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Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone

Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.

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Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone

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On utilizing player models to predict behavior in crowdsourcing tasks

Player Modeling is a research field that studies player characteristics by analyzing in-game behavior. We aim to develop independent models, which are transferable and useful beyond a game’s context. We shall demonstrate the feasibility of this approach by applying player models to crowdsourcing to predict workers’ task completion effectiveness. Specifically, we model a user’s Need for Cognition based on in-game behavior, and based on that try to assign appropriate tasks to workers.

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Kinetic modelling

Three empirical models were used to fit the formation of acrylamide in crisps of three different cold-sweetened potato genotypes, fried under the same experimental conditions. Statistical methods were used to compare the performance of the models, with the "Logistic-Exponential" model performing the best. The obtained model parameters for the formation of acrylamide showed improvement in precision compared to an earlier study, the precision of the parameter estimates for the degradation of acrylamide was still problematic. Nevertheless, the predictive capacity of the "Logistic-Exponential" model was tested, as this model showed a strong correlation between parameter a and the reducing sugar content of the raw potato. The predictions from this model for the formation of acrylamide in potato crisps were close to earlier reported experimental values. Therefore, the use of the "Logistic-Exponential" model as a tool to predict acrylamide in potato crisps seems promising and should be developed further.

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Personen 4

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Sam Aerts

Associate lector

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Eric Blaauw

Professor

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Gerard Schepers

Professor

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Michiel Punt

Onderzoeker

Projecten 60

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‘Raising the curve’: impuls aan de instroom van Praktische predictie

Middels een RAAK-impuls aanvraag wordt beoogd de vertraging van het RAAK-mkb project Praktische Predictie t.g.v. corona in te halen. In het project Praktische Predictie wordt een prototype app ontwikkeld waarmee fysiotherapeuten in een vroeg stadium het chronisch worden van lage rugpijn kunnen voorspellen. Om chronische rugpijn te voorkomen is het belangrijk om in een vroeg stadium de kans hierop in te schatten door psychosociale en mogelijk andere risicofactoren op chronische pijnklachten te herkennen en hierop te interveniëren. Fysiotherapeuten zijn met deze vraag naar het lectoraat Werkzame factoren in Fysiotherapie en Paramedisch Handelen van de Hogeschool van Arnhem en Nijmegen gegaan en dit heeft aanleiding gegeven een onderzoek op te zetten waarin een dergelijke methodiek ontwikkeld wordt. De voorgestelde methodiek betreft een Clinical Decision Support Tool waarmee een geïndividualiseerde kans op chronische rugpijn kan worden bepaald gekoppeld aan een behandeladvies conform de lage rugpijn richtlijn. Hiervoor is eerst geïnventariseerd welke methoden fysiotherapeuten reeds gebruiken en welke in de literatuur worden genoemd. Op basis hiervan is een keuze gemaakt ten aanzien van data die digitaal verzameld worden in minimaal 16 fysiotherapiepraktijken waarbij patiënten gedurende 12 weken gevolgd worden. Met de verzamelde data worden met machine learning algoritmes ontwikkeld voor het berekenen van de kans op chroniciteit. De algoritmes worden ingebouwd in de Clinical Decision Support Tool: een gebruiksvriendelijke prototype app. Bij het ontwikkelen van de tool worden eindgebruikers (fysiotherapeuten en patiënten) intensief betrokken. Op deze manier wordt gegarandeerd dat de tool aansluit bij de wensen en behoeften van de doelgroep. De tool berekent de kans op chroniciteit en geeft een behandeladvies. Daarnaast kan de tool gebruikt worden om patiënten te informeren en te betrekken bij de besluitvorming. Vanwege de coronacrisis is er een aanzienlijke vertraging in de patiënten-instroom (doel n= 300) ontstaan die we met ondersteuning van een RAAK-impuls subsidie willen inlopen.

