We analyze an 'up-the-gradient' model for the formation of transport channels of the phytohormone auxin, through auxin-mediated polarization of the PIN1 auxin transporter. We show that this model... Show moreWe analyze an 'up-the-gradient' model for the formation of transport channels of the phytohormone auxin, through auxin-mediated polarization of the PIN1 auxin transporter. We show that this model admits a family of travelling wave solutions that is parameterized by the height of the auxin-pulse. We uncover scaling relations for the speed and width of these waves and verify these rigorous results with numerical computations. In addition, we provide explicit expressions for the leading-order wave profiles, which allows the influence of the biological parameters in the problem to be readily identified. Our proofs are based on a generalization of the scaling principle developed by Friesecke and Pego to construct pulse solutions to the classic Fermi-Pasta-Ulam-Tsingou model, which describes a one-dimensional chain of coupled nonlinear springs. Show less
In this thesis we study bistable reaction-diffusion equations on lattice domains. The power of reaction-diffusion equations is that they can successfully model various natural and social phenomena... Show moreIn this thesis we study bistable reaction-diffusion equations on lattice domains. The power of reaction-diffusion equations is that they can successfully model various natural and social phenomena with their intuitive and relatively simple (mathematical) representation. One of the main features of reaction-diffusion equations, both on discrete and continuous domains, is that they admit special solutions, so-called ‘travelling waves’, which we can describe as fixed profiles that move in a particular direction with some speed. Depending on their shape, we can roughly divide waves into three categories: pulses or solitons, periodic pulses (wave trains), and monotone wave fronts that connect two constant states. In this thesis we focus on the latter type of wave and we study their existence, propagation and long term behaviour on two type of discrete domains - infinite trees, and two-dimensional square lattices. Show less
The main topic of this PhD thesis is the Arakelov ray class group of a number field, an algebraic object that contains both the ideal class group structure and the unit group structure. The main... Show moreThe main topic of this PhD thesis is the Arakelov ray class group of a number field, an algebraic object that contains both the ideal class group structure and the unit group structure. The main result consists of the fact that certain specific random walks on the Arakelov ray class group result in a target point that is uniformly distributed on this group, under the assumption of an extended version of the Riemann Hypothesis. Almost all other results of this work are consequences of this fact. Show less
Gomon, D.; Putter, H.; Nelissen, R.G.H.H.; Pas, S.L. van der 2022
Rapidly detecting problems in the quality of care is of utmost importance for the well-being of patients. Without proper inspection schemes, such problems can go undetected for years. Cumulative... Show moreRapidly detecting problems in the quality of care is of utmost importance for the well-being of patients. Without proper inspection schemes, such problems can go undetected for years. Cumulative sum (CUSUM) charts have proven to be useful for quality control, yet available methodology for survival outcomes is limited. The few available continuous time inspection charts usually require the researcher to specify an expected increase in the failure rate in advance, thereby requiring prior knowledge about the problem at hand. Misspecifying parameters can lead to false positive alerts and large detection delays. To solve this problem, we take a more general approach to derive the new Continuous time Generalized Rapid response CUSUM (CGR-CUSUM) chart. We find an expression for the approximate average run length (average time to detection) and illustrate the possible gain in detection speed by using the CGR-CUSUM over other commonly used monitoring schemes on a real-life data set from the Dutch Arthroplasty Register as well as in simulation studies. Besides the inspection of medical procedures, the CGR-CUSUM can also be used for other real-time inspection schemes such as industrial production lines and quality control of services. Show less
