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1. Bridging Impulse Control of Piecewise Deterministic Markov Processes and Markov Decision Processes: Frameworks, Extensions, and Open Challenges

Author

Cleynen, Alice, de Saporta, Benoîte, Rossini, Orlane, Sabbadin, Régis, and Vernay, Amélie

Subjects
Statistics - Methodology, Electrical Engineering and Systems Science - Systems and Control
Abstract

Control theory plays a pivotal role in understanding and optimizing the behavior of complex dynamical systems across various scientific and engineering disciplines. Two key frameworks that have emerged for modeling and solving control problems in stochastic systems are piecewise deterministic Markov processes (PDMPs) and Markov decision processes (MDPs). Each framework has its unique strengths, and their intersection offers promising opportunities for tackling a broad class of problems, particularly in the context of impulse controls and decision-making in complex systems. The relationship between PDMPs and MDPs is a natural subject of exploration, as embedding impulse control problems for PDMPs into the MDP framework could open new avenues for their analysis and resolution. Specifically, this integration would allow leveraging the computational and theoretical tools developed for MDPs to address the challenges inherent in PDMPs. On the other hand, PDMPs can offer a versatile and simple paradigm to model continuous time problems that are often described as discrete-time MDPs parametrized by complex transition kernels. This transformation has the potential to bridge the gap between the two frameworks, enabling solutions to previously intractable problems and expanding the scope of both fields. This paper presents a comprehensive review of two research domains, illustrated through a recurring medical example. The example is revisited and progressively formalized within the framework of thevarious concepts and objects introduced

Published
2025

2. Expressed fusion gene landscape and its impact in multiple myeloma

Author

A. Cleynen, R. Szalat, M. Kemal Samur, S. Robiou du Pont, L. Buisson, E. Boyle, M. L. Chretien, K. Anderson, S. Minvielle, P. Moreau, M. Attal, G. Parmigiani, J. Corre, N. Munshi, and H. Avet-Loiseau

Subjects
Science
Abstract

Multiple myeloma is a malignancy of plasma cells in the blood. Here, the authors establish the landscape of fusion genes within this disease, identifying novel recurrent fusion genes that impact survival and may drive disease progression.

Published
2017
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3. Medical follow-up optimization: A Monte-Carlo planning strategy

Author

de Saporta, Benoîte, d'Argenlieu, Aymar Thierry, Sabbadin, Régis, and Cleynen, Alice

Subjects
Mathematics - Optimization and Control
Abstract

Designing patient-specific follow-up strategy is a crucial step towards personalized medicine in cancer. Tools to help doctors deciding on treatment allocation together with next visit date, based on patient preferences and medical observations, would be particularly beneficial. Such tools should be based on realistic models of disease progress under the impact of medical treatments, involve the design of (multi-)objective functions that a treatment strategy should optimize along the patient's medical journey, and include efficient resolution algorithms to optimize personalized follow-up by taking the patient's history and preferences into account. We propose to model cancer evolution with a Piecewise Deterministic Markov Process where patients alternate between remission and relapse phases with disease-specific tumor evolution. This model is controlled via the online optimization of a long-term cost function accounting for treatment side-effects, hospital visits burden and disease impact on the quality of life. Optimization is based on noisy measurements of blood markers at visit dates. We leverage the Partially-Observed Monte-Carlo Planning algorithm to solve this continuous-time, continuous-state problem, taking advantage of the nearly-deterministic nature of cancer evolution. We show that this approximate solution approach of the exact model performs better than the counterpart exact resolution of the discrete model, while allowing for more versatility in the cost function model.

Published
2024

4. Embedding risk monitoring in infectious disease surveillance for timely and effective outbreak prevention and control

Author

Marianne A B van der Sande, Niel Hens, Brecht Ingelbeen, Placide Mbala, Esther van Kleef, Ivalda Macicame, Kostas Danis, and Eveline Cleynen

Subjects
Medicine (General), R5-920, Infectious and parasitic diseases, RC109-216
Abstract

Epidemic intelligence efforts aim to predict, timely detect and assess (re-)emerging pathogens, guide and evaluate infectious disease prevention or control. We emphasise the underused potential of integrating the monitoring of risks related to exposure, disease or death, particularly in settings where limited diagnostic capacity and access to healthcare hamper timely prevention/control measures. Monitoring One Health exposures, human behaviour, immunity, comorbidities, uptake of control measures or pathogen characteristics can complement facility-based surveillance in generating signals of imminent or ongoing outbreaks, and in targeting preventive/control interventions or epidemic preparedness to high-risk areas or subpopulations. Low-cost risk data sources include electronic medical records, existing household/patient/environmental surveys, Health and Demographic Surveillance Systems, medicine distribution and programmatic data. Public health authorities need to identify and prioritise risk data that effectively fill gaps in intelligence that facility-based surveillance can not timely or accurately answer, determine indicators to generate from the data, ensure data availability, regular analysis and dissemination.

Published
2025
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5. Numerical method to solve impulse control problems for partially observed piecewise deterministic Markov processes

Author

Cleynen, Alice and de Saporta, Benoîte

Subjects
Mathematics - Statistics Theory, Mathematics - Optimization and Control
Abstract

Designing efficient and rigorous numerical methods for sequential decision-making under uncertainty is a difficult problem that arises in many applications frameworks. In this paper we focus on the numerical solution of a subclass of impulse control problem for piecewise deterministic Markov process (PDMP) when the jump times are hidden. We first state the problem as a partially observed Markov decision process (POMDP) on a continuous state space and with controlled transition kernels corresponding to some specific skeleton chains of the PDMP. Then we proceed to build a numerically tractable approximation of the POMDP by tailor-made discretizations of the state spaces. The main difficulty in evaluating the discretization error come from the possible random or boundary jumps of the PDMP between consecutive epochs of the POMDP and requires special care. Finally we extensively discuss the practical construction of discretization grids and illustrate our method on simulations.

Published
2021

6. Peer-Graded Individualised Student Homework in a Single-Instructor Undergraduate Engineering Course

Author

Cleynen, Olivier, Santa-Maria, Germán, Magdowski, Mathias, and Thévenin, Dominique

Abstract

This article reports on the implementation of a programme of individualised, peer-graded homework assignments in a large-scale engineering course, with minimal resources. Participation in the programme allows students to receive grades for problem-solving work in a setting more conducive to learning than the traditional final examination. The homework programme was designed to support the ordinary course work and examination preparation of students along the semester, rather than an expansion of the curriculum. The implementation is carried out using a series of scripts on a local computer, for speed of deployment, portability and privacy protection. Data relevant to instructors are provided, showing that the programme integrates well within an existing grading system, at a relatively low time cost for the instructor, resulting in a relatively large enhancement in the students' learning experience.

