Search

Your search keyword '"Vanderschueren P"' showing total 151 results
Start Over Author "Vanderschueren P" Search Limiters Available in Library Collection
151 results on '"Vanderschueren P"'

1. Sources of Gain: Decomposing Performance in Conditional Average Dose Response Estimation

Author

Bockel-Rickermann, Christopher, Vanderschueren, Toon, Verdonck, Tim, and Verbeke, Wouter

Subjects
Computer Science - Machine Learning, 62D20
Abstract

Estimating conditional average dose responses (CADR) is an important but challenging problem. Estimators must correctly model the potentially complex relationships between covariates, interventions, doses, and outcomes. In recent years, the machine learning community has shown great interest in developing tailored CADR estimators that target specific challenges. Their performance is typically evaluated against other methods on (semi-) synthetic benchmark datasets. Our paper analyses this practice and shows that using popular benchmark datasets without further analysis is insufficient to judge model performance. Established benchmarks entail multiple challenges, whose impacts must be disentangled. Therefore, we propose a novel decomposition scheme that allows the evaluation of the impact of five distinct components contributing to CADR estimator performance. We apply this scheme to eight popular CADR estimators on four widely-used benchmark datasets, running nearly 1,500 individual experiments. Our results reveal that most established benchmarks are challenging for reasons different from their creators' claims. Notably, confounding, the key challenge tackled by most estimators, is not an issue in any of the considered datasets. We discuss the major implications of our findings and present directions for future research., Comment: 25 pages, 9 figures

Published
2024

2. Network Analytics for Anti-Money Laundering -- A Systematic Literature Review and Experimental Evaluation

Author

Deprez, Bruno, Vanderschueren, Toon, Baesens, Bart, Verdonck, Tim, and Verbeke, Wouter

Subjects
Computer Science - Social and Information Networks, Computer Science - Machine Learning
Abstract

Money laundering presents a pervasive challenge, burdening society by financing illegal activities. To more effectively combat and detect money laundering, the use of network information is increasingly being explored, exploiting that money laundering necessarily involves interconnected parties. This has lead to a surge in literature on network analytics (NA) for anti-money laundering (AML). The literature, however, is fragmented and a comprehensive overview of existing work is missing. This results in limited understanding of the methods that may be applied and their comparative detection power. Therefore, this paper presents an extensive and systematic review of the literature. We identify and analyse 97 papers in the Web of Science and Scopus databases, resulting in a taxonomy of approaches following the fraud analytics framework of Bockel-Rickermann et al.. Moreover, this paper presents a comprehensive experimental framework to evaluate and compare the performance of prominent NA methods in a uniform setup. The framework is applied on the publicly available Elliptic data set and implements manual feature engineering, random walk-based methods, and deep learning GNNs. We conclude from the results that network analytics increases the predictive power of the AML model with graph neural networks giving the best results. An open source implementation of the experimental framework is provided to facilitate researchers and practitioners to extend upon these results and experiment on proprietary data. As such, we aim to promote a standardised approach towards the analysis and evaluation of network analytics for AML.

Published
2024

3. Metalearners for Ranking Treatment Effects

Author

Vanderschueren, Toon, Verbeke, Wouter, Moraes, Felipe, and Proença, Hugo Manuel

Subjects
Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

Efficiently allocating treatments with a budget constraint constitutes an important challenge across various domains. In marketing, for example, the use of promotions to target potential customers and boost conversions is limited by the available budget. While much research focuses on estimating causal effects, there is relatively limited work on learning to allocate treatments while considering the operational context. Existing methods for uplift modeling or causal inference primarily estimate treatment effects, without considering how this relates to a profit maximizing allocation policy that respects budget constraints. The potential downside of using these methods is that the resulting predictive model is not aligned with the operational context. Therefore, prediction errors are propagated to the optimization of the budget allocation problem, subsequently leading to a suboptimal allocation policy. We propose an alternative approach based on learning to rank. Our proposed methodology directly learns an allocation policy by prioritizing instances in terms of their incremental profit. We propose an efficient sampling procedure for the optimization of the ranking model to scale our methodology to large-scale data sets. Theoretically, we show how learning to rank can maximize the area under a policy's incremental profit curve. Empirically, we validate our methodology and show its effectiveness in practice through a series of experiments on both synthetic and real-world data.

Published
2024

5. Using representation balancing to learn conditional-average dose responses from clustered data

Author

Bockel-Rickermann, Christopher, Vanderschueren, Toon, Berrevoets, Jeroen, Verdonck, Tim, and Verbeke, Wouter

Subjects
Computer Science - Machine Learning, Statistics - Methodology, 62D20
Abstract

Estimating a unit's responses to interventions with an associated dose, the "conditional average dose response" (CADR), is relevant in a variety of domains, from healthcare to business, economics, and beyond. Such a response typically needs to be estimated from observational data, which introduces several challenges. That is why the machine learning (ML) community has proposed several tailored CADR estimators. Yet, the proposal of most of these methods requires strong assumptions on the distribution of data and the assignment of interventions, which go beyond the standard assumptions in causal inference. Whereas previous works have so far focused on smooth shifts in covariate distributions across doses, in this work, we will study estimating CADR from clustered data and where different doses are assigned to different segments of a population. On a novel benchmarking dataset, we show the impacts of clustered data on model performance and propose an estimator, CBRNet, that learns cluster-agnostic and hence dose-agnostic covariate representations through representation balancing for unbiased CADR inference. We run extensive experiments to illustrate the workings of our method and compare it with the state of the art in ML for CADR estimation., Comment: 21 pages, 7 figures, v2: updated methodology and experiments

Published
2023

6. Accounting For Informative Sampling When Learning to Forecast Treatment Outcomes Over Time

Author

Vanderschueren, Toon, Curth, Alicia, Verbeke, Wouter, and van der Schaar, Mihaela

Subjects
Statistics - Machine Learning, Computer Science - Machine Learning
Abstract

Machine learning (ML) holds great potential for accurately forecasting treatment outcomes over time, which could ultimately enable the adoption of more individualized treatment strategies in many practical applications. However, a significant challenge that has been largely overlooked by the ML literature on this topic is the presence of informative sampling in observational data. When instances are observed irregularly over time, sampling times are typically not random, but rather informative -- depending on the instance's characteristics, past outcomes, and administered treatments. In this work, we formalize informative sampling as a covariate shift problem and show that it can prohibit accurate estimation of treatment outcomes if not properly accounted for. To overcome this challenge, we present a general framework for learning treatment outcomes in the presence of informative sampling using inverse intensity-weighting, and propose a novel method, TESAR-CDE, that instantiates this framework using Neural CDEs. Using a simulation environment based on a clinical use case, we demonstrate the effectiveness of our approach in learning under informative sampling., Comment: To appear in the Proceedings of the 40th International Conference on Machine Learning, Honolulu, Hawaii, USA. PMLR 202, 2023