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A predictive model of symptoms for pain in independently living frail elderly in palliative care

Observationele studie

Afgerond

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A tool for co-designing healthy environments for older citizens in Emerging Smart Neighborhoods

Due to societal developments, like the introduction of the ‘civil society’, policy stimulating longer living at home and the separation of housing and care, the housing situation of older citizens is a relevant and pressing issue for housing-, governance- and care organizations. The current situation of living with care already benefits from technological advancement. The wide application of technology especially in care homes brings the emergence of a new source of information that becomes invaluable in order to understand how the smart urban environment affects the health of older people. The goal of this proposal is to develop an approach for designing smart neighborhoods, in order to assist and engage older adults living there. This approach will be applied to a neighborhood in Aalst-Waalre which will be developed into a living lab. The research will involve: (1) Insight into social-spatial factors underlying a smart neighborhood; (2) Identifying governance and organizational context; (3) Identifying needs and preferences of the (future) inhabitant; (4) Matching needs & preferences to potential socio-techno-spatial solutions. A mixed methods approach fusing quantitative and qualitative methods towards understanding the impacts of smart environment will be investigated. After 12 months, employing several concepts of urban computing, such as pattern recognition and predictive modelling , using the focus groups from the different organizations as well as primary end-users, and exploring how physiological data can be embedded in data-driven strategies for the enhancement of active ageing in this neighborhood will result in design solutions and strategies for a more care-friendly neighborhood.

Afgerond

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Assessing functional vision using innovative eye tracking solutions to improve participation of people with visual, and severe or profound intellectual and multiple disabilities.

Everyone has the right to participate in society to the best of their ability. This right also applies to people with a visual impairment, in combination with a severe or profound intellectual and possibly motor disability (VISPIMD). However, due to their limitations, for their participation these people are often highly dependent on those around them, such as family members andhealthcare professionals. They determine how people with VISPIMD participate and to what extent. To optimize this support, they must have a good understanding of what people with disabilities can still do with their remaining vision.It is currently difficult to gain insight into the visual abilities of people with disabilities, especially those with VISPIMD. As a professional said, "Everything we can think of or develop to assess the functional vision of this vulnerable group will help improve our understanding and thus our ability to support them. Now, we are more or less guessing about what they can see.Moreover, what little we know about their vision is hard to communicate to other professionals”. Therefore, there is a need for methods that can provide insight into the functional vision of people with VISPIMD, in order to predict their options in daily life situations. This is crucial knowledge to ensure that these people can participate in society to their fullest extent.What makes it so difficult to get this insight at the moment? Visual impairments can be caused by a range of eye or brain disorders and can manifest in various ways. While we understand fairly well how low vision affects a person's abilities on relatively simple visual tasks, it is much more difficult to predict this in more complex dynamic everyday situations such asfinding your way or moving around during daily activities. This is because, among other things, conventional ophthalmic tests provide little information about what people can do with their remaining vision in everyday life (i.e., their functional vision).An additional problem in assessing vision in people with intellectual disabilities is that many conventional tests are difficult to perform or are too fatiguing, resulting in either no or the wrong information. In addition to their visual impairment, there is also a very serious intellectual disability (possibly combined with a motor impairment), which makes it even more complex to assesstheir functional vision. Due to the interplay between their visual, intellectual, and motor disabilities, it is almost impossible to determine whether persons are unable to perform an activity because they do not see it, do not notice it, do not understand it, cannot communicate about it, or are not able to move their head towards the stimulus due to motor disabilities.Although an expert professional can make a reasonable estimate of the functional possibilities through long-term and careful observation, the time and correct measurement data are usually lacking to find out the required information. So far, it is insufficiently clear what people with VZEVMB provoke to see and what they see exactly.Our goal with this project is to improve the understanding of the visual capabilities of people with VISPIMD. This then makes it possible to also improve the support for participation of the target group. We want to achieve this goal by developing and, in pilot form, testing a new combination of measurement and analysis methods - primarily based on eye movement registration -to determine the functional vision of people with VISPIMD. Our goal is to systematically determine what someone is responding to (“what”), where it may be (“where”), and how much time that response will take (“when”). When developing methods, we take the possibilities and preferences of the person in question as a starting point in relation to the technological possibilities.Because existing technological methods were originally developed for a different purpose, this partly requires adaptation to the possibilities of the target group.The concrete end product of our pilot will be a manual with an overview of available technological methods (as well as the methods themselves) for assessing functional vision, linked to the specific characteristics of the target group in the cognitive, motor area: 'Given that a client has this (estimated) combination of limitations (cognitive, motor and attention, time in whichsomeone can concentrate), the order of assessments is as follows:' followed by a description of the methods. We will also report on our findings in a workshop for professionals, a Dutch-language article and at least two scientific articles. This project is executed in the line: “I am seen; with all my strengths and limitations”. During the project, we closely collaborate with relevant stakeholders, i.e. the professionals with specific expertise working with the target group, family members of the persons with VISPIMD, and persons experiencing a visual impairment (‘experience experts’).

