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57. Effects of Long-Term Averaging of Quantitative Blood Pressure Traits on the Detection of Genetic Associations

Author

Ganesh, Santhi K, Chasman, Daniel I, Larson, Martin G, Guo, Xiuqing, Verwoert, Germain, Bis, Joshua C, Gu, Xiangjun, Smith, Albert V, Yang, Min-Lee, Zhang, Yan, Ehret, Georg, Rose, Lynda M, Hwang, Shih-Jen, Papanicolau, George J, Sijbrands, Eric J, Rice, Kenneth, Eiriksdottir, Gudny, Pihur, Vasyl, Ridker, Paul M, Vasan, Ramachandran S, Newton-Cheh, Christopher, Consortium, Global Blood Pressure Genetics, Johnson, Toby, Gateva, Vesela, Tobin, Martin D, Bochud, Murielle, Coin, Lachlan, Najjar, Samer S, Zhao, Jing Hua, Heath, Simon C, Eyheramendy, Susana, Papadakis, Konstantinos, Voight, Benjamin F, Scott, Laura J, Zhang, Feng, Farrall, Martin, Tanaka, Toshiko, Wallace, Chris, Chambers, John C, Khaw, Kay-Tee, Nilsson, Peter, van der Harst, Pim, Polidoro, Silvia, Grobbee, Diederick E, Onland-Moret, N Charlotte, Bots, Michiel L, Wain, Louise V, Elliott, Katherine S, Teumer, Alexander, Luan, Jian’an, Lucas, Gavin, Kuusisto, Johanna, Burton, Paul R, Hadley, David, McArdle, Wendy L, Brown, Morris, Dominiczak, Anna, Newhouse, Stephen J, Samani, Nilesh J, Webster, John, Zeggini, Eleftheria, Beckmann, Jacques S, Bergmann, Sven, Lim, Noha, Song, Kijoung, Vollenweider, Peter, Waeber, Gerard, Waterworth, Dawn M, Yuan, Xin, Groop, Leif, Orho-Melander, Marju, Allione, Alessandra, Di Gregorio, Alessandra, Guarrera, Simonetta, Panico, Salvatore, Ricceri, Fulvio, Romanazzi, Valeria, Sacerdote, Carlotta, Vineis, Paolo, Barroso, Inês, Sandhu, Manjinder S, Luben, Robert N, Crawford, Gabriel J, Jousilahti, Pekka, Perola, Markus, Boehnke, Michael, Bonnycastle, Lori L, Collins, Francis S, Jackson, Anne U, Mohlke, Karen L, Stringham, Heather M, Valle, Timo T, Willer, Cristen J, Bergman, Richard N, Morken, Mario A, Döring, Angela, Gieger, Christian, Illig, Thomas, and Meitinger, Thomas

Subjects
Genetics, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Blood Pressure, Genome-Wide Association Study, Humans, Longitudinal Studies, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Global Blood Pressure Genetics Consortium, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

Published
2014

58. Digital twins, the journey of an operational weather system into the heart of Destination Earth.

Author

Geenen, Thomas, Wedi, Nils, Milinski, Sebastian, Hadade, Ioan, Reuter, Balthasar, Smart, Simon, Hawkes, James, Kuwertz, Emma, Quintino, Tiago, Danovaro, Emanuele, Sarmany, Domokos, Aguridan, Razvan, Maciel, Pedro, Suttie, Martin, Duma, Cristina, Griffith, Matthew, Burton, Paul, Bennet, Andrew, Horvjar, Tryggvi, and Hernandez, Bentorey

Subjects
CLIMATE change adaptation, EXTREME weather, NUMERICAL weather forecasting, HIGH performance computing, DIGITAL twins
Abstract