Published
2023

7. Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

Author

Bhasin, Shalender, Biggs, Mary, Cawthon, Peggy, Couper, David, Dobs, Adrian, Flicker, Leon, Handelsman, David, Hankey, Graeme, Hannemann, Anke, Haring, Robin, Hsu, Benjumin, Karlsson, Magnus, Martin, Sean, Matsumoto, Alvin, Mellström, Dan, Ohlsson, Claes, ONeill, Terence, Orwoll, Eric, Quartagno, Matteo, Shores, Molly, Steveling, Antje, Tivesten, Åsa, Travison, Thomas, Vanderschueren, Dirk, Wittert, Gary, Wu, Frederick, Yeap, Bu, Marriott, Ross, Murray, Kevin, Adams, Robert, Antonio, Leen, Ballantyne, Christie, and Bauer, Douglas

Subjects
Humans, Male, Adolescent, Young Adult, Adult, Middle Aged, Aged, Sex Hormone-Binding Globulin, Cross-Sectional Studies, Prospective Studies, Gonadal Steroid Hormones, Testosterone, Luteinizing Hormone
Abstract

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Published
2023

8. Are Straight-Through gradients and Soft-Thresholding all you need for Sparse Training?

Author

Vanderschueren, Antoine and De Vleeschouwer, Christophe

Subjects
Computer Science - Computer Vision and Pattern Recognition, Computer Science - Artificial Intelligence
Abstract

Turning the weights to zero when training a neural network helps in reducing the computational complexity at inference. To progressively increase the sparsity ratio in the network without causing sharp weight discontinuities during training, our work combines soft-thresholding and straight-through gradient estimation to update the raw, i.e. non-thresholded, version of zeroed weights. Our method, named ST-3 for straight-through/soft-thresholding/sparse-training, obtains SoA results, both in terms of accuracy/sparsity and accuracy/FLOPS trade-offs, when progressively increasing the sparsity ratio in a single training cycle. In particular, despite its simplicity, ST-3 favorably compares to the most recent methods, adopting differentiable formulations or bio-inspired neuroregeneration principles. This suggests that the key ingredients for effective sparsification primarily lie in the ability to give the weights the freedom to evolve smoothly across the zero state while progressively increasing the sparsity ratio. Source code and weights available at https://github.com/vanderschuea/stthree

Published
2022

9. Prescriptive maintenance with causal machine learning

Author

Vanderschueren, Toon, Boute, Robert, Verdonck, Tim, Baesens, Bart, and Verbeke, Wouter

Subjects
Economics - General Economics, Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

Machine maintenance is a challenging operational problem, where the goal is to plan sufficient preventive maintenance to avoid machine failures and overhauls. Maintenance is often imperfect in reality and does not make the asset as good as new. Although a variety of imperfect maintenance policies have been proposed in the literature, these rely on strong assumptions regarding the effect of maintenance on the machine's condition, assuming the effect is (1) deterministic or governed by a known probability distribution, and (2) machine-independent. This work proposes to relax both assumptions by learning the effect of maintenance conditional on a machine's characteristics from observational data on similar machines using existing methodologies for causal inference. By predicting the maintenance effect, we can estimate the number of overhauls and failures for different levels of maintenance and, consequently, optimize the preventive maintenance frequency to minimize the total estimated cost. We validate our proposed approach using real-life data on more than 4,000 maintenance contracts from an industrial partner. Empirical results show that our novel, causal approach accurately predicts the maintenance effect and results in individualized maintenance schedules that are more accurate and cost-effective than supervised or non-individualized approaches.

Published
2022

10. A new perspective on classification: optimally allocating limited resources to uncertain tasks

Author

Vanderschueren, Toon, Baesens, Bart, Verdonck, Tim, and Verbeke, Wouter

Subjects
Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

A central problem in business concerns the optimal allocation of limited resources to a set of available tasks, where the payoff of these tasks is inherently uncertain. In credit card fraud detection, for instance, a bank can only assign a small subset of transactions to their fraud investigations team. Typically, such problems are solved using a classification framework, where the focus is on predicting task outcomes given a set of characteristics. Resources are then allocated to the tasks that are predicted to be the most likely to succeed. However, we argue that using classification to address task uncertainty is inherently suboptimal as it does not take into account the available capacity. Therefore, we first frame the problem as a type of assignment problem. Then, we present a novel solution using learning to rank by directly optimizing the assignment's expected profit given limited, stochastic capacity. This is achieved by optimizing a specific instance of the net discounted cumulative gain, a commonly used class of metrics in learning to rank. Empirically, we demonstrate that our new method achieves higher expected profit and expected precision compared to a classification approach for a wide variety of application areas and data sets. This illustrates the benefit of an integrated approach and of explicitly considering the available resources when learning a predictive model.

Published
2022

11. How semantic and geometric information mutually reinforce each other in ToF object localization

Author

Vanderschueren, Antoine, Joos, Victor, and De Vleeschouwer, Christophe

Subjects
Computer Science - Computer Vision and Pattern Recognition
Abstract

We propose a novel approach to localize a 3D object from the intensity and depth information images provided by a Time-of-Flight (ToF) sensor. Our method uses two CNNs. The first one uses raw depth and intensity images as input, to segment the floor pixels, from which the extrinsic parameters of the camera are estimated. The second CNN is in charge of segmenting the object-of-interest. As a main innovation, it exploits the calibration estimated from the prediction of the first CNN to represent the geometric depth information in a coordinate system that is attached to the ground, and is thus independent of the camera elevation. In practice, both the height of pixels with respect to the ground, and the orientation of normals to the point cloud are provided as input to the second CNN. Given the segmentation predicted by the second CNN, the object is localized based on point cloud alignment with a reference model. Our experiments demonstrate that our proposed two-step approach improves segmentation and localization accuracy by a significant margin compared to a conventional CNN architecture, ignoring calibration and height maps, but also compared to PointNet++.

Published
2020

13. Vitamin D metabolites and the gut microbiome in older men

Author

Thomas, RL, Jiang, L, Adams, JS, Xu, ZZ, Shen, J, Janssen, S, Ackermann, G, Vanderschueren, D, Pauwels, S, Knight, R, Orwoll, ES, and Kado, DM

Abstract

The vitamin D receptor is highly expressed in the gastrointestinal tract where it transacts gene expression. With current limited understanding of the interactions between the gut microbiome and vitamin D, we conduct a cross-sectional analysis of 567 older men quantifying serum vitamin D metabolites using LC-MSMS and defining stool sub-Operational Taxonomic Units from16S ribosomal RNA gene sequencing data. Faith’s Phylogenetic Diversity and non-redundant covariate analyses reveal that the serum 1,25(OH)2D level explains 5% of variance in α-diversity. In β-diversity analyses using unweighted UniFrac, 1,25(OH)2D is the strongest factor assessed, explaining 2% of variance. Random forest analyses identify 12 taxa, 11 in the phylum Firmicutes, eight of which are positively associated with either 1,25(OH)2D and/or the hormone-to-prohormone [1,25(OH)2D/25(OH)D] “activation ratio.” Men with higher levels of 1,25(OH)2D and higher activation ratios, but not 25(OH)D itself, are more likely to possess butyrate producing bacteria that are associated with better gut microbial health.