This dissertation is a collection of four research articles devoted tothe study of Kummer theory for commutative algebraic groups. In numbertheory, Kummer theory refers to the study of field... Show moreThis dissertation is a collection of four research articles devoted tothe study of Kummer theory for commutative algebraic groups. In numbertheory, Kummer theory refers to the study of field extensions generatedby n-th roots of some base field. Its generalization to commutativealgebraic groups involves fields generated by the division points of afixed algebraic group, such as an elliptic curve or a higher dimensionalabelian variety. Of particular interest in this dissertation is the degreeof such field extensions. In the first two chapter, classical results forelliptic curves are improved by providing explicitly computable bounds anduniform and explicit bounds over the field of rational numbers. In thelast two chapters a general framework for the study of similar problemsis developed. Show less
Skin contraction is an important biophysical process that takes place during and after recovery of deep tissue injury. This process is mainly caused by fibroblasts (skin cells) and myofibroblasts ... Show moreSkin contraction is an important biophysical process that takes place during and after recovery of deep tissue injury. This process is mainly caused by fibroblasts (skin cells) and myofibroblasts (differentiated fibroblasts which exert larger pulling forces and produce larger amounts of collagen) that both exert pulling forces on the surrounding extracellular matrix (ECM). Modelling is done in multiple scales: agent-based modelling on the microscale and continuum-based modelling on the macroscale. In this manuscript we present some results from our study of the connection between these scales. For the one-dimensional case, we managed to rigorously establish the link between the two modelling approaches for both closed-form solutions and finite-element approximations. For the multi-dimensional case, we computationally evidence the connection between the agent-based and continuum-based modelling approaches. Show less
Deep dermal wounds induce skin contraction as a result of the traction forcing exerted by (myo)fibroblasts on their immediate environment. These (myo)fibroblasts are skin cells that are responsible... Show moreDeep dermal wounds induce skin contraction as a result of the traction forcing exerted by (myo)fibroblasts on their immediate environment. These (myo)fibroblasts are skin cells that are responsible for the regeneration of collagen that is necessary for the integrity of skin We consider several mathematical issues regarding models that simulate traction forces exerted by (myo)fibroblasts. Since the size of cells (e.g. (myo)fibroblasts) is much smaller than the size of the domain of computation, one often considers point forces, modelled by Dirac Delta distributions on boundary segments of cells to simulate the traction forces exerted by the skin cells. In the current paper, we treat the forces that are directed normal to the cell boundary and toward the cell centre. Since it can be shown that there exists no smooth solution, at least not in H1 for solutions to the governing momentum balance equation, we analyse the convergence and quality of approximation. Furthermore, the expected finite element problems that we get necessitate to scrutinize alternative model formulations, such as the use of smoothed Dirac Delta distributions, or the so-called smoothed particle approach as well as the so-called 'hole' approach where cellular forces are modelled through the use of (natural) boundary conditions. In this paper, we investigate and attempt to quantify the conditions for consistency between the various approaches. This has resulted into error analyses in the L2-norm of the numerical solution based on Galerkin principles that entail Lagrangian basis functions. The paper also addresses well-posedness in terms of existence and uniqueness. The current analysis has been performed for the linear steady-state (hence neglecting inertia and damping) momentum equations under the assumption of Hooke's law. (C) 2022 The Author(s). Published by Elsevier B.V. on behalf of International Association for Mathematics and Computers in Simulation (IMACS). Show less
Mirven, P.B. van; Dirven, L.; Fiocco, M.; Vos, M.J.; Kouwenhoven, M.C.M.; Bent, M.J. van den; ... ; Koekkoek, J.A.F. 2022
We describe a theory of logarithmic Chow rings and tautological subrings for logarithmically smooth algebraic stacks, via a generalisation of the notion of piecewise-polynomial functions. Using... Show moreWe describe a theory of logarithmic Chow rings and tautological subrings for logarithmically smooth algebraic stacks, via a generalisation of the notion of piecewise-polynomial functions. Using this machinery we prove that the double-double ramification cycle lies in the tautological subring of the (classical) Chow ring of the moduli space of curves and that the logarithmic double ramification cycle is divisorial (as conjectured by Molcho, Pandharipande, and Schmitt). Show less