Moving a world leading numerical weather prediction system that runs on a dedicated, bespoke, high performance computing cluster and supporting infrastructure, into the heart of a digital twin for climate change adaptation and extreme weather events has been a challenging and exciting journey. In this paper we describe this journey with a focus on those aspects required to leverage the pre-exascale EuroHPC systems that have been made available to Destination Earth (DestinE) to run its computational representation[1]. EuroHPC systems can be effectively used for DestinE and are in fact key assets to deliver the computational power required for Earth system digital twins at global km-scale resolution. At the same time, EuroHPC systems were newly installed and procedures to run them efficiently are evolving. We find that each of these systems is operated by a national hosting entity that implements its own procedures, e.g. for identity and access management, specific system configuration like schedulers, filesystems, software management systems, and specific, sometimes vendor associated, toolchains, tooling, and container runtimes. In particular, the different scheduling policies encountered, required us to adapt our workflows for each site. We found that having dedicated resources available, which was trialed in a period from 16th February to 14th April on LUMI, allowed to achieve high occupation rates, with 92% on the reserved GPU allocation and greater than 97% efficiency on the CPU reservation. Also a stronger focus on federation of these systems, with a focus not only on federation of identities and accounts, but also in the areas of data ownership/transfer, observability, services and service accounts, maintenance coordination and performance portability is required. In general, it should become much easier to transfer a workload, or a digital twin system, from one EuroHPC site to the next and run and maintain them across several sites concurrently. [ABSTRACT FROM AUTHOR]

Published
2024
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59. Advancing tools for human early lifecourse exposome research and translation (ATHLETE): Project overview

Author

Vrijheid, Martine, Basagaña, Xavier, Gonzalez, Juan R., Jaddoe, Vincent W. V., Jensen, Genon, Keun, Hector C., McEachan, Rosemary R. C., Porcel, Joana, Siroux, Valerie, Swertz, Morris A., Thomsen, Cathrine, Aasvang, Gunn Marit, Andrušaitytė, Sandra, Angeli, Karine, Avraam, Demetris, Ballester, Ferran, Burton, Paul, Bustamante, Mariona, Casas, Maribel, Chatzi, Leda, Chevrier, Cécile, Cingotti, Natacha, Conti, David, Crépet, Amélie, Dadvand, Payam, Duijts, Liesbeth, van Enckevort, Esther, Esplugues, Ana, Fossati, Serena, Garlantezec, Ronan, Gómez Roig, María Dolores, Grazuleviciene, Regina, Gützkow, Kristine B., Guxens, Mònica, Haakma, Sido, Hessel, Ellen V. S., Hoyles, Lesley, Hyde, Eleanor, Klanova, Jana, van Klaveren, Jacob D., Kortenkamp, Andreas, Le Brusquet, Laurent, Leenen, Ivonne, Lertxundi, Aitana, Lertxundi, Nerea, Lionis, Christos, Llop, Sabrina, Lopez-Espinosa, Maria-Jose, Lyon-Caen, Sarah, Maitre, Lea, Mason, Dan, Mathy, Sandrine, Mazarico, Edurne, Nawrot, Tim, Nieuwenhuijsen, Mark, Ortiz, Rodney, Pedersen, Marie, Perelló, Josep, Pérez-Cruz, Míriam, Philippat, Claire, Piler, Pavel, Pizzi, Costanza, Quentin, Joane, Richiardi, Lorenzo, Rodriguez, Adrian, Roumeliotaki, Theano, Sabin Capote, José Manuel, Santiago, Leonardo, Santos, Susana, Siskos, Alexandros P., Strandberg-Larsen, Katrine, Stratakis, Nikos, Sunyer, Jordi, Tenenhaus, Arthur, Vafeiadi, Marina, Wilson, Rebecca C., Wright, John, Yang, Tiffany, and Slama, Remy

Published
2021
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60. The Evaluation of Gastric Emptying Using Nuclear Scintigraphy Compared to Three-Dimensional Multi-detector Computed Tomography (3D-MDCT) Gastric Volumetry in the Assessment of Poor Weight Loss Following Sleeve Gastrectomy

Author

Wickremasinghe, Anagi, primary, Ferdinands, Jessica, additional, Johari, Yazmin, additional, Ho, Patrick, additional, Leang, Yit, additional, Yue, Helen, additional, Laurie, Cheryl, additional, Beech, Paul, additional, Nadebaum, David P., additional, Yap, Kenneth S., additional, Hebbard, Geoffrey, additional, Brown, Wendy, additional, and Burton, Paul, additional

Published
2023
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62. Impact of information and deliberation on the consistency of preferences for prioritization in health care – evidence from discrete choice experiments undertaken alongside citizens’ juries

Author

Whitty, Jennifer A., primary, Littlejohns, Peter, additional, Ratcliffe, Julie, additional, Rixon, Kylie, additional, Wilson, Andrew, additional, Kendall, Elizabeth, additional, Burton, Paul, additional, Chalkidou, Kalipso, additional, and Scuffham, Paul A., additional

