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315 results on '"Leebeek, F. W. G."'

2. Mixed effect estimation in deep compartment models: Variational methods outperform first-order approximations.

Author

Janssen, Alexander, Bennis, Frank C., Cnossen, Marjon H., Mathôt, Ron A. A., Reitsma, S. H., Leebeek, F. W. G., Coppens, M., Fijnvandraat, K., Meijer, K., Schols, S. E. M., Eikenboom, H. C. J., Schutgens, R. E. G., Heubel-Moenen, F., Nieuwenhuizen, L., Ypma, P., Driessens, M. H. E., van Vliet, I., Kruip, M. J. H. A., Polinder, S., and Brons, P.

Abstract

This work focusses on extending the deep compartment model (DCM) framework to the estimation of mixed-effects. By introducing random effects, model predictions can be personalized based on drug measurements, enabling the testing of different treatment schedules on an individual basis. The performance of classical first-order (FO and FOCE) and machine learning based variational inference (VI) algorithms were compared in a simulation study. In VI, posterior distributions of the random variables are approximated using variational distributions whose parameters can be directly optimized. We found that variational approximations estimated using the path derivative gradient estimator version of VI were highly accurate. Models fit on the simulated data set using the FO and VI objective functions gave similar results, with accurate predictions of both the population parameters and covariate effects. Contrastingly, models fit using FOCE depicted erratic behaviour during optimization, and resulting parameter estimates were inaccurate. Finally, we compared the performance of the methods on two real-world data sets of haemophilia A patients who received standard half-life factor VIII concentrates during prophylactic and perioperative settings. Again, models fit using FO and VI depicted similar results, although some models fit using FO presented divergent results. Again, models fit using FOCE were unstable. In conclusion, we show that mixed-effects estimation using the DCM is feasible. VI performs conditional estimation, which might lead to more accurate results in more complex models compared to the FO method. [ABSTRACT FROM AUTHOR]

Published
2024
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3. In silico evaluation of limited sampling strategies for individualized dosing of extended half-life factor IX concentrates in hemophilia B patients

Author

Poli Van Creveldkliniek Medisch, Child Health, Circulatory Health, Preijers, T, van Spengler, M W F, Meijer, K, Fijnvandraat, K, Fischer, K, Leebeek, F W G, Cnossen, M H, Mathôt, R A A, Poli Van Creveldkliniek Medisch, Child Health, Circulatory Health, Preijers, T, van Spengler, M W F, Meijer, K, Fijnvandraat, K, Fischer, K, Leebeek, F W G, Cnossen, M H, and Mathôt, R A A

Published
2022

13. Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B.

Author

Pipe, S. W., Leebeek, F. W. G., Recht, M., Key, N. S., Castaman, G., Miesbach, W., Lattimore, S., Peerlinck, K., Van der Valk, P., Coppens, M., Kampmann, P., Meijer, K., O'Connell, N., Pasi, K. J., Hart, D. P., Kazmi, R., Astermark, J-, Hermans, C. R. J. R., Klamroth, R., and Lemons, R.

Abstract

BACKGROUND Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. [ABSTRACT FROM AUTHOR]

Published
2023
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15. BMI is an important determinant of VWF and FVIII levels and bleeding phenotype in patients with von Willebrand disease

Author

Atiq, Ferdows, Fijnvandraat, Karin, van Galen, Karin P. M., Laros-van Gorkom, Britta A. P., Meijer, Karina, de Meris, Joke, Coppens, Michiel, Mauser-Bunschoten, Eveline P., Cnossen, Marjon H., van der Bom, Johanna G., Eikenboom, Jeroen, Leebeek, Frank W. G., Coppens, M., Kors, A., Zweegman, S., de Meris, J., Goverde, G. J., Jonkers, M. H., Dors, N., Nijziel, M. R., Nieuwenhuizen, L., Meijer, K., Tamminga, R. Y. J., van der LindenHagaZiekenhuis, P. W., Ypma, P. F., Eikenboom, H. C. J., van der Bom, J. G., Smiers, F. J. W., Granzen, B., Hamulyák, K., Brons, P., Laros‐van Gorkom, B. A. P., Leebeek, F. W. G., Cnossen, M. H., Atiq, F., Mauser-Bunschoten, E. P., van Galen, K. P. M., Hematology, Pediatrics, Paediatric Haematology, ACS - Pulmonary hypertension & thrombosis, Vascular Medicine, ARD - Amsterdam Reproduction and Development, VU University medical center, Kindergeneeskunde, MUMC+: MA Medische Staf Kindergeneeskunde (9), RS: FHML non-thematic output, and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Subjects
Male, medicine.medical_specialty, Letter, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], E–Only Articles, Hemorrhage, von Willebrand Disease, Type 2, von Willebrand Disease, Type 1, Body Mass Index, Text mining, Internal medicine, von Willebrand Factor, Correspondence, Von Willebrand disease, Medicine, Humans, In patient, Hematology, Factor VIII, business.industry, Middle Aged, Blood coagulation factors, medicine.disease, Phenotype, Immunology, Female, business, Body mass index
Abstract