Published
2020

15. Associations of total and free 25OHD and 1,25(OH)2D with serum markers of inflammation in older men

Author

Srikanth, P, Chun, RF, Hewison, M, Adams, JS, Bouillon, R, Vanderschueren, D, Lane, N, Cawthon, PM, Dam, T, Barrett-Connor, E, Daniels, LB, Shikany, JM, Stefanick, ML, Cauley, JA, Orwoll, ES, Nielson, CM, and for the Osteoporotic Fractures in Men (MrOS) Study Research Group

Subjects
Biomedical and Clinical Sciences, Nutrition and Dietetics, Inflammatory and immune system, Aged, Aged, 80 and over, Biomarkers, Humans, Inflammation, Interleukin-6, Male, Receptors, Tumor Necrosis Factor, Vitamin D, Elderly, Free 1, 25(OH)(2)D, Free 25OHD, Men, Total 1, 25(OH)(2)D, Total 25OHD, Osteoporotic Fractures in Men (MrOS) Study Research Group, Free 1, 25(OH)2D, Total 1, 25(OH)2D, Biomedical Engineering, Clinical Sciences, Public Health and Health Services, Endocrinology & Metabolism, Clinical sciences, Epidemiology
Abstract

UnlabelledVitamin D is hypothesized to suppress inflammation. We tested total and free vitamin D metabolites and their association with inflammatory markers. Interleukin-6 levels were lower with higher 25-hydroxyvitamin D. 1,25-dihydroxyvitamin D and free 25OHD associations mirrored those of 25OHD. However, associations for the two metabolites diverged for tumor necrosis factor alpha (TNF-α) soluble receptors.IntroductionVitamin D is hypothesized to suppress inflammation, and circulating 25-hydroxyvitamin D (25OHD) and inflammatory markers are inversely correlated. However, total serum 25OHD may not be the best indicator of biologically active vitamin D.MethodsWe tested serum total 25OHD, total 1,25(OH)2D, vitamin D binding protein (DBP), and estimated free 25OHD and free 1,25(OH)2D associations with inflammatory markers serum interleukin-6 (IL-6), TNF-α and their soluble receptors, interleukin-10 (IL-10), and C-reactive protein (CRP) as continuous outcomes and the presence of ≥2 inflammatory markers in the highest quartile as a dichotomous outcome, in a random subcohort of 679 men in the Osteoporotic Fractures in Men (MrOS) study.ResultsIL-6 was lower in men with higher 25OHD (-0.23 μg/mL per standard deviation (SD) increase in 25OHD, 95 % confidence intervals (CI) -0.07 to -0.38 μg/mL) and with higher 1,25(OH)2D (-0.20 μg/mL, 95 % CI -0.0004 to -0.39 μg/mL); free D associations were slightly stronger. 25OHD and DBP, but not 1,25(OH)2D, were independently associated with IL-6. TNF-α soluble receptors were inversely associated with 1,25(OH)2D but positively associated with 25OHD, and each had independent effects. The strongest association with ≥2 inflammatory markers in the highest quartile was for free 1,25(OH)2D (odds ratios (OR) 0.70, 95 % CI 0.54 to 0.89 per SD increase in free 1,25(OH)2D).ConclusionsAssociations of 1,25(OH)2D and free 25OHD with IL-6 mirrored those of 25OHD, suggesting that 1,25(OH)2D and free D do not improve upon 25OHD in population-based IL-6 studies. However, associations for the two metabolites diverged for TNF-α soluble receptor, warranting examination of both metabolites in studies of TNF-α and its antagonists.

Published
2016

16. Associations of 25‐Hydroxyvitamin D and 1,25‐Dihydroxyvitamin D With Bone Mineral Density, Bone Mineral Density Change, and Incident Nonvertebral Fracture

Author

Swanson, Christine M, Srikanth, Priya, Lee, Christine G, Cummings, Steven R, Jans, Ivo, Cauley, Jane A, Bouillon, Roger, Vanderschueren, Dirk, Orwoll, Eric S, Nielson, Carrie M, and Group, for the Osteoporotic Fractures in Men MrOS Study Research

Subjects
Physical Injury - Accidents and Adverse Effects, Aging, Prevention, Nutrition, Osteoporosis, Musculoskeletal, Aged, Aged, 80 and over, Bone Density, Follow-Up Studies, Hip Fractures, Humans, Incidence, Male, Radiography, Risk Factors, Vitamin D, Osteoporotic Fractures in Men MrOS Study Research Group, 1, 25-DIHYDROXYVITAMIN D, 25-HYDROXYVITAMIN D, BONE MINERAL DENSITY, CALCITRIOL, FRACTURE, Biological Sciences, Engineering, Medical and Health Sciences, Anatomy & Morphology
Abstract

Relationships between 1,25-dihydroxyvitamin D (1,25(OH)2 D) and skeletal outcomes are uncertain. We examined the associations of 1,25(OH)2 D with bone mineral density (BMD), BMD change, and incident non-vertebral fractures in a cohort of older men and compared them with those of 25-hydroxyvitamin D (25OHD). The study population included 1000 men (aged 74.6 ± 6.2 years) in the Osteoporotic Fractures in Men (MrOS) study, of which 537 men had longitudinal dual-energy X-ray absorptiometry (DXA) data (4.5 years of follow-up). A case-cohort design and Cox proportional hazards models were used to test the association between vitamin D metabolite levels and incident nonvertebral and hip fractures. Linear regression models were used to estimate the association between vitamin D measures and baseline BMD and BMD change. Interactions between 25OHD and 1,25(OH)2 D were tested for each outcome. Over an average follow-up of 5.1 years, 432 men experienced incident nonvertebral fractures, including 81 hip fractures. Higher 25OHD was associated with higher baseline BMD, slower BMD loss, and lower hip fracture risk. Conversely, men with higher 1,25(OH)2 D had lower baseline BMD. 1,25(OH)2 D was not associated with BMD loss or nonvertebral fracture. Compared with higher levels of calcitriol, the risk of hip fracture was higher in men with the lowest 1,25(OH)2 D levels (8.70 to 51.60 pg/mL) after adjustment for baseline hip BMD (hazard ratio [HR] = 1.99, 95% confidence interval [CI] 1.19-3.33). Adjustment of 1,25(OH)2 D data for 25OHD (and vice versa) had little effect on the associations observed but did attenuate the hip fracture association of both vitamin D metabolites. In older men, higher 1,25(OH)2 D was associated with lower baseline BMD but was not related to the rate of bone loss or nonvertebral fracture risk. However, with BMD adjustment, a protective association for hip fracture was found with higher 1,25(OH)2 D. The associations of 25OHD with skeletal outcomes were generally stronger than those for 1,25(OH)2 D. These results do not support the hypothesis that measures of 1,25(OH)2 D improve the ability to predict adverse skeletal outcomes when 25OHD measures are available. © 2015 American Society for Bone and Mineral Research.