Published
2020

7. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Author

Cleynen, Isabelle, Engchuan, Worrawat, Hestand, Matthew S, Heung, Tracy, Holleman, Aaron M, Johnston, H Richard, Monfeuga, Thomas, McDonald-McGinn, Donna M, Gur, Raquel E, Morrow, Bernice E, Swillen, Ann, Vorstman, Jacob AS, Bearden, Carrie E, Chow, Eva WC, van den Bree, Marianne, Emanuel, Beverly S, Vermeesch, Joris R, Warren, Stephen T, Owen, Michael J, Chopra, Pankaj, Cutler, David J, Duncan, Richard, Kotlar, Alex V, Mulle, Jennifer G, Voss, Anna J, Zwick, Michael E, Diacou, Alexander, Golden, Aaron, Guo, Tingwei, Lin, Jhih-Rong, Wang, Tao, Zhang, Zhengdong, Zhao, Yingjie, Marshall, Christian, Merico, Daniele, Jin, Andrea, Lilley, Brenna, Salmons, Harold I, Tran, Oanh, Holmans, Peter, Pardinas, Antonio, Walters, James TR, Demaerel, Wolfram, Boot, Erik, Butcher, Nancy J, Costain, Gregory A, Lowther, Chelsea, Evers, Rens, van Amelsvoort, Therese AMJ, van Duin, Esther, Vingerhoets, Claudia, Breckpot, Jeroen, Devriendt, Koen, Vergaelen, Elfi, Vogels, Annick, Crowley, T Blaine, McGinn, Daniel E, Moss, Edward M, Sharkus, Robert J, Unolt, Marta, Zackai, Elaine H, Calkins, Monica E, Gallagher, Robert S, Gur, Ruben C, Tang, Sunny X, Fritsch, Rosemarie, Ornstein, Claudia, Repetto, Gabriela M, Breetvelt, Elemi, Duijff, Sasja N, Fiksinski, Ania, Moss, Hayley, Niarchou, Maria, Murphy, Kieran C, Prasad, Sarah E, Daly, Eileen M, Gudbrandsen, Maria, Murphy, Clodagh M, Murphy, Declan G, Buzzanca, Antonio, Fabio, Fabio Di, Digilio, Maria C, Pontillo, Maria, Marino, Bruno, Vicari, Stefano, Coleman, Karlene, Cubells, Joseph F, Ousley, Opal Y, Carmel, Miri, Gothelf, Doron, Mekori-Domachevsky, Ehud, Michaelovsky, Elena, Weinberger, Ronnie, Weizman, Abraham, Kushan, Leila, Jalbrzikowski, Maria, Armando, Marco, Eliez, Stéphan, Sandini, Corrado, and Schneider, Maude

Subjects
International 22q11.2DS Brain and Behavior Consortium, Prevention, Serious Mental Illness, Genetics, Human Genome, Schizophrenia, Neurosciences, Mental Health, Clinical Research, Pediatric, Brain Disorders, 2.1 Biological and endogenous factors, Mental health, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

Published
2021

9. A Monte-Carlo planning strategy for medical follow-up optimization: Illustration on multiple myeloma data.

Author

Benoîte de Saporta, Aymar Thierry d'Argenlieu, Régis Sabbadin, and Alice Cleynen

Subjects
Medicine, Science
Abstract

Designing patient-specific follow-up strategies is key to personalized cancer care. Tools to assist doctors in treatment decisions and scheduling follow-ups based on patient preferences and medical data would be highly beneficial. These tools should incorporate realistic models of disease progression under treatment, multi-objective optimization of treatment strategies, and efficient algorithms to personalize follow-ups by considering patient history. We propose modeling cancer evolution using a Piecewise Deterministic Markov Process, where patients alternate between remission and relapse phases, and control the model via long-term cost function optimization. This considers treatment side effects, visit burden, and quality of life, using noisy blood marker measurements for feedback. Instead of discretizing the problem with a discrete Markov Decision Process, we apply the Partially-Observed Monte-Carlo Planning algorithm to solve the continuous-time, continuous-state problem, leveraging the near-deterministic nature of cancer progression. Our approach, tested on multiple myeloma patient data, outperforms exact solutions of the discrete model and allows greater flexibility in cost function modeling, enabling patient-specific follow-ups. This method can also be adapted to other diseases.

Published
2024
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10. HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Author