Contains fulltext : 208376.pdf (Publisher’s version ) (Open Access)

Published
2019
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19. CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease

Author

Sanders, Y. V., van der Bom, J. G., Isaacs, A., Cnossen, M. H., de Maat, M. P. M., Laros-van Gorkom, B. A. P., Fijnvandraat, K., Meijer, K., van Duijn, C. M., Mauser-Bunschoten, E. P., Eikenboom, J., Leebeek, F. W. G., Coppens, M., Kors, A., de Meris, J., Nijziel, M. R., Tamminga, R. Y. J., Ypma, P. F., Smiers, F. J. W., Granzen, B., Hamulyák, K., and Brons, P.

Published
2015
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25. Application of SHAP values for inferring the optimal functional form of covariates in pharmacokinetic modeling.

Author

Janssen, Alexander, Hoogendoorn, Mark, Cnossen, Marjon H., Mathôt, Ron A. A., Cnossen, M. H., Reitsma, S. H., Leebeek, F. W. G., Mathôt, R. A. A., Fijnvandraat, K., Coppens, M., Meijer, K., Schols, S. E. M., Eikenboom, H. C. J., Schutgens, R. E. G., Beckers, E. A. M., Ypma, P., Kruip, M. J. H. A., Polinder, S., Tamminga, R. Y. J., and Brons, P.

Subjects
FIXED effects model, BLOOD coagulation factor VIII antibodies, PHARMACOKINETICS, BLOOD coagulation factor VIII, RANDOM forest algorithms, MACHINE learning
Abstract

In population pharmacokinetic (PK) models, interindividual variability is explained by implementation of covariates in the model. The widely used forward stepwise selection method is sensitive to bias, which may lead to an incorrect inclusion of covariates. Alternatives, such as the full fixed effects model, reduce this bias but are dependent on the chosen implementation of each covariate. As the correct functional forms are unknown, this may still lead to an inaccurate selection of covariates. Machine learning (ML) techniques can potentially be used to learn the optimal functional forms for implementing covariates directly from data. A recent study suggested that using ML resulted in an improved selection of influential covariates. However, how do we select the appropriate functional form for including these covariates? In this work, we use SHapley Additive exPlanations (SHAP) to infer the relationship between covariates and PK parameters from ML models. As a case‐study, we use data from 119 patients with hemophilia A receiving clotting factor VIII concentrate peri‐operatively. We fit both a random forest and a XGBoost model to predict empirical Bayes estimated clearance and central volume from a base nonlinear mixed effects model. Next, we show that SHAP reveals covariate relationships which match previous findings. In addition, we can reveal subtle effects arising from combinations of covariates difficult to obtain using other methods of covariate analysis. We conclude that the proposed method can be used to extend ML‐based covariate selection, and holds potential as a complete full model alternative to classical covariate analyses. [ABSTRACT FROM AUTHOR]

Published
2022
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37. The Hypercoagulable State in Cushingʼs Disease Is Associated with Increased Levels of Procoagulant Factors and Impaired Fibrinolysis, But Is Not Reversible after Short-Term Biochemical Remission Induced by Medical Therapy

Author

van der Pas, R., de Bruin, C., Leebeek, F. W. G., de Maat, M. P. M., Rijken, D. C., Pereira, A. M., Romijn, J. A., Netea-Maier, R. T., Hermus, A. R., Zelissen, P. M. J., de Jong, F. H., van der Lely, A. J., de Herder, W. W., Lamberts, S. W. J., Hofland, L. J., and Feelders, R. A.

Published
2012

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