Published
2015

17. The androgen receptor depends on ligand-binding domain dimerization for transcriptional activation

Author

El Kharraz, Sarah, Dubois, Vanessa, van Royen, Martin E, Houtsmuller, Adriaan B, Pavlova, Ekatarina, Atanassova, Nina, Nguyen, Tien, Voet, Arnout, Eerlings, Roy, Handle, Florian, Prekovic, Stefan, Smeets, Elien, Moris, Lisa, Devlies, Wout, Ohlsson, Claes, Poutanen, Matti, Verstrepen, Kevin J, Carmeliet, Geert, Launonen, Kaisa-Mari, Helminen, Laura, Palvimo, Jorma J, Libert, Claude, Vanderschueren, Dirk, Helsen, Christine, and Claessens, Frank

Published
2021
Full Text
View/download PDF

19. Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Author

Moayyeri, Alireza, Hsu, Yi-Hsiang, Karasik, David, Estrada, Karol, Xiao, Su-Mei, Nielson, Carrie, Srikanth, Priya, Giroux, Sylvie, Wilson, Scott G, Zheng, Hou-Feng, Smith, Albert V, Pye, Stephen R, Leo, Paul J, Teumer, Alexander, Hwang, Joo-Yeon, Ohlsson, Claes, McGuigan, Fiona, Minster, Ryan L, Hayward, Caroline, Olmos, José M, Lyytikäinen, Leo-Pekka, Lewis, Joshua R, Swart, Karin MA, Masi, Laura, Oldmeadow, Chris, Holliday, Elizabeth G, Cheng, Sulin, van Schoor, Natasja M, Harvey, Nicholas C, Kruk, Marcin, del Greco M, Fabiola, Igl, Wilmar, Trummer, Olivia, Grigoriou, Efi, Luben, Robert, Liu, Ching-Ti, Zhou, Yanhua, Oei, Ling, Medina-Gomez, Carolina, Zmuda, Joseph, Tranah, Greg, Brown, Suzanne J, Williams, Frances M, Soranzo, Nicole, Jakobsdottir, Johanna, Siggeirsdottir, Kristin, Holliday, Kate L, Hannemann, Anke, Go, Min Jin, Garcia, Melissa, Polasek, Ozren, Laaksonen, Marika, Zhu, Kun, Enneman, Anke W, McEvoy, Mark, Peel, Roseanne, Sham, Pak Chung, Jaworski, Maciej, Johansson, Åsa, Hicks, Andrew A, Pludowski, Pawel, Scott, Rodney, Dhonukshe-Rutten, Rosalie AM, van der Velde, Nathalie, Kähönen, Mika, Viikari, Jorma S, Sievänen, Harri, Raitakari, Olli T, González-Macías, Jesús, Hernández, Jose L, Mellström, Dan, Ljunggren, Osten, Cho, Yoon Shin, Völker, Uwe, Nauck, Matthias, Homuth, Georg, Völzke, Henry, Haring, Robin, Brown, Matthew A, McCloskey, Eugene, Nicholson, Geoffrey C, Eastell, Richard, Eisman, John A, Jones, Graeme, Reid, Ian R, Dennison, Elaine M, Wark, John, Boonen, Steven, Vanderschueren, Dirk, Wu, Frederick CW, Aspelund, Thor, Richards, J Brent, Bauer, Doug, Hofman, Albert, Khaw, Kay-Tee, Dedoussis, George, Obermayer-Pietsch, Barbara, Gyllensten, Ulf, Pramstaller, Peter P, and Lorenc, Roman S

Subjects
Calcaneus, Humans, Osteoporosis, Genetic Predisposition to Disease, Ultrasonography, Cohort Studies, Bone Density, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Fractures, Bone, Genome-Wide Association Study, Young Adult, Human Genome, Genetics, Aging, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Published
2014

20. Time to onset of antifracture efficacy and year‐by‐year persistence of effect of zoledronic acid in women with osteoporosis

Author

Boonen, Steven, Eastell, Richard, Su, Guoqin, Mesenbrink, Peter, Cosman, Felicia, Cauley, Jane A, Reid, Ian R, Claessens, Frank, Vanderschueren, Dirk, Lyles, Kenneth W, and Black, Dennis M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Osteoporosis, Aging, Clinical Trials and Supportive Activities, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Aged, Aged, 80 and over, Algorithms, Bone Density, Bone Density Conservation Agents, Diphosphonates, Double-Blind Method, Female, Humans, Imidazoles, Osteoporosis, Postmenopausal, Osteoporotic Fractures, Placebos, Proportional Hazards Models, Risk, Time Factors, Zoledronic Acid, FRACTURES, POSTMENOPAUSAL OSTEOPOROSIS, REACTION TIME, ZOLEDRONIC ACID, BONE MINERAL DENSITY, Biological Sciences, Engineering, Medical and Health Sciences, Anatomy & Morphology, Biological sciences, Biomedical and clinical sciences
Abstract

Oral bisphosphonates reduce fracture risk in osteoporotic patients but are often associated with poor compliance, which may impair their antifracture effects. This post hoc analysis assessed the time to onset and persistence of the antifracture effect of zoledronic acid, a once-yearly bisphosphonate infusion, in women with osteoporosis. Data from 9355 women who were randomized in two placebo-controlled pivotal trials were included. Endpoints included reduction in the rate of any clinical fracture at 6, 12, 18, 24, and 36 months in the zoledronic acid group compared with placebo, and the year-by-year incidence of all clinical fractures over 3 years. Cox proportional hazards regression was used to determine the timing of onset of antifracture efficacy. A generalized estimating equation model was used to assess fracture reduction for the 3 consecutive years of treatment, thereby evaluating persistence of effect. Safety results from women in the two studies were collated. Zoledronic acid reduced the risk of all clinical fractures at 12 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] 0.61-0.92, p = 0.0050) with significant reductions maintained at all subsequent time points. Year-by-year analysis showed that zoledronic acid reduced the risk for all clinical fractures compared with the placebo group in each of the 3 years (year 1: odds ratio [OR] = 0.74, 95% CI 0.60-0.91, p = 0.0044; year 2: OR = 0.53, 95% CI 0.42-0.66, p < 0.0001; year 3: OR = 0.61, 95% CI 0.48-0.77, p < 0.0001). This antifracture effect was persistent over 3 years, with the reductions in years 2 and 3 slightly larger than in year 1 (p = 0.097). This analysis shows that zoledronic acid offered significant protection from clinical fractures as early as 12 months. When administered annually, its beneficial effects persisted for at least 3 years.