Akar, Alaa, Flemming, Cornelius, Felix, Flomm, Flosbach, Markus, Jäger, Julia, Jeromin, Niklas, Jung, Johannes, Ohms, Mareike, Reinshagen, Konrad, Rische, Johann, Sagebiel, Adrian, Sandfort, Deborah, Steinert, Fenja, Tomuschat, Christian, Wesche, Jasmin, Shifteh Abedian, Abraham, Clara, Achkar, Jean-Paul, Ahmad, Tariq, Alberts, Rudi, Alizadeh, Behrooz, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Anderson, Carl A., Andrews, Jane M., Annese, Vito, Aumais, Guy, Baidoo, Leonard, Baldassano, Robert N., Bampton, Peter A., Barclay, Murray, Barrett, Jeffrey C., Bethge, Johannes, Bewshea, Claire, Bis, Joshua C., Bitton, Alain, BK, Thelma, Boucher, Gabrielle, Brain, Oliver, Brand, Stephan, Brant, Steven R., Cheon, Jae Hee, Chew, Angela, Cho, Judy H., Cleynen, Isabelle, Cohain, Ariella, Cooney, Rachel, Croft, Anthony, Daly, Mark J., D'Amato, Mauro, Danese, Silvio, Daryani, Naser Ebrahim, Datta, Lisa Wu, Degenhardt, Frauke, Denapiene, Goda, Denson, Lee A., Devaney, Kathy L., Dewit, Olivier, D'Inca, Renata, Drummond, Hazel E., Dubinsky, Marla, Duerr, Richard H., Edwards, Cathryn, Ellinghaus, David, Ellul, Pierre, Esaki, Motohiro, Essers, Jonah, Ferguson, Lynnette R., Festen, Eleonora A., Fleshner, Philip, Florin, Tim, Franchimont, Denis, Franke, Andre, Fuyuno, Yuta, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Goyette, Philippe, Green, Todd, Griffiths, Anne M., Guthery, Stephen L., Hakonarson, Hakon, Halfvarson, Jonas, Hanigan, Katherine, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hayward, Nicholas K., Hedl, Matija, Henderson, Paul, Hold, Georgina L., Hong, Myhunghee, Hu, Xinli, Huang, Hailiang, Hugot, Jean-Pierre, Hui, Ken Y., Imielinski, Marcin, Jazayeri, Omid, Jonaitis, Laimas, Jostins, Luke, Juyal, Garima, Chandra Juyal, Ramesh, Kalla, Rahul, Karlsen, Tom H., Kennedy, Nicholas A., Khan, Mohammed Azam, Kim, Won Ho, Kitazono, Takanari, Kiudelis, Gediminas, Kubo, Michiaki, Kugathasan, Subra, Kupcinskas, Limas, Lamb, Christopher A., de Lange, Katrina M., Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lee, James C., Lees, Charlie W., Leja, Marcis, Lewis, Nina, Van Limbergen, Johan, Lionetti, Paolo, Liu, Jimmy Z., Louis, Edouard, Luo, Yang, Mahy, Gillian, Malekzadeh, Masoud Mohammad, Malekzadeh, Reza, Mansfield, John, Marriott, Suzie, Massey, Dunecan, Mathew, Christopher G., Matsui, Toshiyuki, McGovern, Dermot P.B., van der Meulen, Andrea, Midha, Vandana, Milgrom, Raquel, Mirzaei, Samaneh, Mitrovic, Mitja, Montgomery, Grant W., Mowat, Craig, Müller, Christoph, Newman, William G., Ng, Aylwin, Ng, Siew C., Evelyn Ng, Sok Meng, Nikolaus, Susanna, Ning, Kaida, Nöthen, Markus, Oikonomou, Ioannis, Okou, David, Orchard, Timothy R., Palmieri, Orazio, Parkes, Miles, Phillips, Anne, Ponsioen, Cyriel Y., Potocnik, Urõs, Poustchi, Hossein, Prescott, Natalie J., Proctor, Deborah D., Radford-Smith, Graham, Rahier, Jean- Francois, Regueiro, Miguel, Reinisch, Walter, Rieder, Florian, Rioux, John D., Roberts, Rebecca, Rogler, Gerhard, Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schadt, Eric E., Scharl, Michael, Schembri, John, Schreiber, Stefan, Schumm, L. Philip, Scott, Regan, Seielstad, Mark, Shah, Tejas, Sharma, Yashoda, Silverberg, Mark S., Simmons, Alison, Simms, Lisa A., Singh, Abhey, Skieceviciene, Jurgita, van Sommeren, Suzanne, Song, Kyuyoung, Sood, Ajit, Spain, Sarah L., Steinhart, A. Hillary, Stempak, Joanne M., Stronati, Laura, Sung, Joseph J.Y., Targan, Stephan R., Taylor, Kirstin M., Theatre, Emilie, Torkvist, Leif, Torres, Esther A., Tremelling, Mark, Uhlig, Holm H., Umeno, Junji, Vahedi, Homayon, Vasiliauskas, Eric, Velde, Anje ter, Ventham, Nicholas T., Vermeire, Severine, Verspaget, Hein W., De Vos, Martine, Walters, Thomas, Wang, Kai, Wang, Ming-Hsi, Weersma, Rinse K., Wei, Zhi, Whiteman, David, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Wong, Sunny H., Xavier, Ramnik J., Yamazaki, Keiko, Yang, Suk-Kyun, Ye, Byong Duk, Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhang, Hu, Zhang, Wei, Zhao, Hongyu, Zhao, Zhen Z., Baumdick, Martin E., Niehrs, Annika, Schwerk, Maria, Hinrichs, Ole, Jordan-Paiz, Ana, Padoan, Benedetta, Wegner, Lucy H.M., Schloer, Sebastian, Zecher, Britta F., Malsy, Jakob, Joshi, Vinita R., Illig, Christin, Schröder-Schwarz, Jennifer, Möller, Kimberly J., Martin, Maureen P., Yuki, Yuko, Ozawa, Mikki, Sauter, Jürgen, Schmidt, Alexander H., Perez, Daniel, Giannou, Anastasios D., Carrington, Mary, Davis, Randall S., Schumacher, Udo, Sauter, Guido, Huber, Samuel, Puelles, Victor G., Melling, Nathaniel, Altfeld, Marcus, and Bunders, Madeleine J.

Published
2023
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11. Evaluation of mineralogy per geological layers by Approximate Bayesian Computation

Author

Bruned, Vianney, Cleynen, Alice, Mas, André, and Wlodarczyck, Sylvain

Subjects
Statistics - Applications, Physics - Geophysics
Abstract

We propose a new methodology to perform mineralogic inversion from wellbore logs based on a Bayesian linear regression model. Our method essentially relies on three steps. The first step makes use of Approximate Bayesian Computation (ABC) and selects from the Bayesian generator a set of candidates-volumes corresponding closely to the wellbore data responses. The second step gathers these candidates through a density-based clustering algorithm. A mineral scenario is assigned to each cluster through direct mineralogical inversion, and we provide a confidence estimate for each lithological hypothesis. The advantage of this approach is to explore all possible mineralogy hypotheses that match the wellbore data. This pipeline is tested on both synthetic and real datasets.

Published
2019

13. Genomic analyses of hair from Ludwig van Beethoven

Author

Begg, Tristan James Alexander, Schmidt, Axel, Kocher, Arthur, Larmuseau, Maarten H.D., Runfeldt, Göran, Maier, Paul Andrew, Wilson, John D., Barquera, Rodrigo, Maj, Carlo, Szolek, András, Sager, Michael, Clayton, Stephen, Peltzer, Alexander, Hui, Ruoyun, Ronge, Julia, Reiter, Ella, Freund, Cäcilia, Burri, Marta, Aron, Franziska, Tiliakou, Anthi, Osborn, Joanna, Behar, Doron M., Boecker, Malte, Brandt, Guido, Cleynen, Isabelle, Strassburg, Christian, Prüfer, Kay, Kühnert, Denise, Meredith, William Rhea, Nöthen, Markus M., Attenborough, Robert David, Kivisild, Toomas, and Krause, Johannes

Published
2023
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14. Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects

Author

Zhao, Yingjie, Diacou, Alexander, Johnston, H Richard, Musfee, Fadi I, McDonald-McGinn, Donna M, McGinn, Daniel, Crowley, T Blaine, Repetto, Gabriela M, Swillen, Ann, Breckpot, Jeroen, Vermeesch, Joris R, Kates, Wendy R, Digilio, M Cristina, Unolt, Marta, Marino, Bruno, Pontillo, Maria, Armando, Marco, Di Fabio, Fabio, Vicari, Stefano, van den Bree, Marianne, Moss, Hayley, Owen, Michael J, Murphy, Kieran C, Murphy, Clodagh M, Murphy, Declan, Schoch, Kelly, Shashi, Vandana, Tassone, Flora, Simon, Tony J, Shprintzen, Robert J, Campbell, Linda, Philip, Nicole, Heine-Suñer, Damian, García-Miñaúr, Sixto, Fernández, Luis, Consortium, International 22q11 2 Brain and Behavior, Antonarakis, Stylianos E, Biondi, Massimo, Boot, Erik, Breetvelt, Elemi, Busa, Tiffany, Butcher, Nancy, Buzzanca, Antonino, Carmel, Miri, Cleynen, Isabelle, Cutler, David, Dallapiccola, Bruno, de la Fuente Sanches, María Angeles, Epstein, Michael P, Evers, Rens, Fernandez, Luis, Fritsch, Rosemarie, Algas, Fernando García, Guo, Tingwei, Gur, Raquel, Hestand, Matthew S, Heung, Tracy, Hooper, Stephen, Jin, Andrea, Kushan-Wells, Leila, Laorden-Nieto, Alejandra Teresa, Lattanzi, Guido, Marshall, Christian, McCabe, Kathryn, Michaelovsky, Elena, Ornstein, Claudia, Silversides, Candice, Tran, Oanh, van Duin, Esther DA, Vergaelen, Elfi, Warren, Steve T, Weinberger, Ronnie, Weizman, Abraham, Zhang, Zhengdong, Zwick, Michael, Bearden, Carrie E, Vingerhoets, Claudia, van Amelsvoort, Therese, Eliez, Stephan, Schneider, Maude, Vorstman, Jacob AS, Gothelf, Doron, Zackai, Elaine, Agopian, AJ, Gur, Raquel E, Bassett, Anne S, Emanuel, Beverly S, Goldmuntz, Elizabeth, Mitchell, Laura E, Wang, Tao, and Morrow, Bernice E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Clinical Research, Human Genome, Heart Disease, Cardiovascular, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Chromosome Deletion, Chromosomes, Human, Pair 22, Cohort Studies, Female, Genome-Wide Association Study, Heart Defects, Congenital, Humans, Linkage Disequilibrium, Male, Phenotype, Polymorphism, Single Nucleotide, Proto-Oncogene Mas, Segmental Duplications, Genomic, International 22q11.2 Brain and Behavior Consortium, CRKL, DiGeorge syndrome, TBX1, chromosome 22q11.2 deletion syndrome, complex trait, congenital heart disease, conotruncal heart defects, copy number variation, genetic association, genetic modifier, haploinsufficiency, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

Published
2020

15. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Author

Sazonovs, Aleksejs, Stevens, Christine R., Venkataraman, Guhan R., Yuan, Kai, Avila, Brandon, Abreu, Maria T., Ahmad, Tariq, Allez, Matthieu, Ananthakrishnan, Ashwin N., Atzmon, Gil, Baras, Aris, Barrett, Jeffrey C., Barzilai, Nir, Beaugerie, Laurent, Beecham, Ashley, Bernstein, Charles N., Bitton, Alain, Bokemeyer, Bernd, Chan, Andrew, Chung, Daniel, Cleynen, Isabelle, Cosnes, Jacques, Cutler, David J., Daly, Allan, Damas, Oriana M., Datta, Lisa W., Dawany, Noor, Devoto, Marcella, Dodge, Sheila, Ellinghaus, Eva, Fachal, Laura, Farkkila, Martti, Faubion, William, Ferreira, Manuel, Franchimont, Denis, Gabriel, Stacey B., Ge, Tian, Georges, Michel, Gettler, Kyle, Giri, Mamta, Glaser, Benjamin, Goerg, Siegfried, Goyette, Philippe, Graham, Daniel, Hämäläinen, Eija, Haritunians, Talin, Heap, Graham A., Hiltunen, Mikko, Hoeppner, Marc, Horowitz, Julie E., Irving, Peter, Iyer, Vivek, Jalas, Chaim, Kelsen, Judith, Khalili, Hamed, Kirschner, Barbara S., Kontula, Kimmo, Koskela, Jukka T., Kugathasan, Subra, Kupcinskas, Juozas, Lamb, Christopher A., Laudes, Matthias, Lévesque, Chloé, Levine, Adam P., Lewis, James D., Liefferinckx, Claire, Loescher, Britt-Sabina, Louis, Edouard, Mansfield, John, May, Sandra, McCauley, Jacob L., Mengesha, Emebet, Mni, Myriam, Moayyedi, Paul, Moran, Christopher J., Newberry, Rodney D., O’Charoen, Sirimon, Okou, David T., Oldenburg, Bas, Ostrer, Harry, Palotie, Aarno, Paquette, Jean, Pekow, Joel, Peter, Inga, Pierik, Marieke J., Ponsioen, Cyriel Y., Pontikos, Nikolas, Prescott, Natalie, Pulver, Ann E., Rahmouni, Souad, Rice, Daniel L., Saavalainen, Päivi, Sands, Bruce, Sartor, R. Balfour, Schiff, Elena R., Schreiber, Stefan, Schumm, L. Philip, Segal, Anthony W., Seksik, Philippe, Shawky, Rasha, Sheikh, Shehzad Z., Silverberg, Mark S., Simmons, Alison, Skeiceviciene, Jurgita, Sokol, Harry, Solomonson, Matthew, Somineni, Hari, Sun, Dylan, Targan, Stephan, Turner, Dan, Uhlig, Holm H., van der Meulen, Andrea E., Vermeire, Séverine, Verstockt, Sare, Voskuil, Michiel D., Winter, Harland S., Young, Justine, Duerr, Richard H., Franke, Andre, Brant, Steven R., Cho, Judy, Weersma, Rinse K., Parkes, Miles, Xavier, Ramnik J., Rivas, Manuel A., Rioux, John D., McGovern, Dermot P. B., Huang, Hailiang, Anderson, Carl A., and Daly, Mark J.

Published
2022
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16. Change-point detection for Piecewise Deterministic Markov Processes

Author

Cleynen, Alice and de Saporta, Benoîte

Subjects
Mathematics - Optimization and Control
Abstract

We consider a change-point detection problem for a simple class of Piecewise Deterministic Markov Processes (PDMPs). A continuous-time PDMP is observed in discrete time and through noise, and the aim is to propose a numerical method to accurately detect both the date of the change of dynamics and the new regime after the change. To do so, we state the problem as an optimal stopping problem for a partially observed discrete-time Markov decision process taking values in a continuous state space and provide a discretization of the state space based on quantization to approximate the value function and build a tractable stopping policy. We provide error bounds for the approximation of the value function and numerical simulations to assess the performance of our candidate policy.