Published
2023
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67. Indroduction

Author

Maginn, Paul J., primary, Burton, Paul, additional, and Legacy, Crystal, additional

Published
2020
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68. 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials

Author

Fitter, Heather D., Illoh, Kachikwu, Cavanaugh, Kenneth J., Jr., Scirica, Benjamin M., Irony, Ilan, Brown Kichline, Rachel E., Levine, Jonathan G., Park, Anna, Sacks, Leonard, Szarfman, Ana, Unger, Ellis F., Wachter, Lori Ann, Zuckerman, Bram, Mitchel, Yale, Peddicord, Douglas, Shook, Thomas, Kisler, Bron, Jaffe, Charles, Bartley, Rhonda, DeMets, David L., Mencini, MariJo, Janning, Cheri, Bai, Steve, Lawrence, John, D’Agostino, Ralph B., Sr., Pocock, Stuart J., Hicks, Karen A., Mahaffey, Kenneth W., Mehran, Roxana, Nissen, Steven E., Wiviott, Stephen D., Dunn, Billy, Solomon, Scott D., Marler, John R., Teerlink, John R., Farb, Andrew, Morrow, David A., Targum, Shari L., Sila, Cathy A., Thanh Hai, Mary T., Jaff, Michael R., Joffe, Hylton V., Cutlip, Donald E., Desai, Akshay S., Lewis, Eldrin F., Gibson, C. Michael, Landray, Martin J., Lincoff, A. Michael, White, Christopher J., Brooks, Steven S., Rosenfield, Kenneth, Domanski, Michael J., Lansky, Alexandra J., McMurray, John J.V., Tcheng, James E., Steinhubl, Steven R., Burton, Paul, Mauri, Laura, O’Connor, Christopher M., Pfeffer, Marc A., Hung, H.M. James, Stockbridge, Norman L., Chaitman, Bernard R., and Temple, Robert J.

Published
2018
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73. Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci

Author

Asselbergs, Folkert W, Guo, Yiran, van Iperen, Erik PA, Sivapalaratnam, Suthesh, Tragante, Vinicius, Lanktree, Matthew B, Lange, Leslie A, Almoguera, Berta, Appelman, Yolande E, Barnard, John, Baumert, Jens, Beitelshees, Amber L, Bhangale, Tushar R, Chen, Yii-Der Ida, Gaunt, Tom R, Gong, Yan, Hopewell, Jemma C, Johnson, Toby, Kleber, Marcus E, Langaee, Taimour Y, Li, Mingyao, Li, Yun R, Liu, Kiang, McDonough, Caitrin W, Meijs, Matthijs FL, Middelberg, Rita PS, Musunuru, Kiran, Nelson, Christopher P, O’Connell, Jeffery R, Padmanabhan, Sandosh, Pankow, James S, Pankratz, Nathan, Rafelt, Suzanne, Rajagopalan, Ramakrishnan, Romaine, Simon PR, Schork, Nicholas J, Shaffer, Jonathan, Shen, Haiqing, Smith, Erin N, Tischfield, Sam E, van der Most, Peter J, van Vliet-Ostaptchouk, Jana V, Verweij, Niek, Volcik, Kelly A, Zhang, Li, Bailey, Kent R, Bailey, Kristian M, Bauer, Florianne, Boer, Jolanda MA, Braund, Peter S, Burt, Amber, Burton, Paul R, Buxbaum, Sarah G, Chen, Wei, Cooper-DeHoff, Rhonda M, Cupples, L Adrienne, deJong, Jonas S, Delles, Christian, Duggan, David, Fornage, Myriam, Furlong, Clement E, Glazer, Nicole, Gums, John G, Hastie, Claire, Holmes, Michael V, Illig, Thomas, Kirkland, Susan A, Kivimaki, Mika, Klein, Ronald, Klein, Barbara E, Kooperberg, Charles, Kottke-Marchant, Kandice, Kumari, Meena, LaCroix, Andrea Z, Mallela, Laya, Murugesan, Gurunathan, Ordovas, Jose, Ouwehand, Willem H, Post, Wendy S, Saxena, Richa, Scharnagl, Hubert, Schreiner, Pamela J, Shah, Tina, Shields, Denis C, Shimbo, Daichi, Srinivasan, Sathanur R, Stolk, Ronald P, Swerdlow, Daniel I, Taylor, Herman A, Topol, Eric J, Toskala, Elina, van Pelt, Joost L, van Setten, Jessica, Yusuf, Salim, Whittaker, John C, Zwinderman, AH, Study, LifeLines Cohort, Anand, Sonia S, Balmforth, Anthony J, and Berenson, Gerald S