We study statistical aspects of the case of the British nurse Ben Geen, convicted of 2 counts of murder and 15 of grievous bodily harm following events at Horton General Hospital (in the town of... Show moreWe study statistical aspects of the case of the British nurse Ben Geen, convicted of 2 counts of murder and 15 of grievous bodily harm following events at Horton General Hospital (in the town of Banbury, Oxfordshire, UK) during December 2013-February 2014. We draw attention to parallels with the cases of nurses Lucia de Berk (the Netherlands) and Daniela Poggiali (Italy), in both of which an initial conviction for multiple murders of patients was overturned after the reopening of the case. We pay most attention to the investigative processes by which data, and not just statistical data, is generated; namely, the identification of past cases in which the nurse under suspicion might have been involved. We argue that the investigation and prosecution of such cases are vulnerable to many cognitive biases and errors of reasoning about uncertainty, exacerbated by the fact that fact-finders have to determine not only whether a particular person was guilty of certain crimes, but whether any crimes were committed by anybody at all. The paper includes some new statistical findings on the Ben Geen case and suggests further avenues for investigation. The experiences recounted here have contributed to the writing of the handbook Healthcare Serial Killer or Coincidence? Statistical Issues in Investigation of Suspected Medical Misconduct, Royal Statistical Society, London, 2022. Show less
Manuel Proenca, H.; Grünwald, P.D.; Bäck, T.H.W.; Leeuwen, M. van 2022
We introduce the problem of robust subgroup discovery, i.e., finding a set of interpretable descriptions of subsets that 1) stand out with respect to one or more target attributes, 2) are... Show moreWe introduce the problem of robust subgroup discovery, i.e., finding a set of interpretable descriptions of subsets that 1) stand out with respect to one or more target attributes, 2) are statistically robust, and 3) non-redundant. Many attempts have been made to mine either locally robust subgroups or to tackle the pattern explosion, but we are the first to address both challenges at the same time from a global modelling perspective. First, we formulate the broad model class of subgroup lists, i.e., ordered sets of subgroups, for univariate and multivariate targets that can consist of nominal or numeric variables, including traditional top-1 subgroup discovery in its definition. This novel model class allows us to formalise the problem of optimal robust subgroup discovery using the Minimum Description Length (MDL) principle, where we resort to optimal Normalised Maximum Likelihood and Bayesian encodings for nominal and numeric targets, respectively. Second, finding optimal subgroup lists is NP-hard. Therefore, we propose SSD++, a greedy heuristic that finds good subgroup lists and guarantees that the most significant subgroup found according to the MDL criterion is added in each iteration. In fact, the greedy gain is shown to be equivalent to a Bayesian one-sample proportion, multinomial, or t-test between the subgroup and dataset marginal target distributions plus a multiple hypothesis testing penalty. Furthermore, we empirically show on 54 datasets that SSD++ outperforms previous subgroup discovery methods in terms of quality, generalisation on unseen data, and subgroup list size. Show less
Erinma, O.; Rodrigues Dos Santos Russo, P.M.; Smeets, I. 2022
The Future of SciComm 2.0 conference was a one-day event in Brussels on April 26th 2022. Focusing on the future of European science communication, sixty participants from twelve countries with... Show moreThe Future of SciComm 2.0 conference was a one-day event in Brussels on April 26th 2022. Focusing on the future of European science communication, sixty participants from twelve countries with different expertise discussed the current challenges and possible solutions for the field. Key themes centred around disinformation, communicating global challenges, evidence-based practices and institutional structures woven through the plenary opening, afternoon workshops and the closing public panel discussion. The conclusion is a need for an European science communication ecosystem that is transdisciplinary, connected and cooperative in practice, weaving between policy, research and industry. Finally, citizen science and open science could be included as scholarly praxes to facilitate societal interconnectivity. Show less
Schaik, J. van; Burghard, M.; Lequin, M.H.; Maren, E.A. van; Dijk, A.M. van; Takken, T.; ... ; Santen, H.M. van 2022