Afgerond

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Automated Reasoning on Human Performance Data

The focus of the research is 'Automated Analysis of Human Performance Data'. The three interconnected main components are (i)Human Performance (ii) Monitoring Human Performance and (iii) Automated Data Analysis . Human Performance is both the process and result of the person interacting with context to engage in tasks, whereas the performance range is determined by the interaction between the person and the context. Cheap and reliable wearable sensors allow for gathering large amounts of data, which is very useful for understanding, and possibly predicting, the performance of the user. Given the amount of data generated by such sensors, manual analysis becomes infeasible; tools should be devised for performing automated analysis looking for patterns, features, and anomalies. Such tools can help transform wearable sensors into reliable high resolution devices and help experts analyse wearable sensor data in the context of human performance, and use it for diagnosis and intervention purposes. Shyr and Spisic describe Automated Data Analysis as follows: Automated data analysis provides a systematic process of inspecting, cleaning, transforming, and modelling data with the goal of discovering useful information, suggesting conclusions and supporting decision making for further analysis. Their philosophy is to do the tedious part of the work automatically, and allow experts to focus on performing their research and applying their domain knowledge. However, automated data analysis means that the system has to teach itself to interpret interim results and do iterations. Knuth stated: Science is knowledge which we understand so well that we can teach it to a computer; and if we don't fully understand something, it is an art to deal with it.[Knuth, 1974]. The knowledge on Human Performance and its Monitoring is to be 'taught' to the system. To be able to construct automated analysis systems, an overview of the essential processes and components of these systems is needed.Knuth Since the notion of an algorithm or a computer program provides us with an extremely useful test for the depth of our knowledge about any given subject, the process of going from an art to a science means that we learn how to automate something.

Afgerond

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Certification of production process quality through Artificial Intelligence (CERTIF-AI)

Production processes can be made ‘smarter’ by exploiting the data streams that are generated by the machines that are used in production. In particular these data streams can be mined to build a model of the production process as it was really executed – as opposed to how it was envisioned. This model can subsequently be analyzed and stress-tested to explore possible causes of production prob-lems and to analyze what-if scenarios, without disrupting the production process itself. It has been shown that such models can successfully be used to diagnose possible causes of production problems, including scrap products and machine defects. Ideally, they can even be used to model and analyze production processes that have not been implemented yet, based on data from existing production pro-cesses and techniques from artificial intelligence that can predict how the new process is likely to be-have in practice in terms of data that its machines generate. This is especially important in mass cus-tomization processes, where the process to create each product may be unique, and can only feasibly be tested using model- and data-driven techniques like the one proposed in this project. Against this background, the goal of this project is to develop a method and toolkit for mining, mod-elling and analyzing production processes, using the time series data that is generated by machines, to: (i) analyze the performance of an existing production process; (ii) diagnose causes of production prob-lems; and (iii) certify that a new – not yet implemented – production process leads to high-quality products. The method is developed by researching and combining techniques from the area of Artificial Intelli-gence with techniques from Operations Research. In particular, it uses: process mining to relate time series data to production processes; queueing networks to determine likely paths through the produc-tion processes and detect anomalies that may be the cause of production problems; and generative adversarial networks to generate likely future production scenarios and sample scenarios of production problems for diagnostic purposes. The techniques will be evaluated and adapted in implementations at the partners from industry, using a design science approach. In particular, implementations of the method are made for: explaining production problems; explaining machine defects; and certifying the correct operation of new production processes.

