Metamodel-based importance sampling for the simulation of rare events

In the field of structural reliability, the Monte-Carlo estimator is considered as the reference probability estimator. However, it is still untractable for real engineering cases since it requires a high number of runs of the model. In order to reduce the number of computer experiments, many other approaches known as reliability methods have been proposed. A certain approach consists in replacing the original experiment by a surrogate which is much faster to evaluate. Nevertheless, it is often difficult (or even impossible) to quantify the error made by this substitution. In this paper an alternative approach is developed. It takes advantage of the kriging meta-modeling and importance sampling techniques. The proposed alternative estimator is finally applied to a finite element based structural reliability analysis.Comment: 8 pages, 3 figures, 1 table. Preprint submitted to ICASP11 Mini-symposia entitled "Meta-models/surrogate models for uncertainty propagation, sensitivity and reliability analysis

Metamodel-based importance sampling for structural reliability analysis

Structural reliability methods aim at computing the probability of failure of systems with respect to some prescribed performance functions. In modern engineering such functions usually resort to running an expensive-to-evaluate computational model (e.g. a finite element model). In this respect simulation methods, which may require $10^{3-6}$ runs cannot be used directly. Surrogate models such as quadratic response surfaces, polynomial chaos expansions or kriging (which are built from a limited number of runs of the original model) are then introduced as a substitute of the original model to cope with the computational cost. In practice it is almost impossible to quantify the error made by this substitution though. In this paper we propose to use a kriging surrogate of the performance function as a means to build a quasi-optimal importance sampling density. The probability of failure is eventually obtained as the product of an augmented probability computed by substituting the meta-model for the original performance function and a correction term which ensures that there is no bias in the estimation even if the meta-model is not fully accurate. The approach is applied to analytical and finite element reliability problems and proves efficient up to 100 random variables.Comment: 20 pages, 7 figures, 2 tables. Preprint submitted to Probabilistic Engineering Mechanic

Reliability-based design optimization of shells with uncertain geometry using adaptive Kriging metamodels

Optimal design under uncertainty has gained much attention in the past ten years due to the ever increasing need for manufacturers to build robust systems at the lowest cost. Reliability-based design optimization (RBDO) allows the analyst to minimize some cost function while ensuring some minimal performances cast as admissible failure probabilities for a set of performance functions. In order to address real-world engineering problems in which the performance is assessed through computational models (e.g., finite element models in structural mechanics) metamodeling techniques have been developed in the past decade. This paper introduces adaptive Kriging surrogate models to solve the RBDO problem. The latter is cast in an augmented space that "sums up" the range of the design space and the aleatory uncertainty in the design parameters and the environmental conditions. The surrogate model is used (i) for evaluating robust estimates of the failure probabilities (and for enhancing the computational experimental design by adaptive sampling) in order to achieve the requested accuracy and (ii) for applying a gradient-based optimization algorithm to get optimal values of the design parameters. The approach is applied to the optimal design of ring-stiffened cylindrical shells used in submarine engineering under uncertain geometric imperfections. For this application the performance of the structure is related to buckling which is addressed here by means of a finite element solution based on the asymptotic numerical method

Reliability-based design optimization using kriging surrogates and subset simulation

The aim of the present paper is to develop a strategy for solving reliability-based design optimization (RBDO) problems that remains applicable when the performance models are expensive to evaluate. Starting with the premise that simulation-based approaches are not affordable for such problems, and that the most-probable-failure-point-based approaches do not permit to quantify the error on the estimation of the failure probability, an approach based on both metamodels and advanced simulation techniques is explored. The kriging metamodeling technique is chosen in order to surrogate the performance functions because it allows one to genuinely quantify the surrogate error. The surrogate error onto the limit-state surfaces is propagated to the failure probabilities estimates in order to provide an empirical error measure. This error is then sequentially reduced by means of a population-based adaptive refinement technique until the kriging surrogates are accurate enough for reliability analysis. This original refinement strategy makes it possible to add several observations in the design of experiments at the same time. Reliability and reliability sensitivity analyses are performed by means of the subset simulation technique for the sake of numerical efficiency. The adaptive surrogate-based strategy for reliability estimation is finally involved into a classical gradient-based optimization algorithm in order to solve the RBDO problem. The kriging surrogates are built in a so-called augmented reliability space thus making them reusable from one nested RBDO iteration to the other. The strategy is compared to other approaches available in the literature on three academic examples in the field of structural mechanics.Comment: 20 pages, 6 figures, 5 tables. Preprint submitted to Springer-Verla