Published
2012

23. Sarcopenia‐defining parameters, but not sarcopenia, are associated with cognitive domains in middle‐aged and older European men

Author

Amini, Nadjia, Dupont, Jolan, Lapauw, Laurence, Vercauteren, Laura, Antonio, Leen, O'Neill, Terence W., Vanderschueren, Dirk, Pendleton, Neil, Rastrelli, Giulia, Maggi, Mario, Casanueva, Felipe F., Słowikowska‐Hilczer, Jolanta, Punab, Margus, Huhtaniemi, Ilpo T., Wu, Frederick C.W., Verschueren, Sabine, Tournoy, Jos, and Gielen, Evelien

Abstract

Previous research suggests that sarcopenia is associated with lower cognitive functioning. Evidence on the longitudinal relationship between cognition and sarcopenia, according to the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2), is scarce. This study aimed to investigate both cross‐sectional and longitudinal associations between sarcopenia and its defining parameters (muscle strength, muscle mass and physical performance) and cognitive performance in middle‐aged and older men. This was a secondary analysis of data from the European Male Ageing Study (EMAS), a multicentre cohort study of men aged 40–79 years, recruited from population registers in eight European centres. Cognitive functioning was assessed by using a battery of three neuropsychological tests, measuring fluid intelligence: Rey–Osterrieth Complex Figure (ROCF‐Copy and ROCF‐Recall), Camden Topographical Recognition Memory (CTRM) and Digit Symbol Substitution Test (DSST). Sarcopenia‐defining parameters appendicular lean mass (aLM), gait speed (GS), chair stand test (CST) and handgrip strength (HGS) were measured. Sarcopenia was diagnosed according to the criteria of the EWGSOP2. All measurements were performed at baseline and after a follow‐up of 4.3 years. Cross‐sectional associations between cognition, sarcopenia‐defining parameters and prevalent sarcopenia (EWGSOP2) were analysed. Longitudinally, the predictive value of baseline cognition on decline in sarcopenia‐defining parameters, onset of new sarcopenia and vice versa was examined. Linear and logistic regression were used and adjusted for putative confounders. In the whole cohort (n= 3233), ROCF‐Copy (β = 0.016; P< 0.05), ROCF‐Recall (β = 0.010; P< 0.05), CTRM (β = 0.015; P< 0.05), DSST score (β = 0.032; P< 0.05) and fluid cognition (β = 0.036; P< 0.05) were significantly and independently associated with GS at baseline. In the Leuven + Manchester subcohorts (n= 456), ROCF‐Copy (β = 1.008; P< 0.05), ROCF‐Recall (β = 0.908; P< 0.05) and fluid cognition (β = 1.482; P< 0.05) were associated with HGS. ROCF‐Copy (β = 0.394; P< 0.05), ROCF‐Recall (β = 0.316; P< 0.05), DSST (β = 0.393; P< 0.05) and fluid cognition (β = 0.765; P< 0.05) were associated with aLM. The prevalence of sarcopenia in this population was 17.8%. No associations were detected between cognition and prevalent or incident sarcopenia. Longitudinal analysis showed that low ROCF‐Copy score at baseline was associated with an increase in CST in men ≥70 years (β = −0.599; P< 0.05). In addition, a decrease in ROCF‐Recall was associated with a decrease in GS, and a decrease in DSST was associated with an increase in CST (β = 0.155; P< 0.0001, β = −0.595; P< 0.001, respectively) in persons with the highest change in both cognition and muscle function. Sarcopenia was not associated with cognitive performance in this population, whereas several components of sarcopenia were associated with domain‐specific cognitive performance. Longitudinally, baseline and change in subdomains of cognition predicted change in muscle function in specific subgroups.

Published
2023
Full Text
View/download PDF

26. The Toulouse algorithm identifies patients with increased risk of cardiac decompensation only in patients with TIPS for refractory ascites

Author

Vanderschueren, Emma, Bekhuis, Youri, Clerick, Jan, Decock, Jappe, Meersseman, Philippe, Wilmer, Alexander, Claus, Eveline, Bonne, Lawrence, Claessen, Guido, Verslype, Chris, Maleux, Geert, and Laleman, Wim

Abstract

TIPS placement is an effective, possibly life-saving, treatment for complications of portal hypertension. The pressure shift induced by the stent can lead to cardiac decompensation (CD). We investigated the incidence of CD, possible variables associated with CD and the validity of the Toulouse algorithm for risk prediction of CD post-TIPS.

Published
2025
Full Text
View/download PDF

33. Clinical characteristics of sarcoidosis patients in Belgium

Author

De Ridder, Jolien, Ronsmans, Steven, Vanderschueren, Steven, Wuyts, Wim, and Yserbyt, Jonas

Abstract

ABSTRACTBackgroundSarcoidosis is a non-caseating granulomatous disease, mostly affecting previously healthy persons in their fourth and fifth decade. In Belgium, there is a paucity of epidemiological data concerning sarcoidosis and it is unknown to what respect national data on sarcoidosis relates to the global epidemiology of the disease.ObjectivesIn this cohort study we describe the patient population in an academic center of reference, serving both as a regional care center and a center for a tertiary referral.MethodsWe collected epidemiological data among 234 consecutive patients consulting the outpatient sarcoidosis clinic during a two-year time period. We manually explored the electronic patient file for data retrieval.ResultsOut of the 234 patients, 140 are male (60%) and 94 are female (40%) patients. Forced vital capacity showed a median decline of 2% during follow-up, whereas median diffusion capacity increased with 4% over the same period of time. Within our study cohort, we observed a preponderance in employment as construction workers (14%), the chemical industry (6%) and in the metal processing industry (6%).ConclusionThe current study reports on epidemiological findings among the largest cohort of sarcoidosis patients in Belgium published to date.Graphical abstract

Published
2022
Full Text
View/download PDF

36. Prospective evaluation of hypogonadism in male metastatic renal cell carcinoma patients treated with targeted therapies

Author

Bastin, Julie, Werbrouck, Emilie, Verbiest, Annelies, Punie, Kevin, Bechter, Oliver, Woei-A-Jin, Feng Jung, Wolter, Pascal, Wildiers, Hans, Lerut, Evelyne, Dumez, Herlinde, Decallonne, Brigitte, Clement, Paul, Vanderschueren, Dirk, Albersen, Maarten, Oyen, Raymond, Schöffski, Patrick, and Beuselinck, Benoit

Abstract

AbstractObjectives: To study the prevalence of hypogonadism in male patients with metastatic renal cell carcinoma (mRCC) starting with targeted therapies and the impact of the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) sunitinib and pazopanib on the luteinizing hormone (LH)/testosterone (TT)-axis.Methods: Male mRCC patients starting with targeted therapies were prospectively included in this study. TT- and LH-levels were sampled at start as well as during systemic therapy. Endpoints of the study were gonadal status (TT- and LH-levels) at start of targeted therapy and TT- and LH-evolution during targeted therapy.Results: Sixty-three patients were included in this study. At start of targeted therapy, 30% of patients were eugonadal and 48% had secondary hypogonadism. Decreased TT- and increased LH-levels were associated with inflammatory state and poor prognosis. During sunitinib therapy, TT-levels decreased with 32% (p = 0.004) and LH-levels with 14% (p = 0.03). TT-levels were 13% lower (p = 0.007) and LH-levels 15% lower (p = 0.004) on day 28 compared to day 1. In four patients, a dramatic TT decrease was observed shortly after starting sunitinib. In patients treated with pazopanib, no impact on TT- or LH-levels was observed.Conclusion: Hypogonadism is a frequent finding in male mRCC-patients at start of targeted therapies. In contrast to pazopanib, during sunitinib therapy, TT- and LH-levels tend to decrease, leading to an increased incidence of secondary hypogonadism.