Lopend

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CONNECT: Collective process development for an innovative chemical industry

The SPRONG-collaboration “Collective process development for an innovative chemical industry” (CONNECT) aims to accelerate the chemical industry’s climate/sustainability transition by process development of innovative chemical processes. The CONNECT SPRONG-group integrates the expertise of the research groups “Material Sciences” (Zuyd Hogeschool), “Making Industry Sustainable” (Hogeschool Rotterdam), “Innovative Testing in Life Sciences & Chemistry” and “Circular Water” (both Hogeschool Utrecht) and affiliated knowledge centres (Centres of Expertise CHILL [affiliated to Zuyd] and HRTech, and Utrecht Science Park InnovationLab). The combined CONNECT-expertise generates critical mass to facilitate process development of necessary energy-/material-efficient processes for the 2050 goals of the Knowledge and Innovation Agenda (KIA) Climate and Energy (mission C) using Chemical Key Technologies. CONNECT focuses on process development/chemical engineering. We will collaborate with SPRONG-groups centred on chemistry and other non-SPRONG initiatives. The CONNECT-consortium will generate a Learning Community of the core group (universities of applied science and knowledge centres), companies (high-tech equipment, engineering and chemical end-users), secondary vocational training, universities, sustainability institutes and regional network organizations that will facilitate research, demand articulation and professionalization of students and professionals. In the CONNECT-trajectory, four field labs will be integrated and strengthened with necessary coordination, organisation, expertise and equipment to facilitate chemical innovations to bridge the innovation valley-of-death between feasibility studies and high technology-readiness-level pilot plant infrastructure. The CONNECT-field labs will combine experimental and theoretical approaches to generate high-quality data that can be used for modelling and predict the impact of flow chemical technologies. The CONNECT-trajectory will optimize research quality systems (e.g. PDCA, data management, impact). At the end of the CONNECT-trajectory, the SPRONG-group will have become the process development/chemical engineering SPRONG-group in the Netherlands. We can then meaningfully contribute to further integrate the (inter)national research ecosystem to valorise innovative chemical processes for the KIA Climate and Energy.

Lopend

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Creating Changemakers: A Serious Game for Disaster Preparedness

In recent years, disasters are increasing in numbers, location, intensity and impact; they have become more unpredictable due to climate change, raising questions about disaster preparedness and management. Attempts by government entities at limiting the impact of disasters are insufficient, awareness and action are urgently needed at the citizen level to create awareness, develop capacity, facilitate implementation of management plans and to coordinate local action at times of uncertainty. We need a cultural and behavioral change to create resilient citizens, communities, and environments. To develop and maintain new ways of thinking has to start by anticipating long-term bottom-up resilience and collaborations. We propose to develop a serious game on a physical tabletop that allows individuals and communities to work with a moderator and to simulate disasters and individual and collective action in their locality, to mimic real-world scenarios using game mechanics and to train trainers. Two companies–Stratsims, a company specialized in game development, and Society College, an organization that aims to strengthen society, combine their expertise as changemakers. They work with Professor Carola Hein (TU Delft), who has developed knowledge about questions of disaster and rebuilding worldwide and the conditions for meaningful and long-term disaster preparedness. The partners have already reached out to relevant communities in Amsterdam and the Netherlands, including UNUN, a network of Ukrainians in the Netherlands. Jaap de Goede, an experienced strategy simulation expert, will lead outreach activities in diverse communities to train trainers and moderate workshops. This game will be highly relevant for citizens to help grow awareness and capacity for preparing for and coping with disasters in a bottom-up fashion. The toolkit will be available for download and printing open access, and for purchase. The team will offer training and facilitate workshops working with local communities to initiate bottom-up change in policy making and planning.

