrere målemodellen og oppdatere modellparametere ved hjelp av data fra periodiske laboratoriemålinger er diskutert i Paper B. Begrepet SCADA har alltid vært til stede når online overvåking og kontrollstrategi innen WRRF er nevnt. Den nåværende digitale verdenen med god tilgjengelighet av rimelig kommunikasjonsmaskinvare, kompakte enkeltkortprosessorer og høy beregningskraft presenterer flere muligheter for fjernovervåking og implementering av virtuelle sensorer. Paper C viser til utvikling av en kostnadseffektiv IoT-strategi ved hjelp av et programmeringsspråk med åpen kildekode og rimelig maskinvare. Funksjonalitetene i IoT-infrastruktur demonstreres gjennom implementering av et virtuelt sensorprogram i et kontinuerlig flertrinns MBBR pilotanlegg. En kostnadssammenligning mellom de kommersielt tilgjengelige alternativene som presenteres i Paper A og åpen kildekode-IoT-strategi i Paper B og Paper C fremhever fordelene med den nye overvåkingsinfrastrukturen. Mangel på pålitelige kontrollmodeller har ofte vært årsaken til svake resultater i avanserte kontrollstrategier, som for eksempel Model Predictive Control (MPC) når de implementeres i komplekse biologiske prosesser for fjerning av næringsstoffer. Paper D prøver å løse manglene i MPC ved å kombinere en rekursiv modellparameterestimator med lineær MPC. Den nye MPC-varianten, kalt Adaptiv MPC (AMPC), reduserer MPCs avhengighet av nøyaktigheten i prediksjonsmodellen. Ytelsen til AMPC sammenlignes med ytelsen til en lineær MPC, ikke-lineær MPC og tradisjonell proportionalintegral kaskadekontroll gjennom simulatorbaserte evalueringer utført på Benchmark Simulator plattformen (BSM2). Fordelene med AMPC sammenlignet med de andre kontrollstrategiene er fremhevet i Paper D og demonstreres i sammenheng redusering av energibruk ved lufting i luftebasseng, samt redusering i antall brudd på utslippskrav for ammoniakk og bruk av beregningsressurser. De komplekse avhengighetene mellom forskjellige prosesser i en WRRF utgjør en betydelig utfordring når man skal definere konstante referansepunkter for WRRF under drift. En strategi som bestemmer kontrollsignaler basert på økonomiske parametere i stedet for å opprettholde et fast referansesettpunkt introduseres i Paper E. Den modellbaserte kontrollstrategien fra PaperDforbedres ytterligere ved å inkludere økonomiske parametere iMPCs objektiv funksjon. Denne kontrollstrategien kalles Economic MPC (EMPC) og er implementert for optimal dosering av magnesiumhydroksid i en struvit utvinningsenhet installert i en WRRF. En sammenligningsstudie utført på BSM2 plattformen viste en betydelig forbedring i den totale lønnsomheten ved bruk av EMPC sammenlignet med en konstant eller en flow proportional kontrollstrategi. Robustheten til EMPC-strategien for variasjoner i markedsprisen på struvit er også demonstrert i Paper E. En kombinasjon av kostnadseffektiv overvåkingsinfrastruktur og avanserte kontrollstrategier ved hjelp av avansert IoT og datavitenskapelige verktøy er brukt for å løse flere kritiske utfordringer i WRRF. Den samlede forbedringen i prosesseffektivitet, reduksjon i operasjonskostnader, økt ressursgjenvinning og en betydelig reduksjon i pris for online overvåkningsinfrastruktur bidrar til det overordnede målet om å gå over til bærekraftige WRRF som er i stand til å generere verdiskapende produkter.DOSCON A

    Bioprocess Monitoring and Control

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    Process monitoring and control are fundamental to all processes; this holds especially for bioprocesses, due to their complex nature. Usually, bioprocesses deal with living cells, which have their own regulatory systems. It helps to adjust the cell to its environmental condition. This must not be the optimal condition that the cell needs to produce whatever is desired. Therefore, a close monitoring of the cell and its environment is essential to provide optimal conditions for production. Without measurement, no information of the current process state is obtained. In this book, methods and techniques are provided for the monitoring and control of bioprocesses. From new developments for sensors, the application of spectroscopy and modelling approaches, the estimation and observer implementation for ethanol production and the development and scale-up of various bioprocesses and their closed loop control information are presented. The processes discussed here are very diverse. The major applications are cultivation processes, where microorganisms were grown, but also an incubation process of bird’s eggs, as well as an indoor climate control for humans, will be discussed. Altogether, in 12 chapters, nine original research papers and three reviews are presented