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Human Genome, Cardiovascular, Atherosclerosis, Aetiology, 2.1 Biological and endogenous factors, Cholesterol, HDL, Cholesterol, LDL, Female, Genome-Wide Association Study, Genotype, Humans, Lipids, Male, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sex Factors, Triglycerides, White People, LifeLines Cohort Study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

Published
2012

74. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

Author

Lanktree, Matthew B, Guo, Yiran, Murtaza, Muhammed, Glessner, Joseph T, Bailey, Swneke D, Onland-Moret, N Charlotte, Lettre, Guillaume, Ongen, Halit, Rajagopalan, Ramakrishnan, Johnson, Toby, Shen, Haiqing, Nelson, Christopher P, Klopp, Norman, Baumert, Jens, Padmanabhan, Sandosh, Pankratz, Nathan, Pankow, James S, Shah, Sonia, Taylor, Kira, Barnard, John, Peters, Bas J, Maloney, Cliona M, Lobmeyer, Maximilian T, Stanton, Alice, Zafarmand, M Hadi, Romaine, Simon PR, Mehta, Amar, van Iperen, Erik PA, Gong, Yan, Price, Tom S, Smith, Erin N, Kim, Cecilia E, Li, Yun R, Asselbergs, Folkert W, Atwood, Larry D, Bailey, Kristian M, Bhatt, Deepak, Bauer, Florianne, Behr, Elijah R, Bhangale, Tushar, Boer, Jolanda MA, Boehm, Bernhard O, Bradfield, Jonathan P, Brown, Morris, Braund, Peter S, Burton, Paul R, Carty, Cara, Chandrupatla, Hareesh R, Chen, Wei, Connell, John, Dalgeorgou, Chrysoula, de Boer, Anthonius, Drenos, Fotios, Elbers, Clara C, Fang, James C, Fox, Caroline S, Frackelton, Edward C, Fuchs, Barry, Furlong, Clement E, Gibson, Quince, Gieger, Christian, Goel, Anuj, Grobbee, Diederik E, Hastie, Claire, Howard, Philip J, Huang, Guan-Hua, Johnson, W Craig, Li, Qing, Kleber, Marcus E, Klein, Barbara EK, Klein, Ronald, Kooperberg, Charles, Ky, Bonnie, LaCroix, Andrea, Lanken, Paul, Lathrop, Mark, Li, Mingyao, Marshall, Vanessa, Melander, Olle, Mentch, Frank D, Meyer, Nuala J, Monda, Keri L, Montpetit, Alexandre, Murugesan, Gurunathan, Nakayama, Karen, Nondahl, Dave, Onipinla, Abiodun, Rafelt, Suzanne, Newhouse, Stephen J, Otieno, F George, Patel, Sanjey R, Putt, Mary E, Rodriguez, Santiago, Safa, Radwan N, Sawyer, Douglas B, Schreiner, Pamela J, Simpson, Claire, Sivapalaratnam, Suthesh, Srinivasan, Sathanur R, and Suver, Christine

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Adult, Black or African American, Asian People, Body Height, Cardiovascular System, Female, Gene Frequency, Genetic Heterogeneity, Genetic Loci, Genome-Wide Association Study, Hispanic or Latino, Humans, Interleukin-11, Male, Polymorphism, Single Nucleotide, Smad3 Protein, White People, Hugh Watkins on behalf of PROCARDIS, Meena Kumari on behalf of the Whitehall II Study and the WHII 50K Group, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