Lopend

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CureQ Predict, Delay & Cure polyglutamine(Q) caused neurodegeneration

Huntington’s disease (HD) and various spinocerebellar ataxias (SCA) are autosomal dominantly inherited neurodegenerative disorders caused by a CAG repeat expansion in the disease-related gene1. The impact of HD and SCA on families and individuals is enormous and far reaching, as patients typically display first symptoms during midlife. HD is characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. SCAs are mainly characterized by ataxia but also other symptoms including cognitive deficits, similarly affecting quality of life and leading to disability. These problems worsen as the disease progresses and affected individuals are no longer able to work, drive, or care for themselves. It places an enormous burden on their family and caregivers, and patients will require intensive nursing home care when disease progresses, and lifespan is reduced. Although the clinical and pathological phenotypes are distinct for each CAG repeat expansion disorder, it is thought that similar molecular mechanisms underlie the effect of expanded CAG repeats in different genes. The predicted Age of Onset (AO) for both HD, SCA1 and SCA3 (and 5 other CAG-repeat diseases) is based on the polyQ expansion, but the CAG/polyQ determines the AO only for 50% (see figure below). A large variety on AO is observed, especially for the most common range between 40 and 50 repeats11,12. Large differences in onset, especially in the range 40-50 CAGs not only imply that current individual predictions for AO are imprecise (affecting important life decisions that patients need to make and also hampering assessment of potential onset-delaying intervention) but also do offer optimism that (patient-related) factors exist that can delay the onset of disease.To address both items, we need to generate a better model, based on patient-derived cells that generates parameters that not only mirror the CAG-repeat length dependency of these diseases, but that also better predicts inter-patient variations in disease susceptibility and effectiveness of interventions. Hereto, we will use a staggered project design as explained in 5.1, in which we first will determine which cellular and molecular determinants (referred to as landscapes) in isogenic iPSC models are associated with increased CAG repeat lengths using deep-learning algorithms (DLA) (WP1). Hereto, we will use a well characterized control cell line in which we modify the CAG repeat length in the endogenous ataxin-1, Ataxin-3 and Huntingtin gene from wildtype Q repeats to intermediate to adult onset and juvenile polyQ repeats. We will next expand the model with cells from the 3 (SCA1, SCA3, and HD) existing and new cohorts of early-onset, adult-onset and late-onset/intermediate repeat patients for which, besides accurate AO information, also clinical parameters (MRI scans, liquor markers etc) will be (made) available. This will be used for validation and to fine-tune the molecular landscapes (again using DLA) towards the best prediction of individual patient related clinical markers and AO (WP3). The same models and (most relevant) landscapes will also be used for evaluations of novel mutant protein lowering strategies as will emerge from WP4.This overall development process of landscape prediction is an iterative process that involves (a) data processing (WP5) (b) unsupervised data exploration and dimensionality reduction to find patterns in data and create “labels” for similarity and (c) development of data supervised Deep Learning (DL) models for landscape prediction based on the labels from previous step. Each iteration starts with data that is generated and deployed according to FAIR principles, and the developed deep learning system will be instrumental to connect these WPs. Insights in algorithm sensitivity from the predictive models will form the basis for discussion with field experts on the distinction and phenotypic consequences. While full development of accurate diagnostics might go beyond the timespan of the 5 year project, ideally our final landscapes can be used for new genetic counselling: when somebody is positive for the gene, can we use his/her cells, feed it into the generated cell-based model and better predict the AO and severity? While this will answer questions from clinicians and patient communities, it will also generate new ones, which is why we will study the ethical implications of such improved diagnostics in advance (WP6).

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Producten 2.450

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Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone

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