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12 results on '"Benoît Tyl"'

1. Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure

Author

Claire Baudier, Françoise Fougerousse, Folkert W. Asselbergs, Mickael Guedj, Michel Komajda, Dipak Kotecha, R. Thomas Lumbers, Amand F. Schmidt, and Benoît Tyl

Subjects
Mendelian randomization, adrenergic receptors, beta-blockers, alpha-blockers, target validation, drug, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

BackgroundThe effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF.MethodsGenetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases).ResultsLower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74–0.93, P = 0.001) and 0.95 (95% CI 0.93–0.97, P = 8 × 10−6). Conversely, lower α2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05–1.12, P = 3 × 10−7). No evidence of an effect of lower ß2 activity on HF risk was found: OR 0.99 (95% CI 0.92–1.07, P = 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease.ConclusionsThis study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.

Published
2023
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2. Genetic drug target validation using Mendelian randomisation

Author

Amand F. Schmidt, Chris Finan, Maria Gordillo-Marañón, Folkert W. Asselbergs, Daniel F. Freitag, Riyaz S. Patel, Benoît Tyl, Sandesh Chopade, Rupert Faraway, Magdalena Zwierzyna, and Aroon D. Hingorani

Subjects
Science
Abstract

Mendelian randomisation (MR) analysis of drug targets has potential to aid drug development. Here, the authors introduce a mathematical framework to elucidate this specific application of MR.

Published
2020
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4. Key Considerations for Designing Clinical Studies to Evaluate Digital Health Solutions

Author

Elaina Bolinger and Benoit Tyl

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract

Evidence of clinical impact is critical to unlock the potential of digital health solutions (DHSs), yet many solutions are failing to deliver positive clinical results. We argue in this viewpoint that this failure is linked to current approaches to DHS evaluation design, which neglect numerous key characteristics (KCs) requiring specific scientific and design considerations. We first delineate the KCs of DHSs: (1) they are implemented at health care system and patient levels; (2) they are “complex” interventions; (3) they can drive multiple clinical outcomes indirectly through a multitude of smaller clinical benefits; (4) their mechanism of action can vary between individuals and change over time based on patient needs; and (5) they develop through short, iterative cycles—optimally within a real-world use context. Following our objective to drive better alignment between clinical evaluation design and the unique traits of DHSs, we then provide methodological suggestions that better address these KCs, including tips on mechanism-of-action mapping, alternative randomization methods, control-arm adaptations, and novel end-point selection, as well as innovative methods utilizing real-world data and platform research.

Published
2024
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5. The genomics of heart failure: design and rationale of the HERMES consortium

Author

R. Thomas Lumbers, Sonia Shah, Honghuang Lin, Tomasz Czuba, Albert Henry, Daniel I. Swerdlow, Anders Mälarstig, Charlotte Andersson, Niek Verweij, Michael V. Holmes, Johan Ärnlöv, Per Svensson, Harry Hemingway, Neneh Sallah, Peter Almgren, Krishna G. Aragam, Geraldine Asselin, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R. Brown, Hans‐Peter Brunner‐La Rocca, David J. Carey, Mark D. Chaffin, Daniel I. Chasman, Olympe Chazara, Xing Chen, Xu Chen, Jonathan H. Chung, William Chutkow, John G.F. Cleland, James P. Cook, Simon deDenus, Abbas Dehghan, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Gunnar Engström, Tõnu Esko, Ghazaleh Fatemifar, Stephan B. Felix, Chris Finan, Ian Ford, Francoise Fougerousse, René Fouodjio, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Christopher M. Haggerty, Pim van derHarst, Åsa K. Hedman, Anna Helgadottir, Hans Hillege, Craig L. Hyde, Jaison Jacob, J. Wouter Jukema, Frederick Kamanu, Isabella Kardys, Maryam Kavousi, Kay‐Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Bill Kraus, Karoline Kuchenbaecker, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian'an Luan, Patrik Magnusson, Anubha Mahajan, Douglas Mann, Kenneth B. Margulies, Nicholas A. Marston, Winfried März, John J.V. McMurray, Olle Melander, Giorgio Melloni, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Christopher Newton‐Cheh, Alexander Niessner, Teemu Niiranen, Christoph Nowak, Michelle L. O'Donoghue, Anjali T. Owens, Colin N.A. Palmer, Guillaume Paré, Markus Perola, Louis‐Philippe Lemieux Perreault, Eliana Portilla‐Fernandez, Bruce M. Psaty, Kenneth M. Rice, Paul M. Ridker, Simon P.R. Romaine, Carolina Roselli, Jerome I. Rotter, Christian T. Ruff, Marc S. Sabatine, Perttu Salo, Veikko Salomaa, Jessica vanSetten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Kari Stefansson, Steen Stender, David J. Stott, Garðar Sveinbjörnsson, Mari‐Liis Tammesoo, Jean‐Claude Tardif, Kent D. Taylor, Maris Teder‐Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp‐Pedersen, Stella Trompet, Danny Tuckwell, Benoit Tyl, Andre G. Uitterlinden, Felix Vaura, Abirami Veluchamy, Peter M. Visscher, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Peter E. Weeke, Raul Weiss, Harvey D. White, Kerri L. Wiggins, Heming Xing, Jian Yang, Yifan Yang, Laura M. Yerges‐Armstrong, Bing Yu, Faiez Zannad, Faye Zhao, Regeneron Genetics Center, Jemma B. Wilk, Hilma Holm, Naveed Sattar, Steven A. Lubitz, David E. Lanfear, Svati Shah, Michael E. Dunn, Quinn S. Wells, Folkert W. Asselbergs, Aroon D. Hingorani, Marie‐Pierre Dubé, Nilesh J. Samani, Chim C. Lang, Thomas P. Cappola, Patrick T. Ellinor, Ramachandran S. Vasan, and J. Gustav Smith