Objective: Children with suprasellar brain damage are at risk of hypothalamic dysfunction (HD). HD may lead to decreased resting energy expenditure (REE). Decreased REE, however, is not present in... Show moreObjective: Children with suprasellar brain damage are at risk of hypothalamic dysfunction (HD). HD may lead to decreased resting energy expenditure (REE). Decreased REE, however, is not present in all children with HD. Our aim was to assess which children suspect for HD have low REE, and its association with clinical severity of HD or radiological hypothalamic damage.Patients and methods: A retrospective cohort study was performed. Measured REE (mREE) of children at risk of HD was compared to predicted REE (pREE). Low REE was defined as mREE <90% of predicted. The mREE/pREE quotient was associated to a clinical score for HD symptoms and to radiological hypothalamic damage.Results: In total, 67 children at risk of HD (96% brain tumor diagnosis) with a mean BMI SDS of +2.3 +/- 1.0 were included. Of these, 45 (67.2%) had low mREE. Children with severe HD had a significant lower mean mREE/pREE quotient compared to children with no, mild, or moderate HD. Mean mREE/pREE quotient of children with posterior hypothalamic damage was significantly lower compared to children with no or anterior damage. Tumor progression or tumor recurrence, severe clinical HD, and panhypopituitarism with diabetes insipidus (DI) were significant risk factors for reduced REE.Conclusion: REE may be lowered in children with hypothalamic damage and is associated to the degree of clinical HD. REE is, however, not lowered in all children suspect for HD. For children with mild or moderate clinical HD symptoms, REE measurements may be useful to distinguish between those who may benefit from obesity treatment that increases REE from those who would be better helped using other obesity interventions. Show less
Bosch, C.H. van den; Spijkerman, J.; Wijnen, M.H.W.A.; Kremer Hovinga, I.C.L.; Meyer-Wentrup, F.A.G.; Steeg, F.W. van der; ... ; Beishuizen, A. 2022
Purpose The purpose of this study was to determine the most optimal central venous catheter (CVC) for pediatric patients with Hodgkin lymphoma (HL) in terms of complications.Methods A retrospective... Show morePurpose The purpose of this study was to determine the most optimal central venous catheter (CVC) for pediatric patients with Hodgkin lymphoma (HL) in terms of complications.Methods A retrospective study including patients diagnosed with HL from 2015 to 2021 at the Princess Maxima Center was performed. Patients were followed from CVC insertion until removal or 06-2021, whichever came first. The primary outcome was the CVC-related complication incidence rate (IR) per 1000 CVC-days. Furthermore, the incidence rate ratio (IRR) was calculated by comparing complication IRs between peripherally inserted central catheters (PICC) and totally implantable venous access ports (TIVAP). Additionally, risk factors for central venous thrombosis (CVT) were identified.Results A total of 98 patients were included. The most frequently observed complications were local irritation/infections (18%; IR 0.93), malfunctions (15%; IR 0.88), and CVC-related CVTs (10%; IR 0.52). Single lumen PICCs were associated with a higher risk of complications (49% vs. 26%; IRR 5.12, CI95% 2.76-9.50), severe complications (19% vs. 7%; IRR 11.96, CI95% 2.68-53.42), and early removal (18% vs. 7%; IRR 9.96, CI95% 2.18-45.47). A single lumen PICC was identified as a risk factor for CVC-related CVT when compared to TIVAPs (12% vs. 7%, IRR 6.98, CI95% 1.45-33.57).Conclusion The insertion of a TIVAP rather than a PICC should be recommended for pediatric patients with HL, especially in the presence of CVT-related risk factors. Future trials should evaluate the efficacy and safety of direct oral anticoagulants for the primary prevention of CVT in pediatric patients with a PICC and other CVT-related risk factors. Show less
Objective: To examine patient activation from the start of stroke rehabilitation and its course up until the 6-month follow-up. Design: Inception cohort study with a follow-up of 6 months. Setting:... Show moreObjective: To examine patient activation from the start of stroke rehabilitation and its course up until the 6-month follow-up. Design: Inception cohort study with a follow-up of 6 months. Setting: Multidisciplinary rehabilitation facility. Participants: A total of 478 patients (N=478) with stroke who received inpatient or outpatient rehabilitation, with a median age of 63.0 years (interquartile range, 56.0-70.0 years) with 308 (64.2%) being men. The study was completed by 439 patients (91.8%). Interventions: Not applicable. Main Outcome Measures: Patient activation was measured with the Patient Activation Measure (PAM) (score 0-100, 4 levels, where a higher score and level denotes more patient activation). The PAM was measured at the start of the rehabilitation (baseline) and 3 and 6 months thereafter and was analyzed using the multivariate mixed model analysis. Results: At baseline, the mean PAM score was 60.2 +/- 14.3, with the number of patients in PAM levels 1, 2, 3, and 4 being 76 (17.8%), 85 (19.9%), 177 (41.4%), and 90 (21.0%), respectively. The multivariate mixed-model analysis demonstrated that the PAM score increased over time (baseline 60.2 +/- 14.3 vs 3 months 60.7 +/- 14.8 vs 6 months 61.9 +/- 18.0; P.007). Between baseline and 6 months, 122 patients (41.4%) remained at the same PAM level, 105 patients (35.6%) increased, and 68 patients (23.1%) decreased. At all time points, > 35% of patients were in level 1 or 2. Conclusions: PAM scores increased slightly over time from the start of rehabilitation up to the 6-month follow-up. However, more than one-third of patients remained at low levels (ie, level 1 and 2) of patient activation, which indicates that specific interventions during rehabilitation to increase patient activation might be of value. Archives of Physical Medicine and Rehabilitation 2022;103:1360-7 (c) 2022 by the American Congress of Rehabilitation Medicine. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
Bosch, C.H. van den; Spijkerman, J.; Wijnen, M.H.W.A.; Kremer Hovinga, I.C.L.; Meyer-Wentrup, F.A.G.; Steeg, A.F.W.; ... ; Beishuizen, A. 2022
Background Developing predictive models for precision psychiatry is challenging because of unavailability of the necessary data: extracting useful information from existing electronic health record... Show moreBackground Developing predictive models for precision psychiatry is challenging because of unavailability of the necessary data: extracting useful information from existing electronic health record (EHR) data is not straightforward, and available clinical trial datasets are often not representative for heterogeneous patient groups. The aim of this study was constructing a natural language processing (NLP) pipeline that extracts variables for building predictive models from EHRs. We specifically tailor the pipeline for extracting information on outcomes of psychiatry treatment trajectories, applicable throughout the entire spectrum of mental health disorders ("transdiagnostic"). Methods A qualitative study into beliefs of clinical staff on measuring treatment outcomes was conducted to construct a candidate list of variables to extract from the EHR. To investigate if the proposed variables are suitable for measuring treatment effects, resulting themes were compared to transdiagnostic outcome measures currently used in psychiatry research and compared to the HDRS (as a gold standard) through systematic review, resulting in an ideal set of variables. To extract these from EHR data, a semi-rule based NLP pipeline was constructed and tailored to the candidate variables using Prodigy. Classification accuracy and F1-scores were calculated and pipeline output was compared to HDRS scores using clinical notes from patients admitted in 2019 and 2020. Results Analysis of 34 questionnaires answered by clinical staff resulted in four themes defining treatment outcomes: symptom reduction, general well-being, social functioning and personalization. Systematic review revealed 242 different transdiagnostic outcome measures, with the 36-item Short-Form Survey for quality of life (SF36) being used most consistently, showing substantial overlap with the themes from the qualitative study. Comparing SF36 to HDRS scores in 26 studies revealed moderate to good correlations (0.62-0.79) and good positive predictive values (0.75-0.88). The NLP pipeline developed with notes from 22,170 patients reached an accuracy of 95 to 99 percent (F1 scores: 0.38 - 0.86) on detecting these themes, evaluated on data from 361 patients. Conclusions The NLP pipeline developed in this study extracts outcome measures from the EHR that cater specifically to the needs of clinical staff and align with outcome measures used to detect treatment effects in clinical trials. Show less
Misleading graphs are a source of misinformation that worry many experts. Especially people with a low graph literacy are thought to be persuaded by graphs that misrepresent the underlying data.... Show moreMisleading graphs are a source of misinformation that worry many experts. Especially people with a low graph literacy are thought to be persuaded by graphs that misrepresent the underlying data. But we know little about how people interpret misleading graphs and how these graphs influence their opinions. In this study we focus on the effect of truncating the y-axis for a line chart which exaggerates an upgoing trend. In a randomized controlled trial, we showed participants either a normal or a misleading chart, and we did so in two different contexts. After they had seen the graphs, we asked participants their opinion on the trend and to give an estimation of the increase. Finally we measured their graph literacy. Our results show that context is the only significant factor in opinion-forming; the misleading graph and graph literacy had no effect. None of these factors had a significant impact on estimations for the increase. These results show that people might be less susceptible to misleading graphs than we thought and that context has more impact than a misleading y-axis. Show less