Published
2019
Full Text
View/download PDF

37. Incidence and risk factors of fever in a contemporary cohort of HIV-patients with good access to antiretroviral therapy

Author

De Munter, Paul, Derdelinckx, Inge, Peetermans, Willy E., Fieuws, Steffen, Vanderschueren, Steven, and Van Wijngaerden, Eric

Abstract

Objective: To study incidence and to determine risk factors of fever in a contemporary cohort of HIV-infected patients with access to antiretroviral therapy.Methods: Prospective study in a cohort of HIV-infected patients in Belgium from 2009 to 2013.Results: 759 patients were followed for a total of 2136 patient years. The incidence of fever was low, with an incidence rate of 0.103 (95% CI 0.078; 0.135) febrile episodes per patient per year for temperature 38.3 °C or higher measured by a health care provider. Gender, age, ethnicity, and calendar year of measurement were no significant risk factors for fever in univariable analysis, but recent HIV diagnosis, prior AIDS, nadir CD4 cell count, last CD4 cell count, and viral load were, as were use of antiretroviral therapy, recent start of antiretroviral therapy and recent switch of antiretroviral therapy. Recent stop of antiretroviral therapy was no significant risk factor. In multivariable analysis prior AIDS, last CD4 and viral load remained significant risk factors, but use of antiretroviral therapy not.Conclusion: In this contemporary cohort, incidence of fever was low but CD4 cell count less than 200/mm³ remained associated with the highest incidence of fever.

Published
2017
Full Text
View/download PDF

38. Androgen Receptor Polymorphism-Dependent Variation in Prostate-Specific Antigen Concentrations of European Men.

Author

Holgersson, Magdalena Bentmar, Giwercman, Aleksander, Bjartell, Anders, Wu, Frederick C.W., Huhtaniemi, Ilpo T., O'Neill, Terence W., Pendleton, Neil, Vanderschueren, Dirk, Lean, Michael E. J., Han, Thang S., Finn, Joseph D., Kula, Krzysztof, Forti, Gianni, Casanueva, Felipe F., Bartfai, György, Punab, Margus, and Giwercman, Yvonne Lundberg

Abstract

The article discusses a study to investigate the association of androgen receptor variants with the risk of prostate-specific antigen (PSA) concentrations and its impact on the risk of being diagnosed with prostate cancer. Topics discussed include need of improving Serum PSA, a clinical marker with the adjustment of AR genotype, use the European Male Ageing Study (EMAS) to provide baseline information, and benefits of screening prostate cancer using PSA measurements.

Published
2014
Full Text
View/download PDF

39. Androgen Deficiency Exacerbates High-Fat Diet-Induced Metabolic Alterations in Male Mice

Author

Dubois, Vanessa, Laurent, Michaël R., Jardi, Ferran, Antonio, Leen, Lemaire, Katleen, Goyvaerts, Lotte, Deldicque, Louise, Carmeliet, Geert, Decallonne, Brigitte, Vanderschueren, Dirk, and Claessens, Frank

Abstract

Androgen deficiency is associated with obesity, metabolic syndrome, and type 2 diabetes mellitus in men, but the mechanisms behind these associations remain unclear. In this study, we investigated the combined effects of androgen deficiency and high-fat diet (HFD) on body composition and glucose homeostasis in C57BL/6J male mice. Two models of androgen deficiency were used: orchidectomy (ORX) and androgen receptor knockout mice. Both models displayed higher adiposity and serum leptin levels upon HFD, whereas no differences were seen on a regular diet. Fat accumulation in HFD ORX animals was accompanied by increased sedentary behavior and occurred in spite of reduced food intake. HFD ORX mice showed white adipocyte hypertrophy, correlated with decreased mitochondrial content but not function as well as increased lipogenesis and decreased lipolysis suggested by the up-regulation of fatty acid synthase and the down-regulation of hormone-sensitive lipase. Both ORX and androgen receptor knockout exacerbated HFD-induced glucose intolerance by impairing insulin action in liver and skeletal muscle, as evidenced by the increased triglyceride and decreased glycogen content in these tissues. In addition, serum IL-1β levels were elevated, and pancreatic insulin secretion was impaired after ORX. Testosterone but not dihydrotestosterone supplementation restored the castration effects on body composition and glucose homeostasis. We conclude that sex steroid deficiency in combination with HFD exacerbates adiposity, insulin resistance, and β-cell failure in 2 preclinical male mouse models. Our findings stress the importance of a healthy diet in a clinical context of androgen deficiency and may have implications for the prevention of metabolic alterations in hypogonadal men.

Published
2016
Full Text
View/download PDF

40. Enobosarm (GTx-024) Modulates Adult Skeletal Muscle Mass Independently of the Androgen Receptor in the Satellite Cell Lineage

Author

Dubois, Vanessa, Simitsidellis, Ioannis, Laurent, Michaël R., Jardi, Ferran, Saunders, Philippa T. K., Vanderschueren, Dirk, and Claessens, Frank

Abstract

Androgens increase skeletal muscle mass, but their clinical use is hampered by a lack of tissue selectivity and subsequent side effects. Selective androgen receptor modulators elicit muscle-anabolic effects while only sparingly affecting reproductive tissues. The selective androgen receptor modulator, GTx-024 (enobosarm), is being investigated for cancer cachexia, sarcopenia, and muscle wasting diseases. Here we investigate the role of muscle androgen receptor (AR) in the anabolic effect of GTx-024. In mice lacking AR in the satellite cell lineage (satARKO), the weight of the androgen-sensitive levator ani muscle was lower but was decreased further upon orchidectomy. GTx-024 was as effective as DHT in restoring levator ani weights to sham levels. Expression of the muscle-specific, androgen-responsive genes S-adenosylmethionine decarboxylase and myostatin was decreased by orchidectomy and restored by GTx-024 and DHT in control mice, whereas the expression was low and unaffected by androgen status in satARKO. In contrast, insulin-like growth factor 1Ea expression was not different between satARKO and control muscle, decreased upon castration, and was restored by DHT and GTx-024 in both genotypes. These data indicate that GTx-024 does not selectively modulate AR in the satellite cell lineage and that cells outside this lineage remain androgen responsive in satARKO muscle. Indeed, residual AR-positive cells were present in satARKO muscle, coexpressing the fibroblast-lineage marker vimentin. AR positive, muscle-resident fibroblasts could therefore be involved in the indirect effects of androgens on muscle. In conclusion, both DHT and GTx-024 target AR pathways in the satellite cell lineage, but cells outside this lineage also contribute to the anabolic effects of androgens.

Published
2015
Full Text
View/download PDF

41. In reply to ‘clinical biochemistry test eliminator providing cost-effectiveness with five algorithms’: the Casablanca strategy

Author

Betrains, Albrecht and Vanderschueren, Steven

Abstract

ABSTRACTIn this journal, Ataman Gönel recently demonstrated that elimination of requested unnecessary tests by means of algorithms in an artificial intelligence program may contribute to the cost-effectiveness of medicine. However, test ordering is an essential part of clinical medicine and decision-making. Interns are responsible for a modest but significant excess in laboratory utilization and underestimate their control over laboratory testing. Even in the hands of experts, rational approaches to test ordering may be subverted by the Casablanca Strategy. Establishing a differential diagnosis and ordering only tests deemed necessary reflect the attainment of expertise in the clinical decision-making process. Residents and attendings in teaching roles should not underestimate the extent to which their clinical decision-making may be mimicked.