Published
2017

19. A Monte-Carlo planning strategy for medical follow-up optimization: Illustration on multiple myeloma data.

Author

de Saporta, Benoîte, Thierry d'Argenlieu, Aymar, Sabbadin, Régis, and Cleynen, Alice

Subjects
COST functions, MULTI-objective optimization, MARKOV processes, MULTIPLE myeloma, CANCER treatment
Abstract

Designing patient-specific follow-up strategies is key to personalized cancer care. Tools to assist doctors in treatment decisions and scheduling follow-ups based on patient preferences and medical data would be highly beneficial. These tools should incorporate realistic models of disease progression under treatment, multi-objective optimization of treatment strategies, and efficient algorithms to personalize follow-ups by considering patient history. We propose modeling cancer evolution using a Piecewise Deterministic Markov Process, where patients alternate between remission and relapse phases, and control the model via long-term cost function optimization. This considers treatment side effects, visit burden, and quality of life, using noisy blood marker measurements for feedback. Instead of discretizing the problem with a discrete Markov Decision Process, we apply the Partially-Observed Monte-Carlo Planning algorithm to solve the continuous-time, continuous-state problem, leveraging the near-deterministic nature of cancer progression. Our approach, tested on multiple myeloma patient data, outperforms exact solutions of the discrete model and allows greater flexibility in cost function modeling, enabling patient-specific follow-ups. This method can also be adapted to other diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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20. Associations between AD polygenic risk scores and global amyloid deposition in the European AMYPAD consortium.

Author

Luckett, Emma S., Abakkouy, Yasmina, Collij, Lyduine E., García, David Vállez, Alves, Isadora Lopes, Lorenzini, Luigi, Gispert, Juan Domingo, Visser, Pieter Jelle, den Braber, Anouk, Ritchie, Craig W, Vandenberghe, Rik, Wolz, Robin, Shekari, Mahnaz, Vilor‐Tejedor, Natalia, Farrar, Gill, Barkhof, Frederik, and Cleynen, Isabelle

Abstract

Background: Published data have highlighted associations between Alzheimer's disease (AD) susceptibility loci and AD‐related brain changes. The amyloid imaging to prevent AD (AMYPAD) consortium is a European collaboration consisting of several parent cohorts, four of which had raw genotype array data available. We sought to integrate and harmonise the genetic data, calculate AD polygenic risk scores (PRS), and investigate their association with global amyloid deposition. Method: Raw genetic data (GRCh37) was available for 753 non‐demented participants, which underwent standard pre‐imputation quality control (QC) using PLINK. Imputation was performed using the Michigan Imputation server and HRC reference panel, and standard post‐imputation QC was done prior to the final merging of cohorts. PRSice was used for PRS calculations with Stage 1 summary statistics from Kunkle et al. (2019) as base file and European individuals from 1000 Genomes as reference for clumping. We calculated several builds of PRS at three p‐value thresholds for SNP inclusion: 5 × 10‐8, 1 × 10‐5, and 0.1. These included PRSall, PRSAPOEonly (Chr19:45‐48.8Mb), APOEε2+ε4 (the weighted sum of the two major APOE SNPs rs429358 and rs7412), PRSnoAPOE (all SNPs excluding Chr19:45‐48.8Mb), and a composite PRSnoAPOE+APOEε2+ε4. All were corrected for genetic principal components 1‐5 and standardised against 1000 Genomes. Cross‐sectional global amyloid burden (expressed in Centiloids) was available for everyone. Linear regression models determined if PRS were associated with amyloid deposition (age, sex, and education as covariates). Significance was based on an uncorrected p<0.05 divided by the number of SNP inclusion thresholds (N = 3). Result: Participants were 66.9±7.6 years, 58.6% female, and 207 (27%) considered amyloid positive (CL>21). In this preliminary analysis, we found that most PRS builds were significantly associated with amyloid at all SNP inclusion thresholds assessed (Table 1, representative plots Fig. 1A,1B), except for PRSnoAPOE (Table 1, representative plot Fig. 1C). Conclusion: We highlight the significant influence of APOE in determining AD genetic predisposition, and that AD PRS are associated with amyloid deposition. Our results show that AMYPAD is a suitable cohort for studying genetic factors driving amyloid deposition before clinical onset, which we aim to extend with the inclusion of more parent cohorts, and regional and longitudinal amyloid data. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Plasma pTau181 and pTau217 predict asymptomatic amyloid accumulation equally well as amyloid-PET

Author

De Meyer, Steffi, primary, Schaeverbeke, Jolien M, additional, Luckett, Emma S, additional, Reinartz, Mariska, additional, Blujdea, Elena R, additional, Cleynen, Isabelle, additional, Dupont, Patrick, additional, Van Laere, Koen, additional, Vanbrabant, Jeroen, additional, Stoops, Erik, additional, Vanmechelen, Eugeen, additional, di Molfetta, Guglielmo, additional, Zetterberg, Henrik, additional, Ashton, Nicholas J, additional, Teunissen, Charlotte E, additional, Poesen, Koen, additional, and Vandenberghe, Rik, additional

Published
2024
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23. Model selection for the segmentation of multiparameter exponential family distributions

Author

Cleynen, Alice and Lebarbier, Emilie

Subjects
Mathematics - Statistics Theory
Abstract

We consider the segmentation problem of univariate distributions from the exponential family with multiple parameters. In segmentation, the choice of the number of segments remains a difficult issue due to the discrete nature of the change-points. In this general exponential family distribution framework, we propose a penalized log-likelihood estimator where the penalty is inspired by papers of L. Birg\'e and P. Massart. The resulting estimator is proved to satisfy an oracle inequality. We then further study the particular case of categorical variables by comparing the values of the key constants when derived from the specification of our general approach and when obtained by working directly with the characteristics of this distribution. Finally, a simulation study is conducted to assess the performance of our criterion for the exponential distribution, and an application on real data modelled by the categorical distribution is provided.