Published
2011

78. Genome-wide association study identifies eight loci associated with blood pressure

Author

Newton-Cheh, Christopher, Johnson, Toby, Gateva, Vesela, Tobin, Martin D, Bochud, Murielle, Coin, Lachlan, Najjar, Samer S, Zhao, Jing Hua, Heath, Simon C, Eyheramendy, Susana, Papadakis, Konstantinos, Voight, Benjamin F, Scott, Laura J, Zhang, Feng, Farrall, Martin, Tanaka, Toshiko, Wallace, Chris, Chambers, John C, Khaw, Kay-Tee, Nilsson, Peter, van der Harst, Pim, Polidoro, Silvia, Grobbee, Diederick E, Onland-Moret, N Charlotte, Bots, Michiel L, Wain, Louise V, Elliott, Katherine S, Teumer, Alexander, Luan, Jian'an, Lucas, Gavin, Kuusisto, Johanna, Burton, Paul R, Hadley, David, McArdle, Wendy L, Brown, Morris, Dominiczak, Anna, Newhouse, Stephen J, Samani, Nilesh J, Webster, John, Zeggini, Eleftheria, Beckmann, Jacques S, Bergmann, Sven, Lim, Noha, Song, Kijoung, Vollenweider, Peter, Waeber, Gerard, Waterworth, Dawn M, Yuan, Xin, Groop, Leif, Orho-Melander, Marju, Allione, Alessandra, Di Gregorio, Alessandra, Guarrera, Simonetta, Panico, Salvatore, Ricceri, Fulvio, Romanazzi, Valeria, Sacerdote, Carlotta, Vineis, Paolo, Barroso, Inês, Sandhu, Manjinder S, Luben, Robert N, Crawford, Gabriel J, Jousilahti, Pekka, Perola, Markus, Boehnke, Michael, Bonnycastle, Lori L, Collins, Francis S, Jackson, Anne U, Mohlke, Karen L, Stringham, Heather M, Valle, Timo T, Willer, Cristen J, Bergman, Richard N, Morken, Mario A, Döring, Angela, Gieger, Christian, Illig, Thomas, Meitinger, Thomas, Org, Elin, Pfeufer, Arne, Wichmann, H Erich, Kathiresan, Sekar, Marrugat, Jaume, O'Donnell, Christopher J, Schwartz, Stephen M, Siscovick, David S, Subirana, Isaac, Freimer, Nelson B, Hartikainen, Anna-Liisa, McCarthy, Mark I, O'Reilly, Paul F, Peltonen, Leena, Pouta, Anneli, de Jong, Paul E, Snieder, Harold, van Gilst, Wiek H, Clarke, Robert, Goel, Anuj, Hamsten, Anders, and Peden, John F

Subjects
Biological Sciences, Genetics, Hypertension, Cardiovascular, Prevention, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Adaptor Proteins, Signal Transducing, Blood Pressure, Cardiovascular Diseases, Chromosome Mapping, Cytochrome P-450 CYP1A2, DNA-Binding Proteins, Diastole, Europe, Fibroblast Growth Factor 5, Genetic Variation, Genome-Wide Association Study, Humans, India, Intracellular Signaling Peptides and Proteins, Methylenetetrahydrofolate Reductase (NADPH2), Open Reading Frames, Phospholipase C delta, Polymorphism, Single Nucleotide, Proteins, Steroid 17-alpha-Hydroxylase, Systole, White People, Wellcome Trust Case Control Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Published
2009

79. Malnutrition defined by GLIM criteria identifies a higher incidence of malnutrition and is associated with pulmonary complications after oesophagogastric cancer surgery, compared to ICD‐10‐defined malnutrition

Author

Murnane, Lisa C., primary, Forsyth, Adrienne K., additional, Koukounaras, Jim, additional, Shaw, Kalai, additional, King, Susannah, additional, Brown, Wendy A., additional, Mourtzakis, Marina, additional, Tierney, Audrey C., additional, and Burton, Paul R., additional

Published
2023
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81. The length of hospital stay following bariatric surgery in Australia: the impact of patient, procedure, system and surgeon.

Author

Chadwick, Chiara, Burton, Paul R., Brown, Dianne, Holland, Jennifer F., Campbell, Angus, Cottrell, Jenifer, Reilly, Jennifer, MacCormick, Andrew D., Caterson, Ian, and Brown, Wendy A.