Published
2021
Full Text
View/download PDF

42. Outcome of Patients Requiring Valve Surgery During Active Infective Endocarditis.

Author

Hill, Evelyn E., Herregods, Marie-Christine, Vanderschueren, Steven, Claus, Piet, Peetermans, Willy E., and Herijgers, Paul

Subjects
HEART diseases, CARDIAC arrest, STAPHYLOCOCCUS
Abstract

Background: The optimal timing of cardiac operations in patients with infective endocarditis continues to be debated. This observational study analyzed the profile and outcome of patients with active infective endocarditis undergoing operations. Methods: Between June 2000 and June 2006, 95 surgically treated patients with definite infective endocarditis by the modified Duke criteria were included. Results: Fifty-eight patients were operated on within the first 7 days after diagnosis of infective endocarditis and 37 at more than 7 days after diagnosis up to immediately after completion of antibiotic treatment. Staphylococci predominated and were significantly associated with embolism, abscess, and septic shock. The most frequent indication for operation was severe regurgitation with heart failure. The 6-month mortality was 15%. Early operation showed a trend towards increased mortality vs late operation. In univariable analysis, factors associated with 6-month mortality included staphylococci and septic shock. Multivariable analysis revealed that septic shock predicted 6-month mortality. Despite early operation in patients experiencing septic shock, 57% died. No patients without heart failure died after undergoing (early or late) procedures for severe regurgitation. Conclusions: The prognosis in surgically treated patients was determined by the occurrence of septic shock. The outcome in patients who underwent late operations was favorable compared with the early group. This difference was probably not due to the timing of the surgical intervention but to the severity of infective endocarditis. In patients with severe regurgitation without heart failure, early operation may offer benefit in length of hospitalization and prevention of development of new heart failure. [Copyright &y& Elsevier]

Published
2008
Full Text
View/download PDF

43. N/C Interactions Are Dispensable for Normal In Vivo Functioning of the Androgen Receptor in Male Mice

Author

El Kharraz, Sarah, Dubois, Vanessa, Launonen, Kaisa-Mari, Helminen, Laura, Palvimo, Jorma J, Libert, Claude, Smeets, Elien, Moris, Lisa, Eerlings, Roy, Vanderschueren, Dirk, Helsen, Christine, and Claessens, Frank

Abstract

The androgen receptor (AR) plays a central role in the development and maintenance of the male phenotype. The binding of androgens to the receptor induces interactions between the carboxyterminal ligand-binding domain and the highly conserved 23FQNLF27motif in the aminoterminal domain. The role of these so-called N/C interactions in AR functioning is debated. In vitro assays show that mutating the AR in the 23FQNLF27motif (called ARNoC) attenuates the AR transactivation of reporter genes, has no effect on ligand binding, but does affect protein-protein interactions with several AR coregulators. To test the in vivo relevance of the N/C interaction, we analyzed the consequences of the genomic introduction of the ARNoCmutation in mice. Surprisingly, the ARNoC/Ymice show a normal male development, with unaffected male anogenital distance and normal accessory sex glands, male circulating androgen levels, body composition, and fertility. The responsiveness of androgen target genes in kidney, prostate, and testes was also unaffected. We thus conclude that the N/C interactions in the AR are not essential for the development of a male phenotype under normal physiological conditions.

Published
2022
Full Text
View/download PDF

45. Inactivation of AR or ERα in Extrahypothalamic Neurons Does not Affect Osteogenic Response to Loading in Male Mice

Author

Kim, Na Ri, David, Karel, Sommers, Vera, Schollaert, Dieter, Deboel, Ludo, Ohlsson, Claes, Gustafsson, Jan-Åke, Antonio, Leen, Decallonne, Brigitte, Claessens, Frank, Vanderschueren, Dirk, and Dubois, Vanessa

Abstract

Failure of bone mass maintenance in spite of functional loading is an important contributor to osteoporosis and related fractures. While the link between sex steroids and the osteogenic response to loading is well established, the underlying mechanisms are unknown, hampering clinical relevance. Androgens inhibit mechanoresponsiveness in male mice, but the cell type mediating this effect remains unidentified. To evaluate the role of neuronal sex steroid receptor signaling in the male bone’s adaptive capacity, we subjected adult male mice with an extrahypothalamic neuron-specific knockout of the androgen receptor (N-ARKO) or the estrogen receptor alpha (N-ERαKO) to in vivo mechanical stimulation of the tibia. Loading increased cortical thickness in the control animals mainly through periosteal expansion, as total cross-sectional tissue area and cortical bone area but not medullary area were higher in the loaded than the unloaded tibia. Trabecular bone volume fraction also increased upon loading in the control group, mostly due to trabecular thickening. N-ARKO and N-ERαKO males displayed a loading response at both the cortical and trabecular bone compartments that was not different from their control littermates. In conclusion, we show that the presence of androgen receptor or estrogen receptor alpha in extrahypothalamic neurons is dispensable for the osteogenic response to mechanical loading in male mice.

Published
2022
Full Text
View/download PDF

47. Dihydrotestosterone Treatment Results in Obesity and Altered Lipid Metabolism in Orchidectomized Mice*

Author

Movérare-Skrtic, Sofia, Venken, Katrien, Andersson, Niklas, Lindberg, Marie K., Svensson, Johan, Swanson, Charlotte, Vanderschueren, Dirk, Oscarsson, Jan, Gustafsson, Jan-Åke, and Ohlsson, Claes

Abstract

AbstractObjective: To determine the role of androgen receptor (AR) activation for adipose tissue metabolism. Sex steroids are important regulators of adipose tissue metabolism in men. Androgens may regulate the adipose tissue metabolism in men either directly by stimulation of the AR or indirectly by aromatization of androgens into estrogens and, thereafter, by stimulation of the estrogen receptors. Previous studies have shown that estrogen receptor α stimulation results in reduced fat mass in men.Research Methods and Procedures: Orchidectomized mice were treated with the non-aromatizable androgen 5α-dihydrotestosterone (DHT), 17β-estradiol, or vehicle. VO2, VCO2, resting metabolic rate, locomotor activity, and food consumption were measured. Furthermore, changes in hepatic gene expression were analyzed.Results: DHT treatment resulted in obesity, associated with reduced energy expenditure and fat oxidation. In contrast, DHT did not affect food consumption or locomotor activity. Furthermore, DHT treatment resulted in increased high-density lipoprotein-cholesterol and triglyceride levels associated with markedly decreased 7α-hydroxylase gene expression, indicating decreased bile acid production.Discussion: We showed that AR activation results in obesity and altered lipid metabolism in orchidectomized mice. One may speculate that AR antagonists might be useful in the treatment of obesity in men.