Published
2014

24. Peer-graded individualised student homework in a single-instructor undergraduate engineering course

Author

Olivier Cleynen, Germán Santa-Maria, Mathias Magdowski, and Dominique Thévenin

Subjects
peer grading, flipped classroom, student feedback, active learning, engineering education, problem solving, Education
Abstract

This article reports on the implementation of a programme of individualised, peer-graded homework assignments in a large-scale engineering course, with minimal resources. Participation in the programme allows students to receive grades for problem-solving work in a setting more conducive to learning than the traditional final examination. The homework programme was designed to support the ordinary course work and examination preparation of students along the semester, rather than an expansion of the curriculum. The implementation is carried out using a series of scripts on a local computer, for speed of deployment, portability and privacy protection. Data relevant to instructors are provided, showing that the programme integrates well within an existing grading system, at a relatively low time cost for the instructor, resulting in a relatively large enhancement in the students’ learning experience.

Published
2020
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25. Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects

Author

Antonarakis, Stylianos E., Biondi, Massimo, Boot, Erik, Breetvelt, Elemi, Busa, Tiffany, Butcher, Nancy, Buzzanca, Antonino, Carmel, Miri, Cleynen, Isabelle, Cutler, David, Dallapiccola, Bruno, de la Fuente Sanches, María Angeles, Epstein, Michael P., Evers, Rens, Fernandez, Luis, Fritsch, Rosemarie, Algas, Fernando García, Guo, Tingwei, Gur, Raquel, Hestand, Matthew S., Heung, Tracy, Hooper, Stephen, Jin, Andrea, Kushan-Wells, Leila, Laorden-Nieto, Alejandra Teresa, Lattanzi, Guido, Marshall, Christian, McCabe, Kathryn, Michaelovsky, Elena, Ornstein, Claudia, Silversides, Candice, Tran, Oanh, van Duin, Esther D.A., Vergaelen, Elfi, Warren, Steve T., Weinberger, Ronnie, Weizman, Abraham, Zhang, Zhengdong, Zwick, Michael, Zhao, Yingjie, Diacou, Alexander, Johnston, H. Richard, Musfee, Fadi I., McDonald-McGinn, Donna M., McGinn, Daniel, Crowley, T. Blaine, Repetto, Gabriela M., Swillen, Ann, Breckpot, Jeroen, Vermeesch, Joris R., Kates, Wendy R., Digilio, M. Cristina, Unolt, Marta, Marino, Bruno, Pontillo, Maria, Armando, Marco, Di Fabio, Fabio, Vicari, Stefano, van den Bree, Marianne, Moss, Hayley, Owen, Michael J., Murphy, Kieran C., Murphy, Clodagh M., Murphy, Declan, Schoch, Kelly, Shashi, Vandana, Tassone, Flora, Simon, Tony J., Shprintzen, Robert J., Campbell, Linda, Philip, Nicole, Heine-Suñer, Damian, García-Miñaúr, Sixto, Fernández, Luis, Bearden, Carrie E., Vingerhoets, Claudia, van Amelsvoort, Therese, Eliez, Stephan, Schneider, Maude, Vorstman, Jacob A.S., Gothelf, Doron, Zackai, Elaine, Agopian, A.J., Gur, Raquel E., Bassett, Anne S., Emanuel, Beverly S., Goldmuntz, Elizabeth, Mitchell, Laura E., Wang, Tao, and Morrow, Bernice E.

Published
2020
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27. Comparing change-point locations of independent profiles with application to gene annotation

Author

Cleynen, Alice and Robin, Stéphane

Subjects
Statistics - Applications, 62F15, 62F25, 62P10, 92D20
Abstract

We are interested in the comparison of transcript boundaries from cells which originated in different environments. The goal is to assess whether this phenomenon, called differential splicing, is used to modify the transcription of the genome in response to stress factors. We address this question by comparing the change-points locations in the individual segmentation of each profile, which correspond to the RNA-Seq data for a gene in one growth condition. This requires the ability to evaluate the uncertainty of the change-point positions, and the work of Rigaill et. al. (2011) provides an appropriate framework in such case. Building on their approach, we propose two methods for the comparison of change-points, and illustrate our results on a dataset from the yeast specie. We show that the UTR boundaries are subject to differential splicing, while the intron boundaries are conserved in all profiles. Our approach is implemented in an R package called EBS which is available on the CRAN.

Published
2013

28. Finite state space non parametric Hidden Markov Models are in general identifiable

Author

Gassiat, Elisabeth, Cleynen, Alice, and Robin, Stéphane

Subjects
Statistics - Methodology
Abstract

In this paper, we prove that finite state space non parametric hidden Markov models are identifiable as soon as the transition matrix of the latent Markov chain has full rank and the emission probability distributions are linearly independent. We then propose several non parametric likelihood based estimation methods, which we apply to models used in applications. We finally show on examples that the use of non parametric modeling and estimation may improve the classification performances.

Published
2013

29. Segmentation of the Poisson and negative binomial rate models: a penalized estimator

Author

Cleynen, Alice and Lebarbier, Emilie

Subjects
Mathematics - Statistics Theory, Statistics - Methodology, 62G05, 62G07, 62P10
Abstract

We consider the segmentation problem of Poisson and negative binomial (i.e. overdispersed Poisson) rate distributions. In segmentation, an important issue remains the choice of the number of segments. To this end, we propose a penalized log-likelihood estimator where the penalty function is constructed in a non-asymptotic context following the works of L. Birg\'e and P. Massart. The resulting estimator is proved to satisfy an oracle inequality. The performances of our criterion is assessed using simulated and real datasets in the RNA-seq data analysis context.

Published
2013

31. Fast estimation of the ICL criterion for change-point detection problems with applications to Next-Generation Sequencing data

Author

Cleynen, Alice, Luong, The Minh, Rigaill, Guillem, and Nuel, Gregory

Subjects
Statistics - Computation, Statistics - Applications
Abstract

In this paper, we consider the Integrated Completed Likelihood (ICL) as a useful criterion for estimating the number of changes in the underlying distribution of data in problems where detecting the precise location of these changes is the main goal. The exact computation of the ICL requires O(Kn2) operations (with K the number of segments and n the number of data-points) which is prohibitive in many practical situations with large sequences of data. We describe a framework to estimate the ICL with O(Kn) complexity. Our approach is general in the sense that it can accommodate any given model distribution. We checked the run-time and validity of our approach on simulated data and demonstrate its good performance when analyzing real Next-Generation Sequencing (NGS) data using a negative binomial model., Comment: 15 pages, 8 figures

Published
2012

32. Segmentor3IsBack: an R package for the fast and exact segmentation of Seq-data

Author

Cleynen, Alice, Koskas, Michel, Lebarbier, Emilie, Rigaill, Guillem, and Robin, Stephane

Subjects
Statistics - Computation
Abstract

Genome annotation is an important issue in biology which has long been addressed with gene prediction methods and manual experiments requiring biological expertise. The expanding Next Generation Sequencing technologies and their enhanced precision allow a new approach to the domain: the segmentation of RNA-Seq data to determine gene boundaries. Because of its almost linear complexity, we propose to use the Pruned Dynamic Programming Algorithm, which performances had been acknowledged for CGH arrays, for Seq-experiment outputs. This requires the adaptation of the algorithm to the negative binomial distribution with which we model the data. We show that if the dispersion in the signal is known, the PDP algorithm can be used and we provide an estimator for this dispersion. We then propose to estimate the number of segments, which can be associated to coding or non-coding regions of the genome, using an oracle penalty. We illustrate the results of our approach on a real data-set and show its good performance. Our algorithm is available as an R package on the CRAN repository.