Subjects
*BARIATRIC surgery, *LENGTH of stay in hospitals, *GASTRIC bypass, *SURGEONS
Abstract

Background: The length of a patient's stay (LOS) in a hospital is one metric used to compare the quality of care, as a longer LOS may flag higher complication rates or less efficient processes. A meaningful comparison of LOS can only occur if the expected average length of stay (ALOS) is defined first. This study aimed to define the expected ALOS of primary and conversion bariatric surgery in Australia and to quantify the effect of patient, procedure, system, and surgeon factors on ALOS. Methods: This was a retrospective observational study of prospectively maintained data from the Bariatric Surgery Registry of 63 604 bariatric procedures performed in Australia. The primary outcome measure was the expected ALOS for primary and conversion bariatric procedures. The secondary outcome measures quantified the change in ALOS for bariatric surgery resulting from patient, procedure, hospital, and surgeon factors. Results: Uncomplicated primary bariatric surgery had an ALOS (SD) of 2.30 (1.31) days, whereas conversion procedures had an ALOS (SD) of 2.71 (2.75) days yielding a mean difference (SEM) in ALOS of 0.41 (0.05) days, P < 0.001. The occurrence of any defined adverse event extended the ALOS of primary and conversion procedures by 1.14 days (CI 95% 1.04–1.25), P < 0.001 and 2.33 days (CI 95% 1.54–3.11), P < 0.001, respectively. Older age, diabetes, rural home address, surgeon operating volume and hospital case volume increased the ALOS following bariatric surgery. Conclusions: Our findings have defined Australia's expected ALOS following bariatric surgery. Increased patient age, diabetes, rural living, procedural complications and surgeon and hospital case volume exerted a small but significant increase in ALOS. Study type: Retrospective observational study of prospectively collected data. [ABSTRACT FROM AUTHOR]

Published
2023
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86. Deliverable D7.2: ELSI Governance Model and Data Management Plan for Federated Cohort Analysis

Author

Mayrhofer, Michaela Th, Goisauf, Melanie, Akyüz, Kaya, Avraam, Demetris, Wilson, Becca, Swertz, Morris, Burton, Paul, and Murtagh, Madeleine

Abstract

EUCAN-Connect is committed to connecting existing networks via privacy-protecting data-sharing using ‘federated’ analysis infrastructure made stronger through a unique and flexible governance model by design. Within the EUCAN-Connect project, data processing can be considered as having one of three forms or purposes: (1) federated analysis, especially under DataSHIELD, (2), harmonisation of data for federated analysis, and (3) social science data collection and analysis of Ethical, Legal and Social Issues (ELSI). This report describes the integration of ELSI in the governance model and the associated data management and compliance measurements with the required level of data security and privacy integrated for good governance. In particular, this report is concerned with the governance and data management/processing of DataSHIELD.

Published
2023
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87. Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy — A focus on energy expenditure

Author

Stefanidis, Aneta, Lee, C.M.C., Greaves, Erika, Montgomery, Magdalene K., Arnold, Michèle, Newn, S., Budin, Alyssa J., Lemus, Moyra B., Foldi, Claire J., Burton, Paul R., Brown, Wendy A., Lutz, Thomas Alexander, Watt, Matthew J., and Oldfield, Brian J.

Subjects
Bariatric surgery, Metabolic surgery, Vertical sleeve gastrectomy, Animal model, Energy expenditure, Brown adipose tissue thermogenesis
Abstract

Objective: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. Methods: Diet-induced obese male Sprague–Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-D-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. Results: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. Conclusions: Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients., Molecular Metabolism, 73, ISSN:2212-8778

Published
2023

93. Resistance and Response in Planning

Author

Fainstein, Susan S., primary, Forester, John, additional, Lee, Kevin Lujan, additional, Na’puti, Tiara, additional, Agyeman, Julian, additional, Stewart, Nicholas J., additional, Novy, Johannes, additional, Dedekorkut Howes, Aysin, additional, Burton, Paul, additional, Norgaard, Stefan, additional, Smith, Nick R., additional, Zukin, Sharon, additional, Lubinsky, Adam, additional, and Keith, Michael, additional

Published
2023
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95. Gestational age at birth and body size from infancy through adolescence:An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies

Author

Vinther, Johan L., Cadman, Tim, Avraam, Demetris, Ekstrøm, Claus T., Sørensen, Thorkild I.A., Elhakeem, Ahmed, Santos, Ana C., de Moira, Angela Pinot, Heude, Barbara, Iñiguez, Carmen, Pizzi, Costanza, Simons, Elinor, Voerman, Ellis, Corpeleijn, Eva, Zariouh, Faryal, Santorelli, Gilian, Inskip, Hazel M., Barros, Henrique, Carson, Jennie, Harris, Jennifer R., Nader, Johanna L., Ronkainen, Justiina, Strandberg-Larsen, Katrine, Santa-Marina, Loreto, Calas, Lucinda, Cederkvist, Luise, Popovic, Maja, Charles, Marie Aline, Welten, Marieke, Vrijheid, Martine, Azad, Meghan, Subbarao, Padmaja, Burton, Paul, Mandhane, Puishkumar J., Huang, Rae Chi, Wilson, Rebecca C., Haakma, Sido, Fernández-Barrés, Sílvia, Turvey, Stuart, Santos, Susana, Tough, Suzanne C., Sebert, Sylvain, Moraes, Theo J., Salika, Theodosia, Jaddoe, Vincent W.V., Lawlor, Deborah A., Andersen, Anne Marie Nybo, Vinther, Johan L., Cadman, Tim, Avraam, Demetris, Ekstrøm, Claus T., Sørensen, Thorkild I.A., Elhakeem, Ahmed, Santos, Ana C., de Moira, Angela Pinot, Heude, Barbara, Iñiguez, Carmen, Pizzi, Costanza, Simons, Elinor, Voerman, Ellis, Corpeleijn, Eva, Zariouh, Faryal, Santorelli, Gilian, Inskip, Hazel M., Barros, Henrique, Carson, Jennie, Harris, Jennifer R., Nader, Johanna L., Ronkainen, Justiina, Strandberg-Larsen, Katrine, Santa-Marina, Loreto, Calas, Lucinda, Cederkvist, Luise, Popovic, Maja, Charles, Marie Aline, Welten, Marieke, Vrijheid, Martine, Azad, Meghan, Subbarao, Padmaja, Burton, Paul, Mandhane, Puishkumar J., Huang, Rae Chi, Wilson, Rebecca C., Haakma, Sido, Fernández-Barrés, Sílvia, Turvey, Stuart, Santos, Susana, Tough, Suzanne C., Sebert, Sylvain, Moraes, Theo J., Salika, Theodosia, Jaddoe, Vincent W.V., Lawlor, Deborah A., and Andersen, Anne Marie Nybo

Abstract

Background AU Preterm: Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly birth is the leading cause of perinatal morbidity and:mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence. Methods and findings We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother–child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child’s birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and a

Published
2023

96. Gestational age at birth and body size from infancy through adolescence:An individual participant data meta-analysis on 253,810 singletons in 16 birth cohort studies

Author

Vinther, Johan L, Cadman, Tim, Avraam, Demetris, Ekstrøm, Claus T, I A Sørensen, Thorkild, Elhakeem, Ahmed, Santos, Ana C, Pinot de Moira, Angela, Heude, Barbara, Iñiguez, Carmen, Pizzi, Costanza, Simons, Elinor, Voerman, Ellis, Corpeleijn, Eva, Zariouh, Faryal, Santorelli, Gilian, Inskip, Hazel M, Barros, Henrique, Carson, Jennie, Harris, Jennifer R, Nader, Johanna L, Ronkainen, Justiina, Strandberg-Larsen, Katrine, Santa-Marina, Loreto, Calas, Lucinda, Cederkvist, Luise, Popovic, Maja, Charles, Marie-Aline, Welten, Marieke, Vrijheid, Martine, Azad, Meghan, Subbarao, Padmaja, Burton, Paul, Mandhane, Puishkumar J, Huang, Rae-Chi, Wilson, Rebecca C, Haakma, Sido, Fernández-Barrés, Sílvia, Turvey, Stuart, Santos, Susana, Tough, Suzanne C, Sebert, Sylvain, Moraes, Theo J, Salika, Theodosia, Jaddoe, Vincent W V, Lawlor, Deborah A, Nybo Andersen, Anne-Marie, Vinther, Johan L, Cadman, Tim, Avraam, Demetris, Ekstrøm, Claus T, I A Sørensen, Thorkild, Elhakeem, Ahmed, Santos, Ana C, Pinot de Moira, Angela, Heude, Barbara, Iñiguez, Carmen, Pizzi, Costanza, Simons, Elinor, Voerman, Ellis, Corpeleijn, Eva, Zariouh, Faryal, Santorelli, Gilian, Inskip, Hazel M, Barros, Henrique, Carson, Jennie, Harris, Jennifer R, Nader, Johanna L, Ronkainen, Justiina, Strandberg-Larsen, Katrine, Santa-Marina, Loreto, Calas, Lucinda, Cederkvist, Luise, Popovic, Maja, Charles, Marie-Aline, Welten, Marieke, Vrijheid, Martine, Azad, Meghan, Subbarao, Padmaja, Burton, Paul, Mandhane, Puishkumar J, Huang, Rae-Chi, Wilson, Rebecca C, Haakma, Sido, Fernández-Barrés, Sílvia, Turvey, Stuart, Santos, Susana, Tough, Suzanne C, Sebert, Sylvain, Moraes, Theo J, Salika, Theodosia, Jaddoe, Vincent W V, Lawlor, Deborah A, and Nybo Andersen, Anne-Marie