Published
2006
Full Text
View/download PDF

48. Relative Impact of Androgen and Estrogen Receptor Activation in the Effects of Androgens on Trabecular and Cortical Bone in Growing Male Mice: A Study in the Androgen Receptor Knockout Mouse Model*

Author

Venken, Katrien, De Gendt, Karel, Boonen, Steven, Ophoff, Jill, Bouillon, Roger, Swinnen, Johannes V, Verhoeven, Guido, and Vanderschueren, Dirk

Abstract

The relative importance of AR and ER activation has been studied in pubertal male AR knockout and WT mice after orchidectomy and androgen replacement therapy, either with or without an aromatase inhibitor. AR activation dominates normal trabecular bone development and cortical bone modeling in male mice. Moreover, optimal periosteal bone expansion is only observed in the presence of both AR and ER activation.Introduction:Androgen receptor (AR)–mediated androgen action has traditionally been considered a key determinant of male skeletal growth. Increasing evidence, however, suggests that estrogens are also essential for normal male bone growth. Therefore, the relative importance of AR‐mediated and estrogen receptor (ER)–mediated androgen action after aromatization remains to be clarified.Materials and Methods:Trabecular and cortical bone was studied in intact or orchidectomized pubertal AR knockout (ARKO) and male wildtype (WT) mice, with or without replacement therapy (3–8 weeks of age). Nonaromatizable (dihydrotestosterone [DHT]) and aromatizable (testosterone [T]) androgens and T plus an aromatase inhibitor (anastrazole) were administered to orchidectomized ARKO and WT mice. Trabecular and cortical bone modeling were evaluated by static and dynamic histomorphometry, respectively.Results:AR inactivation or orchidectomy induced a similar degree of trabecular bone loss (−68% and −71%, respectively). Both DHT and T prevented orchidectomy‐induced bone loss in WT mice but not in ARKO mice. Administration of an aromatase inhibitor did not affect T action on trabecular bone. AR inactivation and orchidectomy had similar negative effects on cortical thickness (−13% and −8%, respectively) and periosteal bone formation (−50% and −26%, respectively). In orchidectomized WT mice, both DHT and T were found to stimulate periosteal bone formation and, as a result, to increase cortical thickness. In contrast, the periosteum of ARKO mice remained unresponsive to either DHT or T. Interestingly, administration of an aromatase inhibitor partly reduced T action on periosteal bone formation in orchidectomized WT mice (−34% versus orchidectomized WT mice on T), but not in ARKO mice. This effect was associated with a significant decrease in serum IGF‐I (−21% versus orchidectomized WT mice on T).Conclusions:These findings suggest a major role for AR activation in normal development of trabecular bone and periosteal bone growth in male mice. Moreover, optimal stimulation of periosteal growth is only obtained in the presence of both AR and ER activation.

Published
2006
Full Text
View/download PDF

49. Repetitive 18F‐fluorodeoxyglucose positron emission tomography in giant cell arteritis: A prospective study of 35 patients

Author

Blockmans, Daniël, Ceuninck, Liesbet de, Vanderschueren, Steven, Knockaert, Daniël, Mortelmans, Luc, and Bobbaers, Herman

Abstract

To study fluorodeoxyglucose (FDG) uptake in the different vascular beds and in the large joints of patients with giant cell arteritis (GCA) at diagnosis, during steroid treatment, and at relapse.All consecutive patients admitted to our department with a diagnosis of GCA underwent FDG–positron emission tomography (PET) scan before treatment with methylprednisolone was started. PET scans were repeated at 3 and 6 months, if the initial PET scans showed vascular FDG uptake. PET scans were scored at 7 different vascular areas and a total vascular score (TVS) was calculated, ranging from 0 to 21.A total of 35 patients entered the study. At diagnosis, vascular FDG uptake was noted in 29 patients (83%), especially in the subclavian arteries (74%), but also in the aorta (>50%) and up to the femoral arteries (37%). TVS decreased from a mean ± SD score of 7.9 ± 5.5 at baseline to 2.4 ± 3.5 on repeat PET scan at 3 months (P < 0.0005), but did not further decrease at 6 months. The patients who relapsed had similar earlier decreases of TVS compared with those who did not relapse. FDG uptake in the shoulders at diagnosis correlated significantly with the presence of polymyalgia rheumatica (P = 0.005).FDG uptake in the large vessels is a sensitive marker for GCA, which can involve the larger thoracic, abdominal, and peripheral arteries. Polymyalgia rheumatica symptoms in patients with GCA correlate with (peri)synovitis of the shoulders. Relapses of GCA cannot be predicted by results of former PET scintigraphies.

Published
2006
Full Text
View/download PDF

50. Growth Without Growth Hormone Receptor: Estradiol Is a Major Growth Hormone‐Independent Regulator of Hepatic IGF‐I Synthesis1*

Author

Venken, Katrien, Schuit, Frans, Van Lommel, Leentje, Tsukamoto, Katsura, Kopchick, John J, Coschigano, Karen, Ohlsson, Claes, Movérare, Sofia, Boonen, Steven, Bouillon, Roger, and Vanderschueren, Dirk

Abstract

The role of estrogens in the regulation of pubertal growth independently of GH and its receptor was studied in male mice with disrupted GHRKO. E2rescued skeletal growth rates in GHRKO associated with an increase in hepatic and serum IGF‐I. These data show that E2rescues pubertal growth during GH resistance through a novel mechanism of GHR‐independent stimulation of hepatic IGF‐I production.Introduction: Growth hormone (GH) and estrogen play a pivotal role in pubertal growth and bone mineral acquisition. Estrogens can affect GH secretion and thereby provide a GH‐dependent mechanism for their effects on skeletal growth. It is presently unclear if or to what extent estrogens are able to regulate pubertal growth and bone mineral accrual independently of GH and its receptor.Materials and Methods: Estradiol (E2; 0.03 μg/day by subcutaneous silastic implants) was administered to orchidectomized (ORX) male mice with disrupted GHR (GHRKO) and corresponding WTs during late puberty (6–10 weeks). Longitudinal and radial bone growth, IGF‐I in serum and its expression in liver, muscle, and bone, and liver gene expression were studied by histomorphometry, RIA, RT‐PCR, microarrays, and Western blotting, respectively.Results: E2stimulated not only longitudinal (femur length and growth plate thickness) and radial growth (cortical thickness and periosteal perimeter), but also rescued longitudinal and periosteal growth rates in ORX GHRKO, whereas no significant changes occurred in WT. E2thereby upregulated serum IGF‐I and liver IGF‐I synthesis (+21% and +52%, respectively) in ORX GHRKO, whereas IGF‐I synthesis in femur or muscle was unaffected. Study of the underlying mechanism of the stimulation of hepatic IGF‐I expression showed that E2restored downregulated receptor signaling systems, such as the estrogen receptor α and the prolactin receptor. E2thereby recovered the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway as evidenced by a significantly increased activation of the transcription factor STAT5 in ORX GHRKO.Conclusions: Our data show a stimulation of skeletal growth through upregulation of hepatic IGF‐I by a hormone other than GH. E2rescues pubertal skeletal growth during GH resistance through a novel mechanism of GHR‐independent stimulation of IGF‐I synthesis in the liver.

Published
2005
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results