Published
2012

33. Clinical and genetic determinants of vitamin D receptor expression in cutaneous melanoma patients

Author

De Smedt, Julie, primary, Aura, Claudia, additional, Van Kelst, Sofie, additional, Janssen, Laudine, additional, Marasigan, Vivien, additional, Boecxstaens, Veerle, additional, Stas, Marguerite, additional, Bogaerts, Kris, additional, Belmans, Ann, additional, Cleynen, Isabelle, additional, Vanderschueren, Dirk, additional, Vandenberghe, Katleen, additional, Bechter, Oliver, additional, Nikkels, Arjen, additional, Strobbe, Tinne, additional, Emri, Gabriella, additional, Lambrechts, Dieter, additional, and Garmyn, Marjan, additional

Published
2024
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34. DOP73 Early biological use in a Belgian, prospective inception cohort of patients with Inflammatory Bowel Disease: the PANTHER cohort

Author

Verstockt, S, primary, Glorieus, E, additional, De Wolf, M, additional, Lenfant, M, additional, Barbaraci, M, additional, Sabino, J, additional, Ferrante, M, additional, Geldof, J, additional, Verstockt, B, additional, Laukens, D, additional, Cleynen, I, additional, Vandermeulen, L, additional, Lobaton, T, additional, and Vermeire, S, additional

Published
2024
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41. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.

Author

Liu, Jimmy Z, Hov, Johannes Roksund, Folseraas, Trine, Ellinghaus, Eva, Rushbrook, Simon M, Doncheva, Nadezhda T, Andreassen, Ole A, Weersma, Rinse K, Weismüller, Tobias J, Eksteen, Bertus, Invernizzi, Pietro, Hirschfield, Gideon M, Gotthardt, Daniel Nils, Pares, Albert, Ellinghaus, David, Shah, Tejas, Juran, Brian D, Milkiewicz, Piotr, Rust, Christian, Schramm, Christoph, Müller, Tobias, Srivastava, Brijesh, Dalekos, Georgios, Nöthen, Markus M, Herms, Stefan, Winkelmann, Juliane, Mitrovic, Mitja, Braun, Felix, Ponsioen, Cyriel Y, Croucher, Peter JP, Sterneck, Martina, Teufel, Andreas, Mason, Andrew L, Saarela, Janna, Leppa, Virpi, Dorfman, Ruslan, Alvaro, Domenico, Floreani, Annarosa, Onengut-Gumuscu, Suna, Rich, Stephen S, Thompson, Wesley K, Schork, Andrew J, Næss, Sigrid, Thomsen, Ingo, Mayr, Gabriele, König, Inke R, Hveem, Kristian, Cleynen, Isabelle, Gutierrez-Achury, Javier, Ricaño-Ponce, Isis, van Heel, David, Björnsson, Einar, Sandford, Richard N, Durie, Peter R, Melum, Espen, Vatn, Morten H, Silverberg, Mark S, Duerr, Richard H, Padyukov, Leonid, Brand, Stephan, Sans, Miquel, Annese, Vito, Achkar, Jean-Paul, Boberg, Kirsten Muri, Marschall, Hanns-Ulrich, Chazouillères, Olivier, Bowlus, Christopher L, Wijmenga, Cisca, Schrumpf, Erik, Vermeire, Severine, Albrecht, Mario, UK-PSCSC Consortium, Rioux, John D, Alexander, Graeme, Bergquist, Annika, Cho, Judy, Schreiber, Stefan, Manns, Michael P, Färkkilä, Martti, Dale, Anders M, Chapman, Roger W, Lazaridis, Konstantinos N, International PSC Study Group, Franke, Andre, Anderson, Carl A, Karlsen, Tom H, and International IBD Genetics Consortium

Subjects
UK-PSCSC Consortium, International PSC Study Group, International IBD Genetics Consortium, Humans, Cholangitis, Sclerosing, Oligonucleotide Array Sequence Analysis, Risk Factors, Case-Control Studies, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci, Genetic Pleiotropy, Genotyping Techniques, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

Published
2013

44. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Author

Jostins, Luke, Ripke, Stephan, Weersma, Rinse K, Duerr, Richard H, McGovern, Dermot P, Hui, Ken Y, Lee, James C, Philip Schumm, L, Sharma, Yashoda, Anderson, Carl A, Essers, Jonah, Mitrovic, Mitja, Ning, Kaida, Cleynen, Isabelle, Theatre, Emilie, Spain, Sarah L, Raychaudhuri, Soumya, Goyette, Philippe, Wei, Zhi, Abraham, Clara, Achkar, Jean-Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N, Andersen, Vibeke, Andrews, Jane M, Baidoo, Leonard, Balschun, Tobias, Bampton, Peter A, Bitton, Alain, Boucher, Gabrielle, Brand, Stephan, Büning, Carsten, Cohain, Ariella, Cichon, Sven, D’Amato, Mauro, De Jong, Dirk, Devaney, Kathy L, Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Ferguson, Lynnette R, Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hedl, Matija, Hu, Xinli, Karlsen, Tom H, Kupcinskas, Limas, Kugathasan, Subra, Latiano, Anna, Laukens, Debby, Lawrance, Ian C, Lees, Charlie W, Louis, Edouard, Mahy, Gillian, Mansfield, John, Morgan, Angharad R, Mowat, Craig, Newman, William, Palmieri, Orazio, Ponsioen, Cyriel Y, Potocnik, Uros, Prescott, Natalie J, Regueiro, Miguel, Rotter, Jerome I, Russell, Richard K, Sanderson, Jeremy D, Sans, Miquel, Satsangi, Jack, Schreiber, Stefan, Simms, Lisa A, Sventoraityte, Jurgita, Targan, Stephan R, Taylor, Kent D, Tremelling, Mark, Verspaget, Hein W, De Vos, Martine, Wijmenga, Cisca, Wilson, David C, Winkelmann, Juliane, Xavier, Ramnik J, Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K, Zhao, Hongyu, Silverberg, Mark S, Annese, Vito, Hakonarson, Hakon, Brant, Steven R, Radford-Smith, Graham, Mathew, Christopher G, Rioux, John D, and Schadt, Eric E