    Soft sensor development and process control of anaerobic digestion

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    This thesis focuses on soft sensor development based on fuzzy logic used for real time online monitoring of anaerobic digestion to improve methane output and for robust fermentation. Important process parameter indicators such as pH, biogas production, daily difference in pH and daily difference in biogas production were used to infer alkalinity, a reliable indicator of process stability. Additionally, a fuzzy logic and a rule-based controller were developed and tested with single stage anaerobic digesters operating with cow slurry and cellulose. Alkalinity predictions from the fuzzy logic algorithm were used by both controllers to regulate the organic loading rate that aimed to optimise the biogas process. The predictive performance of a software sensor determining alkalinity that was designed using fuzzy logic and subtractive clustering and was validated against multiple linear regression models that were developed (Partner N° 2, Rothamsted Research 2010) for the same purpose. More accurate alkalinity predictions were achieved by utilizing a fuzzy software sensor designed with less amount of data compared to a multiple linear regression model whose design was based on a larger database. Those models were utilised to control the organic loading rate of a twostage, semi-continuously fed stirred reactor system. Three 5l reactors without support media and three 5l reactors with different support media (burst cell reticulated polyurethane foam coarse, burst cell reticulated polyurethane foam medium and sponge) were operated with cow slurry for a period of seven weeks and twenty weeks respectively. Reactors with support media were proven to be more stable than the reactors without support media but did not exhibit higher gas productivity. Biomass support media were found to influence digester recovery positively by reducing the recovery period. Optimum process parameter ranges were identified for reactors with and without support media. Increased biogas production was found to occur when the loading rates were 3-3.5g VS/l/d and 4-5g VS/l/d respectively. Optimum pH ranges were identified between 7.1-7.3 and 6.9-7.2 for reactors with and without support media respectively, whereas all reactors became unstable at ph<6.9. Alkalinity levels for system stability appeared to be above 3500 mg/l of HCO3 - for reactors without media and 3480 mg/l of HCO3 - for reactors with support media. Biogas production was maximized when alkalinity was 3 between 3500-4500 mg/l of HCO3 - for reactors without support media and 3480- 4300 mg/l of HCO3 - for reactors with support media. Two fuzzy logic models predicting alkalinity based on the operation of the three 5l reactors with support media were developed (FIS I, FIS II). The FIS II design was based on a larger database than FIS I. FIS II performance when applied to the reactor where sponge was used as the support media was characterized by quite good MAE and bias values of 466.53 mg/l of HCO3- and an acceptable value for R2= 0.498. The NMSE was close to 0 with a value of 0.03 and a slightly higher FB= 0.154 than desired. The fuzzy system robustness was tested by adding NaHCO3 to the reactor with the burst cell reticulated polyurethane foam medium and by diluting the reactor where sponge was used as the support media with water. FIS I and FIS II were able to follow the system output closely in the first case, but not in the second. FIS II functionality as an alkalinity predictor was tested through the application on a 28l cylindrical reactor with sponge as the biomass support media treating cow manure. If data that was recorded when severe temperature fluctuations occurred (that highly impact digester performance), are excluded, FIS II performance can be characterized as good by having R2= 0.54 and MAE=Bias= 587 mg/l of HCO3-. Predicted alkalinity values followed observed alkalinity values closely during the days that followed NaHCO3 addition and water dilution. In a second experiment a rulebased and a Mamdani fuzzy logic controller were developed to regulate the organic loading rate based on alkalinity predictions from FIS II. They were tested through the operation of five 6.5l reactors with biomass support media treating cellulose. The performance indices of MAE=763.57 mg/l of HCO3-, Bias= 398.39 mg/l of HCO3-, R2= 0.38 and IA= 0.73 indicate a pretty good correlation between predicted and observed values. However, although both controllers managed to keep alkalinity within the desired levels suggested for stability (>3480 mg/l of HCO3-), the reactors did not reach a stable state suggesting that different loading rates should be applied for biogas systems treating cellulose.New Generation Biogas (NGB

    Data-driven, mechanistic and hybrid modelling for statistical fault detection and diagnosis in chemical processes

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    Research and applications of multivariate statistical process monitoring and fault diagnostic techniques for performance monitoring of continuous and batch processes continue to be a very active area of research. Investigations into new statistical and mathematical methods and there applicability to chemical process modelling and performance monitoring is ongoing. Successive researchers have proposed new techniques and models to address the identified limitations and shortcomings of previously applied linear statistical methods such as principal component analysis and partial least squares. This thesis contributes to this volume of research and investigation into alternative approaches and their suitability for continuous and batch process applications. In particular, the thesis proposes a modified canonical variate analysis state space model based monitoring scheme and compares the proposed scheme with several existing statistical process monitoring approaches using a common benchmark simulator – Tennessee Eastman benchmark process. A hybrid data driven and mechanistic model based process monitoring approach is also investigated. The proposed hybrid scheme gives more specific considerations to the implementation and application of the technique for dynamic systems with existing control structures. A nonmechanistic hybrid approach involving the combination of nonlinear and linear data based statistical models to create a pseudo time-variant model for monitoring of large complex plants is also proposed. The hybrid schemes are shown to provide distinct advantages in terms of improved fault detection and reliability. The demonstration of the hybrid schemes were carried out on two separate simulated processes: a CSTR with recycle through a heat exchanger and a CHEMCAD simulated distillation column. Finally, a batch process monitoring schemed based on a proposed implementation of interval partial least squares (IPLS) technique is demonstrated using a benchmark simulated fed-batch penicillin production process. The IPLS strategy employs data unfolding methods and a proposed algorithm for segmentation of the batch duration into optimal intervals to give a unique implementation of a Multiway-IPLS model. Application results show that the proposed method gives better model prediction and monitoring performance than the conventional IPLS approach.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

    Data-Driven Fault Detection and Reasoning for Industrial Monitoring

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    This open access book assesses the potential of data-driven methods in industrial process monitoring engineering. The process modeling, fault detection, classification, isolation, and reasoning are studied in detail. These methods can be used to improve the safety and reliability of industrial processes. Fault diagnosis, including fault detection and reasoning, has attracted engineers and scientists from various fields such as control, machinery, mathematics, and automation engineering. Combining the diagnosis algorithms and application cases, this book establishes a basic framework for this topic and implements various statistical analysis methods for process monitoring. This book is intended for senior undergraduate and graduate students who are interested in fault diagnosis technology, researchers investigating automation and industrial security, professional practitioners and engineers working on engineering modeling and data processing applications. This is an open access book
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