Subjects
Heart failure, Cardiomyopathy, Genetics, Biomarkers, Association studies, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P

Published
2021
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6. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, Ghazaleh Fatemifar, Åsa K. Hedman, Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, Anna Helgadottir, Niek Verweij, Abbas Dehghan, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Jeffrey Brandimarto, Michael R. Brown, Leonard Buckbinder, David J. Carey, Daniel I. Chasman, Xing Chen, Xu Chen, Jonathan Chung, William Chutkow, James P. Cook, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Michael E. Dunn, Gunnar Engström, Tõnu Esko, Stephan B. Felix, Chris Finan, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Rebecca Gutmann, Christopher M. Haggerty, Pim van der Harst, Craig L. Hyde, Erik Ingelsson, J. Wouter Jukema, Maryam Kavousi, Kay-Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian’an Luan, Patrik Magnusson, Anubha Mahajan, Kenneth B. Margulies, Winfried März, Olle Melander, Ify R. Mordi, Thomas Morgan, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Alexander Niessner, Teemu Niiranen, Michelle L. O’Donoghue, Anjali T. Owens, Colin N. A. Palmer, Helen M. Parry, Markus Perola, Eliana Portilla-Fernandez, Bruce M. Psaty, Regeneron Genetics Center, Kenneth M. Rice, Paul M. Ridker, Simon P. R. Romaine, Jerome I. Rotter, Perttu Salo, Veikko Salomaa, Jessica van Setten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Steen Stender, David J. Stott, Per Svensson, Mari-Liis Tammesoo, Kent D. Taylor, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Stella Trompet, Benoit Tyl, Andre G. Uitterlinden, Abirami Veluchamy, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Dawn Waterworth, Peter E. Weeke, Raul Weiss, Kerri L. Wiggins, Heming Xing, Laura M. Yerges-Armstrong, Bing Yu, Faiez Zannad, Jing Hua Zhao, Harry Hemingway, Nilesh J. Samani, John J. V. McMurray, Jian Yang, Peter M. Visscher, Christopher Newton-Cheh, Anders Malarstig, Hilma Holm, Steven A. Lubitz, Naveed Sattar, Michael V. Holmes, Thomas P. Cappola, Folkert W. Asselbergs, Aroon D. Hingorani, Karoline Kuchenbaecker, Patrick T. Ellinor, Chim C. Lang, Kari Stefansson, J. Gustav Smith, Ramachandran S. Vasan, Daniel I. Swerdlow, and R. Thomas Lumbers

Subjects
Science
Abstract

Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.

Published
2020
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11. A genetic model of ivabradine recapitulates results from randomized clinical trials.

Author

Marc-André Legault, Johanna Sandoval, Sylvie Provost, Amina Barhdadi, Louis-Philippe Lemieux Perreault, Sonia Shah, R Thomas Lumbers, Simon de Denus, Benoit Tyl, Jean-Claude Tardif, and Marie-Pierre Dubé

Subjects
Medicine, Science
Abstract

BackgroundNaturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a variant in HCN4, ivabradine's drug target, on safety and efficacy endpoints.MethodsWe used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes.ResultsUsing data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06-1.13, P = 9.3 ×10-9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83-0.98, P = 0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93-1.04, P = 0.61).ConclusionGenetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.

Published
2020
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12. CODE-EHR best-practice framework for the use of structured electronic health-care records in clinical research

Author

Dipak Kotecha, Folkert W Asselbergs, Stephan Achenbach, Stefan D Anker, Dan Atar, Colin Baigent, Amitava Banerjee, Birgit Beger, Gunnar Brobert, Barbara Casadei, Cinzia Ceccarelli, Martin R Cowie, Filippo Crea, Maureen Cronin, Spiros Denaxas, Andrea Derix, Donna Fitzsimons, Martin Fredriksson, Chris P Gale, Georgios V Gkoutos, Wim Goettsch, Harry Hemingway, Martin Ingvar, Adrian Jonas, Robert Kazmierski, Susanne Løgstrup, R Thomas Lumbers, Thomas F Lüscher, Paul McGreavy, Ileana L Piña, Lothar Roessig, Carl Steinbeisser, Mats Sundgren, Benoît Tyl, Ghislaine van Thiel, Kees van Bochove, Panos E Vardas, Tiago Villanueva, Marilena Vrana, Wim Weber, Franz Weidinger, Stephan Windecker, Angela Wood, and Diederick E Grobbee

Subjects
Big Data, Health Information Management, COVID-19, Electronic Health Records, Humans, Medicine (miscellaneous), Health Informatics, Decision Sciences (miscellaneous), 610 Medicine & health, Electronics, 610 Medizin und Gesundheit, Pandemics
Abstract

Big data is important to new developments in global clinical science that aim to improve the lives of patients. Technological advances have led to the regular use of structured electronic health-care records with the potential to address key deficits in clinical evidence that could improve patient care. The COVID-19 pandemic has shown this potential in big data and related analytics but has also revealed important limitations. Data verification, data validation, data privacy, and a mandate from the public to conduct research are important challenges to effective use of routine health-care data. The European Society of Cardiology and the BigData@Heart consortium have brought together a range of international stakeholders, including representation from patients, clinicians, scientists, regulators, journal editors, and industry members. In this Review, we propose the CODE-EHR minimum standards framework to be used by researchers and clinicians to improve the design of studies and enhance transparency of study methods. The CODE-EHR framework aims to develop robust and effective utilisation of health-care data for research purposes.

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