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2. Referral to the NHS Diabetes Prevention Programme and conversion from nondiabetic hyperglycaemia to type 2 diabetes mellitus in England: A matched cohort analysis

Author

Ravindrarajah, Rathi, Sutton, Matt, Reeves, David, Cotterill, Sarah, Mcmanus, Emma, Meacock, Rachel, Whittaker, William, Soiland-Reyes, Claudia, Heller, Simon, Bower, Peter, and Kontopantelis, Evangelos

Subjects
United Kingdom. National Health Service -- Services -- Statistics, Diabetes therapy -- Statistics, Medical referral -- Statistics, Type 2 diabetes -- Risk factors -- Prevention -- Statistics, Hyperglycemia -- Care and treatment -- Complications and side effects -- Statistics, Biological sciences
Abstract

Background The NHS Diabetes Prevention Programme (NDPP) is a behaviour change programme for adults who are at risk of developing type 2 diabetes mellitus (T2DM): people with raised blood glucose levels, but not in the diabetic range, diagnosed with nondiabetic hyperglycaemia (NDH). We examined the association between referral to the programme and reducing conversion of NDH to T2DM. Methods and findings Cohort study of patients attending primary care in England using clinical Practice Research Datalink data from 1 April 2016 (NDPP introduction) to 31 March 2020 was used. To minimise confounding, we matched patients referred to the programme in referring practices to patients in nonreferring practices. Patients were matched based on age ([greater than or equal to]3 years), sex, and [greater than or equal to]365 days of NDH diagnosis. Random-effects parametric survival models evaluated the intervention, controlling for numerous covariates. Our primary analysis was selected a priori: complete case analysis, 1-to-1 practice matching, up to 5 controls sampled with replacement. Various sensitivity analyses were conducted, including multiple imputation approaches. Analysis was adjusted for age (at index date), sex, time from NDH diagnosis to index date, BMI, HbA1c, total serum cholesterol, systolic blood pressure, diastolic blood pressure, prescription of metformin, smoking status, socioeconomic status, a diagnosis of depression, and comorbidities. A total of 18,470 patients referred to NDPP were matched to 51,331 patients not referred to NDPP in the main analysis. Mean follow-up from referral was 482.0 (SD = 317.3) and 472.4 (SD = 309.1) days, for referred to NDPP and not referred to NDPP, respectively. Baseline characteristics in the 2 groups were similar, except referred to NDPP were more likely to have higher BMI and be ever-smokers. The adjusted HR for referred to NDPP, compared to not referred to NDPP, was 0.80 (95% CI: 0.73 to 0.87) (p < 0.001). The probability of not converting to T2DM at 36 months since referral was 87.3% (95% CI: 86.5% to 88.2%) for referred to NDPP and 84.6% (95% CI: 83.9% to 85.4%) for not referred to NDPP. Associations were broadly consistent in the sensitivity analyses, but often smaller in magnitude. As this is an observational study, we cannot conclusively address causality. Other limitations include the inclusion of controls from the other 3 UK countries, data not allowing the evaluation of the association between attendance (rather than referral) and conversion. Conclusions The NDPP was associated with reduced conversion rates from NDH to T2DM. Although we observed smaller associations with risk reduction, compared to what has been observed in RCTs, this is unsurprising since we examined the impact of referral, rather than attendance or completion of the intervention., Author(s): Rathi Ravindrarajah 1, Matt Sutton 1,2, David Reeves 1,2, Sarah Cotterill 1, Emma Mcmanus 1,2, Rachel Meacock 1,2, William Whittaker 1, Claudia Soiland-Reyes 3, Simon Heller 4, Peter Bower [...]

Published
2023
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3. Frailty and obesity in ageing men

Author

Ravindrarajah, Rathi, Wu, Frederick, Pendleton, Neil, O'Neill, Terence, and Lee, David

Subjects
618.97, Frailty, Obesity, Ageing
Abstract

Background & Aim: Frailty is a syndrome characterised by multisystem physiological dysfunction, making older adults vulnerable to stressors. Frailty is often considered as a wasting disorder however there is increasing evidence that many overweight and obese people are also frail. The broad aim of the thesis was to explore whether anthropometric indicators of adiposity and obesity are linked with an increased susceptibility to frailty in middle aged and older European men. Methods: 3,369 men aged 40-79 years were recruited from population registers in eight European centres for participation in the European Male Ageing Study (EMAS) a prospective study of male ageing. Subjects were invited by letter to attend for an interviewer-assisted questionnaire, functional assessments and anthropometric measurements including height (m), weight (Kg), waist (cm) and hip circumference (cm), from which body mass index (BMI) (Kg/m2), and waist hip ratio (WHR) were calculated. Subjects were assessed again after a median of 4.5 years, using the same study instruments. They were asked also about occurrence of falls in the past year. Frailty was assessed using adaptations (because of availability of data) of two established methods, the frailty phenotype (FP) and the Frail Scale (FS), both comprising 5 domains, and also a Frailty Index (FI) a ratio based on observed over a range of potential deficits. Incident frailty was defined as the new occurrence of frailty in those who were not frail at baseline. Results: 3369 men, mean age 60yrs contributed data to this analysis. Using data from the study the prevalence of frailty at baseline was 2.6% using the FP method and 2.7% using the FS and the mean Frailty Index was 0.13 (IQR=0.05-0.18). The prevalence of frailty increased with age. Those who were frail, using either definition had a significantly increased waist circumference (WC) and also WHR. The FI was higher and also correlated with these anthropometric measures. During follow-up there were 193 deaths. Compared to those who were not frail at baseline those who were frail had an increased risk of mortality and also were more likely to experience falls. Of those who were not frail at baseline and who completed the follow-up assessments the incidence of frailty ranged from 2.1% to 3.5% depending on the definition. Mean Frailty Index increased from 0.12 to 0.13, in men who returned at follow-up. An increase in baseline adiposity measures WC & WHR was significantly associated with frailty incidence, at follow-up using both (FP & FS) models, while there was no association with BMI and % body fat. An increase in all baseline adiposity measure was significantly associated with frailty incidence defined by the FI and also a change in the Frailty Index. Conclusion: Frailty models adapted to EMAS predicted adverse outcomes. Obesity was associated with frailty and predicted frailty incidence at follow-up. Interventions to combat obesity in the elderly may help in preventing and reducing the occurrence of frailty.

Published
2015

6. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Author

International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris CA, Patsopoulos, Nikolaos A, Moutsianas, Loukas, Dilthey, Alexander, Su, Zhan, Freeman, Colin, Hunt, Sarah E, Edkins, Sarah, Gray, Emma, Booth, David R, Potter, Simon C, Goris, An, Band, Gavin, Oturai, Annette Bang, Strange, Amy, Saarela, Janna, Bellenguez, Céline, Fontaine, Bertrand, Gillman, Matthew, Hemmer, Bernhard, Gwilliam, Rhian, Zipp, Frauke, Jayakumar, Alagurevathi, Martin, Roland, Leslie, Stephen, Hawkins, Stanley, Giannoulatou, Eleni, D'alfonso, Sandra, Blackburn, Hannah, Martinelli Boneschi, Filippo, Liddle, Jennifer, Harbo, Hanne F, Perez, Marc L, Spurkland, Anne, Waller, Matthew J, Mycko, Marcin P, Ricketts, Michelle, Comabella, Manuel, Hammond, Naomi, Kockum, Ingrid, McCann, Owen T, Ban, Maria, Whittaker, Pamela, Kemppinen, Anu, Weston, Paul, Hawkins, Clive, Widaa, Sara, Zajicek, John, Dronov, Serge, Robertson, Neil, Bumpstead, Suzannah J, Barcellos, Lisa F, Ravindrarajah, Rathi, Abraham, Roby, Alfredsson, Lars, Ardlie, Kristin, Aubin, Cristin, Baker, Amie, Baker, Katharine, Baranzini, Sergio E, Bergamaschi, Laura, Bergamaschi, Roberto, Bernstein, Allan, Berthele, Achim, Boggild, Mike, Bradfield, Jonathan P, Brassat, David, Broadley, Simon A, Buck, Dorothea, Butzkueven, Helmut, Capra, Ruggero, Carroll, William M, Cavalla, Paola, Celius, Elisabeth G, Cepok, Sabine, Chiavacci, Rosetta, Clerget-Darpoux, Françoise, Clysters, Katleen, Comi, Giancarlo, Cossburn, Mark, Cournu-Rebeix, Isabelle, Cox, Mathew B, Cozen, Wendy, Cree, Bruce AC, Cross, Anne H, Cusi, Daniele, Daly, Mark J, Davis, Emma, de Bakker, Paul IW, Debouverie, Marc, D'hooghe, Marie Beatrice, Dixon, Katherine, Dobosi, Rita, Dubois, Bénédicte, and Ellinghaus, David

Subjects
International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, T-Lymphocytes, Helper-Inducer, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, HLA-A Antigens, HLA-DR Antigens, Sample Size, Cell Differentiation, Immunity, Cellular, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, Alleles, Genome, Human, Europe, Genome-Wide Association Study, HLA-DRB1 Chains, Genetics, Neurosciences, Neurodegenerative, Clinical Research, Brain Disorders, Autoimmune Disease, Human Genome, 2.1 Biological and endogenous factors, Neurological, Inflammatory and immune system, General Science & Technology
Abstract

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2011

7. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris CA, Patsopoulos, Nikolaos A, Moutsianas, Loukas, Dilthey, Alexander, Su, Zhan, Freeman, