Microstructural Classification of Bainitic Subclasses in Low-Carbon Multi-Phase Steels Using Machine Learning Techniques

With its excellent property combinations and ability to specifically adjust tailor-made microstructures, steel is still the world’s most important engineering and construction material. To fulfill ever-increasing demands and tighter tolerances in today’s steel industry, steel research remains indispensable. The continuous material development leads to more and more complex microstruc tures, which is especially true for steel designs that include bainitic structures. This poses new challenges for the classification and quantification of these microstructures. Machine learning (ML) based microstructure classification offers exciting potentials in this context. This paper is concerned with the automated, objective, and reproducible classification of the carbon-rich second phase objects in multi-phase steels by using machine learning techniques. For successful applications of ML-based classifications, a holistic approach combining computer science expertise and material science domain knowledge is necessary. Seven microstructure classes are considered: pearlite, martensite, and the bainitic subclasses degenerate pearlite, debris of cementite, incomplete transformation product, and upper and lower bainite, which can all be present simultaneously in one micrograph. Based on SEM images, textural features (Haralick parameters and local binary pattern) and morphological parame ters are calculated and classified with a support vector machine. Of all second phase objects, 82.9% are classified correctly. Regarding the total area of these objects, 89.2% are classified correctly. The reported classification can be the basis for an improved, sophisticated microstructure quantification, enabling process–microstructure–property correlations to be established and thereby forming the backbone of further, microstructure-centered material development

Classification of Bainitic Structures Using Textural Parameters and Machine Learning Techniques

Bainite is an essential constituent of modern high strength steels. In addition to the still great challenge of characterization, the classification of bainite poses difficulties. Challenges when dealing with bainite are the variety and amount of involved phases, the fineness and complexity of the structures and that there is often no consensus among human experts in labeling and classifying those. Therefore, an objective and reproducible characterization and classification is crucial. To achieve this, it is necessary to analyze the substructure of bainite using scanning electron microscope (SEM). This work will present how textural parameters (Haralick features and local binary pattern) calculated from SEM images, taken from specifically produced benchmark samples with defined structures, can be used to distinguish different bainitic microstructures by using machine learning techniques (support vector machine). For the classification task of distinguishing pearlite, granular, degenerate upper, upper and lower bainite as well as martensite a classification accuracy of 91.80% was achieved, by combining Haralick features and local binary pattern

Data Digitizing: Accurate and Precise Data Extraction for Quantitative Systems Pharmacology and Physiologically-Based Pharmacokinetic Modeling

In quantitative systems pharmacology (QSP) and physiologically-based pharmacokinetic (PBPK) modeling, data digitizing is a valuable tool to extract numerical information from published data presented as graphs. To quantify their relevance, a literature search revealed a remarkable mean increase of 16% per year in publications citing digitizing software together with QSP or PBPK. Accuracy, precision, confounder influence, and variability were investigated using scaled median symmetric accuracy (ζ), thus finding excellent accuracy (mean ζ = 0.99%). Although significant, no relevant confounders were found (mean ζ ± SD circles = 0.69% ± 0.68% vs. triangles = 1.3% ± 0.62%). Analysis of 181 literature peak plasma concentration values revealed a considerable discrepancy between reported and post hoc digitized data with 85% having ζ > 5%. Our findings suggest that data digitizing is precise and important. However, because the greatest pitfall comes from pre-existing errors, we recommend always making published data available as raw values

Reproducible Quantification of the Microstructure of Complex Quenched and Quenched and Tempered Steels Using Modern Methods of Machine Learning

Current conventional methods of evaluating microstructures are characterized by a high degree of subjectivity and a lack of reproducibility. Modern machine learning (ML) approaches have already shown great potential in overcoming these challenges. Once trained with representative data in combination with objective ground truth, the ML model is able to perform a task properly in a reproducible and automated manner. However, in highly complex use cases, it is often not possible to create a definite ground truth. This study addresses this problem using the underlying showcase of microstructures of highly complex quenched and quenched and tempered (Q/QT) steels. A patch-wise classification approach combined with a sliding window technique provides a solution for segmenting entire microphotographs where pixel-wise segmentation is not applicable since it is hardly feasible to create reproducible training masks. Using correlative microscopy, consisting of light optical microscope (LOM) and scanning electron microscope (SEM) micrographs, as well as corresponding data from electron backscatter diffraction (EBSD), a training dataset of reference states that covers a wide range of microstructures was acquired in order to train accurate and robust ML models in order to classify LOM or SEM images. Despite the enormous complexity associated with the steels treated here, classification accuracies of 88.8% in the case of LOM images and 93.7% for high-resolution SEM images were achieved. These high accuracies are close to super-human performance, especially in consideration of the reproducibility of the automated ML approaches compared to conventional methods based on subjective evaluations through experts

PBPK Models for CYP3A4 and P-gp DDI Prediction : A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin

According to current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents, physiologically based pharmacokinetic (PBPK) modeling is a powerful tool to explore and quantitatively predict drug-drug interactions (DDIs) and may offer an alternative to dedicated clinical trials. This study provides whole-body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology (OSP) Suite. All models were built independently, coupled using reported interaction parameters, and mutually evaluated to verify their predictive performance by simulating published clinical DDI studies. In total, 112 studies were used for model development and 57 studies for DDI prediction. 93% of the predicted area under the plasma concentration-time curve (AUC) ratios and 94% of the peak plasma concentration (Cmax) ratios are within twofold of the observed values. This study lays a cornerstone for the qualification of the OSP platform with regard to reliable PBPK predictions of enzyme-mediated and transportermediated DDIs during model-informed drug development. All presented models are provided open-source and transparently documented

Numerical simulation of dual-phase steel based on real and virtual three-dimensional microstructures

Dual-phase steel shows a strong connection between its microstructure and its mechanical properties. This structure–property correlation is caused by the composition of the microstructure of a soft ferritic matrix with embedded hard martensite areas, leading to a simultaneous increase in strength and ductility. As a result, dual-phase steels are widely used especially for strength-relevant and energy-absorbing sheet metal structures. However, their use as heavy plate steel is also desirable. Therefore, a better understanding of the structure–property correlation is of great interest. Microstructure-based simulation is essential for a realistic simulation of the mechanical properties of dual-phase steel. This paper describes the entire process route of such a simulation, from the extraction of the microstructure by 3D tomography and the determination of the properties of the individual phases by nanoindentation, to the implementation of a simulation model and its validation by experiments. In addition to simulations based on real microstructures, simulations based on virtual microstructures are also of great importance. Thus, a model for the generation of virtual microstructures is presented, allowing for the same statistical properties as real microstructures. With the help of these structures and the aforementioned simulation model, it is then possible to predict the mechanical properties of a dual-phase steel, whose three-dimensional (3D) microstructure is not yet known with high accuracy. This will enable future investigations of new dual-phase steel microstructures within a virtual laboratory even before their production

RVE-size Estimation and Efficient Microstructure-based Simulation of Dual-Phase Steel

Dual-phase steel shows a pronounced structure-property correlation, caused by its internal structure consisting of asoft ferrite matrix and embedded hard martensite regions. Due to its high strength combined with high ductility, dual-phasesteel is particularly suitable for energy-absorbing and strength-relevant sheet metal applications, but its use as heavy plate isalso desirable. Due to the complex microstructure, microstructure-based simulation is essential for a realistic simulation of themechanical properties of dual-phase steel. This paper describes two important points for the microstructure-based simulation ofdual-phase steel. First a method for the straightforward experimental estimation of the RVE size based on hardness measurementsprior to tomography preparation is presented and evaluated. Secondly, a method for the efficient meshing of these microstructures,based on material definition at the integration points of a finite element model, is developed

Comprehensive Parent-Metabolite PBPK/PD Modeling Insights into Nicotine Replacement Therapy Strategies

Background Nicotine, the pharmacologically active substance in both tobacco and many electronic cigarette (e-cigarette) liquids, is responsible for the addiction that sustains cigarette smoking. With 8 million deaths worldwide annually, smoking remains one of the major causes of disability and premature death. However, nicotine also plays an important role in smoking cessation strategies. Objectives The aim of this study was to develop a comprehensive, whole-body, physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) model of nicotine and its major metabolite cotinine, covering various routes of nicotine administration, and to simulate nicotine brain tissue concentrations after the use of combustible cigarettes, e-cigarettes, nicotine gums, and nicotine patches. Methods A parent–metabolite, PBPK/PD model of nicotine for a non-smoking and a smoking population was developed using 91 plasma and brain tissue concentration–time profles and 11 heart rate profles. Among others, cytochrome P450 (CYP) 2A6 and 2B6 enzymes were implemented, including kinetics for CYP2A6 poor metabolizers. Results The model is able to precisely describe and predict both nicotine plasma and brain tissue concentrations, cotinine plasma concentrations, and heart rate profles. 100% of the predicted area under the concentration–time curve (AUC) and maximum concentration (Cmax) values meet the twofold acceptance criterion with overall geometric mean fold errors of 1.12 and 1.15, respectively. The administration of combustible cigarettes, e-cigarettes, nicotine patches, and nicotine gums was successfully implemented in the model and used to identify diferences in steady-state nicotine brain tissue concentration patterns. Conclusions Our PBPK/PD model may be helpful in further investigations of nicotine dependence and smoking cessation strategies. As the model represents the frst nicotine PBPK/PD model predicting nicotine concentration and heart rate profles after the use of e-cigarettes, it could also contribute to a better understanding of the recent increase in youth e-cigarette use

Efficient reconstruction of prior austenite grains in steel from etched light optical micrographs using deep learning and annotations from correlative microscopy

The high-temperature austenite phase is the initial state of practically all technologically relevant hot forming and heat treatment operations in steel processing. The phenomena occurring in austenite, such as recrystallization or grain growth, can have a decisive influence on the subsequent properties of the material. After the hot forming or heat treatment process, however, the austenite transforms into other microstructural constituents and information on the prior austenite morphology are no longer directly accessible. There are established methods available for reconstructing former austenite grain boundaries via metallographic etching or electron backscatter diffraction (EBSD) which both exhibit shortcomings. While etching is often difficult to reproduce and strongly depend on the investigated steel’s alloying concept, EBSD acquisition and reconstruction is rather time-consuming. But in fact, though, light optical micrographs of steels contrasted with conventional Nital etchant also contain information about the former austenite grains. However, relevant features are not directly apparent or accessible with conventional segmentation approaches. This work presents a deep learning (DL) segmentation of prior austenite grains (PAG) from Nital etched light optical micrographs. The basis for successful segmentation is a correlative characterization from EBSD, light and scanning electron microscopy to specify the ground truth required for supervised learning. The DL model shows good and robust segmentation results. While the intersection over union of 70% does not fully reflect the model performance due to the inherent uncertainty in PAG estimation, a mean error of 6.1% in mean grain size derived from the segmentation clearly shows the high quality of the result

Physiologically-Based Pharmacokinetic Models for CYP1A2 Drug-Drug Interaction Prediction: A Modeling Network of Fluvoxamine, Theophylline, Caffeine, Rifampicin, and Midazolam

This study provides whole-body physiologically-based pharmacokinetic models of the strong index cytochrome P450 (CYP)1A2 inhibitor and moderate CYP3A4 inhibitor fluvoxamine and of the sensitive CYP1A2 substrate theophylline. Both models were built and thoroughly evaluated for their application in drug-drug interaction (DDI) prediction in a network of perpetrator and victim drugs, combining them with previously developed models of caffeine (sensitive index CYP1A2 substrate), rifampicin (moderate CYP1A2 inducer), and midazolam (sensitive index CYP3A4 substrate). Simulation of all reported clinical DDI studies for combinations of these five drugs shows that the presented models reliably predict the observed drug concentrations, resulting in seven of eight of the predicted DDI area under the plasma curve (AUC) ratios (AUC during DDI/AUC control) and seven of seven of the predicted DDI peak plasma concentration (Cmax ) ratios (Cmax during DDI/Cmax control) within twofold of the observed values. Therefore, the models are considered qualified for DDI prediction. All models are comprehensively documented and publicly available, as tools to support the drug development and clinical research community