Abstract

BACKGROUND: Preterm birth is the leading cause of perinatal morbidity and mortality and is associated with adverse developmental and long-term health outcomes, including several cardiometabolic risk factors and outcomes. However, evidence about the association of preterm birth with later body size derives mainly from studies using birth weight as a proxy of prematurity rather than an actual length of gestation. We investigated the association of gestational age (GA) at birth with body size from infancy through adolescence.METHODS AND FINDINGS: We conducted a two-stage individual participant data (IPD) meta-analysis using data from 253,810 mother-child dyads from 16 general population-based cohort studies in Europe (Denmark, Finland, France, Italy, Norway, Portugal, Spain, the Netherlands, United Kingdom), North America (Canada), and Australasia (Australia) to estimate the association of GA with body mass index (BMI) and overweight (including obesity) adjusted for the following maternal characteristics as potential confounders: education, height, prepregnancy BMI, ethnic background, parity, smoking during pregnancy, age at child's birth, gestational diabetes and hypertension, and preeclampsia. Pregnancy and birth cohort studies from the LifeCycle and the EUCAN-Connect projects were invited and were eligible for inclusion if they had information on GA and minimum one measurement of BMI between infancy and adolescence. Using a federated analytical tool (DataSHIELD), we fitted linear and logistic regression models in each cohort separately with a complete-case approach and combined the regression estimates and standard errors through random-effects study-level meta-analysis providing an overall effect estimate at early infancy (>0.0 to 0.5 years), late infancy (>0.5 to 2.0 years), early childhood (>2.0 to 5.0 years), mid-childhood (>5.0 to 9.0 years), late childhood (>9.0 to 14.0 years), and adolescence (>14.0 to 19.0 years). GA was positivel

Published
2023

97. Life course of retrospective harmonization initiatives:key elements to consider

Author

Fortier, Isabel, Wey, Tina W., Bergeron, Julie, Pinot de Moira, Angela, Nybo-Andersen, Anne-Marie, Bishop, Tom, Murtagh, Madeleine J., Miocevic, Milica, Swertz, Morris A., van Enckevort, Esther, Marcon, Yannick, Mayrhofer, Michaela. Th., Ornelas, Jos Pedro, Sebert, Sylvain, Santos, Ana Cristina, Rocha, Artur, Wilson, Rebecca C., Griffith, Lauren E., Burton, Paul, Fortier, Isabel, Wey, Tina W., Bergeron, Julie, Pinot de Moira, Angela, Nybo-Andersen, Anne-Marie, Bishop, Tom, Murtagh, Madeleine J., Miocevic, Milica, Swertz, Morris A., van Enckevort, Esther, Marcon, Yannick, Mayrhofer, Michaela. Th., Ornelas, Jos Pedro, Sebert, Sylvain, Santos, Ana Cristina, Rocha, Artur, Wilson, Rebecca C., Griffith, Lauren E., and Burton, Paul

Abstract

Optimizing research on the developmental origins of health and disease (DOHaD) involves implementing initiatives maximizing the use of the available cohort study data; achieving sufficient statistical power to support subgroup analysis; and using participant data presenting adequate follow-up and exposure heterogeneity. It also involves being able to undertake comparison, cross-validation, or replication across data sets. To answer these requirements, cohort study data need to be findable, accessible, interoperable, and reusable (FAIR), and more particularly, it often needs to be harmonized. Harmonization is required to achieve or improve comparability of the putatively equivalent measures collected by different studies on different individuals. Although the characteristics of the research initiatives generating and using harmonized data vary extensively, all are confronted by similar issues. Having to collate, understand, process, host, and co-analyze data from individual cohort studies is particularly challenging. The scientific success and timely management of projects can be facilitated by an ensemble of factors. The current document provides an overview of the 'life course' of research projects requiring harmonization of existing data and highlights key elements to be considered from the inception to the end of the project.

Published
2023

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