Caractérisation indirecte de défauts géométriques de forme liés au process de fabrication d'un élément d'essuie-glace

Les défauts de forme sont inévitables dans la production série de pièces mécaniques. On doit les caractériser pour quantifier leur impact sur la performance du système complet. Pour estimer les défauts locaux d'un balai d'essuie-glace, on utilise une méthode indirecte (établissement expérimental d'une courbe « caractéristique »). On montre comment identifier le défaut à partir de la courbe par un problème inverse. Le modèle de calcul utilisé étant coûteux (EF non linéaire en grands déplacements, contact), on a recours à un méta-modèle par krigeage pour résoudre le problème d'optimisation

Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment

© 2023 The Author(s). ALTEX. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/New approach methodologies (NAMs) based on human biology enable the assessment of adverse biological effects of pharmaceuticals and other chemicals. Currently, however, it is unclear how NAMs should be used during drug development to improve human safety evaluation. A series of 5 workshops with 13 international experts (regulators, preclinical scientists, and NAMs developers) was conducted to identify feasible NAMs and to discuss how to exploit them in specific safety assessment contexts. Participants generated four “maps” of how NAMs can be exploited in the safety assessment of the liver, respiratory, cardiovascular, and central nervous systems. Each map shows relevant endpoints measured and tools used (e.g., cells, assays, platforms), and highlights gaps where further development and validation of NAMs remains necessary. Each map addresses the fundamental scientific requirements for the safety assessment of that organ system, providing users with guidance on the selection of appropriate NAMs. In addition to generating the maps, participants offered suggestions for encouraging greater NAM adoption within drug development and their inclusion in regulatory guidelines. A specific recommendation was that pharmaceutical companies should be more transparent about how they use NAMs in-house. As well as giving guidance for the four organ systems, the maps provide a template that could be used for additional organ safety testing contexts. Moreover, their conversion to an interactive format would enable users to drill down to the detail necessary to answer specific scientific and regulatory questions.Peer reviewe

Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment

New approach methodologies (NAMs) based on human biology enabletheassessment of adverse biological effects of pharmaceuticals and other chemicals. Currently,however, it is unclear how NAMsshould be usedduring drug development to improve human safety evaluation. A series of 5 workshops with 13 international experts (regulators, preclinical scientists and NAMs developers) were conducted to identify feasible NAMsand to discuss how to exploit them in specific safety assessmentcontexts. Participants generated four‘maps’of how NAMs can be exploited in the safety assessment ofthe liver, respiratory, cardiovascular,and central nervous systems. Each map showsrelevant end points measured, tools used (e.g.,cells, assays, platforms), and highlights gaps where furtherdevelopment and validation of NAMs remainsnecessary. Each map addresses the fundamental scientific requirements for the safety assessment of that organ system, providing users with guidance on the selection of appropriate NAMs. In addition to generating the maps, participants offered suggestions for encouraging greater NAM adoption within drug development and their inclusion in regulatory guidelines. A specific recommendation was that pharmaceutical companies should be more transparent about how they use NAMs in-house. As well as giving guidance for the fourorgan systems, the maps providea template that could be used for additional organ safety testing contexts.Moreover, their conversion to an interactive format would enable users to drill down to the detail necessary to answer specific scientific and regulatory questions. 1IntroductionExtensive nonclinical safety studies are undertaken on new pharmaceuticals prior to and alongside clinical trials. Their purpose is to identify and understand the toxic effects of thecompoundin order to determine whether its anticipated benefit versusrisk profile justifies clinical evaluation and, if so, to inform the design and monitoring of clinical studies. The nonclinical safety studies are mandated by regulatory guidelines and include a variety of safety pharmacologyand toxicology investigations.Safety pharmacology studies aimto determinewhether pharmaceuticalscause on-or off-target effects on biological processes which can affect the function of critical organ systems (e.g.,cardiovascular, respiratory, gastrointestinal,and central nervous systems)and to assess potency, which is needed to assess safety margins versushuman clinical drug exposure. Safety pharmacology studiesalso help informthe selectionof follow-on investigations that can aid human risk assessmentand may provide insight into mechanismswhich underlie any effectsthat arise in humans.Multiple leading pharmaceutical companies (e.g.,AstraZeneca, GlaxoSmithKline, Novartis,and Pfizer) have outlined the advantages provided by in vitrosafety pharmacological profiling, including early identification of off-target interactionsandthe prediction ofclinical side effects that may be missed in animalstudies, and have highlighted that these studies enable much more cost-effective and rapid profiling of large numbers of compounds than animal procedures (Bowes et al., 2012).Toxicology studies evaluate systemic organ toxicities, behavioraleffects, reproductive and developmental toxicology, genetic toxicology,eye irritancy and dermal sensitization. They include single and repeat dose studies in rodent and non-rodentanimal species, which identify target organs, assessseverity andreversibility,and define dose-response and no observed adverse effect levels. These are critical parameters which are essential for regulatory decision-makingon whether the compound can be progressed into clinical trials and if so, estimation ofa suitable starting dose,maximum dose, dose escalation regime,andany non-standard clinical safety monitoringthat may be needed.Toxicity observedinnonclinical animal safety studies is an important cause of the high attrition rate of candidate drugs prior to clinicaltrials that occurs inmultiple pharmaceutical companies(Cook et al., 2014).However, many drugs cause clinically serious adverseeffects in humans which are not detectedin animals(Bailey et al., 2015). For example, human drug induced liver injury(DILI),which is not detected in animal safety studies,is animportant cause of attrition late in clinical development, failed licensing and/or of restrictive drug labelling(Watkins, 2011). Attrition due to toxicity observed in animals and/or in humans isanimportant cause of the high failure rate of clinical drug development(Cook et al., 2014; Watkins, 2011; Thomas et al., 2021).New approach methodologies (NAMs)includemethods which predict and evaluate biological processes by which pharmaceuticals may elicit desirable pharmacological effects and/or may cause undesirable toxicity. Many different types of NAMs have been described. Theseinclude simple in vitrocell-based tests, more complex organotypic or microphysiologicalsystems (MPS)/organ-on-a-chipdevices,and whole human tissuesmaintained ex vivo. Interpretation ofthe invivorelevance of the data providedby these methods is complementedbycomputational toolswhichsimulate and predict in vivodrug disposition and kinetics, in particular physiologically based pharmacokinetic (PBPK) models. Accurate in vitroto in vivoextrapolation isfurther aided by human low-dose testing and microdosing studies (phase 0 testing), which provide precise data on systemic human drug exposure and kineticsin vivo

A decade of inequality in maternity care: antenatal care, professional attendance at delivery, and caesarean section in Bangladesh (1991–2004)

<p>Abstract</p> <p>Background</p> <p>Bangladesh is committed to the fifth Millennium Development Goal (MDG-5) target of reducing its maternal mortality ratio by three-quarters between 1990 and 2015. Since the early 1990s, Bangladesh has followed a strategy of improving access to facilities equipped and staffed to provide emergency obstetric care (EmOC).</p> <p>Methods</p> <p>We used data from four Demographic and Health Surveys conducted between 1993 and 2004 to examine trends in the proportions of live births preceded by antenatal consultation, attended by a health professional, and delivered by caesarean section, according to key socio-demographic characteristics.</p> <p>Results</p> <p>Utilization of antenatal care increased substantially, from 24% in 1991 to 60% in 2004. Despite a relatively greater increase in rural than urban areas, utilization remained much lower among the poorest rural women without formal education (18%) compared with the richest urban women with secondary or higher education (99%). Professional attendance at delivery increased by 50% (from 9% to 14%, more rapidly in rural than urban areas), and caesarean sections trebled (from 2% to 6%), but these indicators remained low even by developing country standards. Within these trends there were huge inequalities; 86% of live births among the richest urban women with secondary or higher education were attended by a health professional, and 35% were delivered by caesarean section, compared with 2% and 0.1% respectively of live births among the poorest rural women without formal education. The trend in professional attendance was entirely confounded by socioeconomic and demographic changes, but education of the woman and her husband remained important determinants of utilization of obstetric services.</p> <p>Conclusion</p> <p>Despite commendable progress in improving uptake of antenatal care, and in equipping health facilities to provide emergency obstetric care, the very low utilization of these facilities, especially by poor women, is a major impediment to meeting MDG-5 in Bangladesh.</p