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Crohn's Disease, Human Genome, Autoimmune Disease, Inflammatory Bowel Disease, Digestive Diseases, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Colitis, Ulcerative, Crohn Disease, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Haplotypes, Host-Pathogen Interactions, Humans, Inflammatory Bowel Diseases, Mycobacterium, Mycobacterium Infections, Mycobacterium tuberculosis, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, International IBD Genetics Consortium, General Science & Technology
Abstract

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Published
2012

45. Genetic Optimisation of a Free-Stream Water Wheel Using 2D Computational Fluid Dynamics Simulations Points towards Design with Fully Immersed Blades

Author

Abhishekkumar Shingala, Olivier Cleynen, Aman Jain, Stefan Hoerner, and Dominique Thévenin

Subjects
free stream, water wheel, optimisation, computational fluid dynamics, genetic algorithm, Technology
Abstract

A large-scale two-dimensional computational fluid dynamics study is conducted in order to maximise the power output and smoothness of power delivery of a free-stream water wheel, a low-impact hydropower device. Based on models and methods developed in previous research, the study uses a genetic algorithm to optimise the geometry of a wheel with a given radius and depth, maximising two objective functions simultaneously. After convergence and suitable post-processing, a single optimal design is identified, featuring eight shortened blades that become fully immersed at the nadir point. The design results in a 71% reduction in blade material and a 113% increase in the work ratio while improving the hydraulic power by 8% compared to the previous best design. These characteristics are applied retroactively to a broad family of designs, resulting in significant improvements in performance. Analysis of the resulting designs indicates that when either the hydraulic power coefficient, rotor power coefficient, or work ratio is considered, free-stream water wheels with fully immersed blades, whose power mechanisms are shown to rely on lift, as well as drag, outperform all other designs studied so far.

Published
2022
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46. An Efficient Method for Computing the Power Potential of Bypass Hydropower Installations

Author

Olivier Cleynen, Dennis Powalla, Stefan Hoerner, and Dominique Thévenin

Subjects
micro-hydro, pico-hydro, efficiency, computational fluid dynamics, Technology
Abstract

Small-scale hydropower installations make possible a transition towards decentralized electrical power production with very low ecological footprint. However, the prediction of their power potential is difficult, because the incoming flow velocity and the inlet and outlet water heights are often outside of the control of the operator. This leads to a need for a method capable of calculating an installation’s power potential and efficiency rapidly, in order to cover for many possible load cases. In this article, the use of a previously-published theoretical framework is demonstrated with the case of a mid-scale hydropower device, a 26 m long water vortex power plant. It is shown that a simplified CFD simulation with a single output (the mass flow rate) is sufficient to obtain values for the two coefficients in the model. Once this is done, it becomes possible to evaluate the device’s real-life performance, benchmarking it against reference values anchored in physical principles. The method can be used to provide design guidance and rapidly compare different load cases, providing answers that are not easily obtained using intuition or even experiments. These results are obtained for a computing cost several orders of magnitude smaller than those associated with a full description of the flow using CFD methods.

Published
2022
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47. In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present From Diagnosis in Tiny, Undetectable Subclonal Populations

Author

Romain Lannes, Mehmet Samur, Aurore Perrot, Celine Mazzotti, Marion Divoux, Titouan Cazaubiel, Xavier Leleu, Anaïs Schavgoulidze, Marie-Lorraine Chretien, Salomon Manier, Didier Adiko, Frederique Orsini-Piocelle, François Lifermann, Sabine Brechignac, Lauris Gastaud, Didier Bouscary, Margaret Macro, Alice Cleynen, Mohamad Mohty, Nikhil Munshi, Jill Corre, and Hervé Avet-Loiseau

Subjects
Cancer Research, Oncology
Abstract

PURPOSE Multiple myeloma (MM) is characterized by copy number abnormalities (CNAs), some of which influence patient outcomes and are sometimes observed only at relapse(s), suggesting their acquisition during tumor evolution. However, the presence of micro-subclones may be missed in bulk analyses. Here, we use single-cell genomics to determine how often these high-risk events are missed at diagnosis and selected at relapse. MATERIALS AND METHODS We analyzed 81 patients with plasma cell dyscrasias using single-cell CNA sequencing. Sixty-six patients were selected at diagnosis, nine at first relapse, and six in presymptomatic stages. A total of 956 newly diagnosed patients with MM and patients with first relapse MM have been identified retrospectively with required cytogenetic data to evaluate enrichment of CNA risk events and survival impact. RESULTS A total of 52,176 MM cells were analyzed. Seventy-four patients (91%) had 2-16 subclones. Among these patients, 28.7% had a subclone with high-risk features (del(17p), del(1p32), and 1q gain) at diagnosis. In a patient with a subclonal 1q gain at diagnosis, we analyzed the diagnosis, postinduction, and first relapse samples, which showed a rise of the high-risk 1q gain subclone (16%, 70%, and 92%, respectively). In our clinical database, we found that the 1q gain frequency increased from 30.2% at diagnosis to 43.6% at relapse (odds ratio, 1.78; 95% CI, 1.58 to 2.00). We subsequently performed survival analyses, which showed that the progression-free and overall survival curves were superimposable between patients who had the 1q gain from diagnosis and those who seemingly acquired it at relapse. This strongly suggests that many patients had 1q gains at diagnosis in microclones that were missed by bulk analyses. CONCLUSION These data suggest that identifying these scarce aggressive cells may necessitate more aggressive treatment as early as diagnosis to prevent them from becoming the dominant clone.

Published
2023
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49. Genetic Variants of the MGAT5 Gene Are Functionally Implicated in the Modulation of T Cells Glycosylation and Plasma IgG Glycome Composition in Ulcerative Colitis

Author

Pereira, Márcia S., Durães, Cecília, Catarino, Telmo A., Costa, José L., Cleynen, Isabelle, Novokmet, Mislav, Krištić, Jasminka, Štambuk, Jerko, Conceição-Neto, Nádia, Machado, José C., Marcos-Pinto, Ricardo, Magro, Fernando, Vermeire, Séverine, Lauc, Gordan, Lago, Paula, and Pinho, Salomé S.

Published
2020
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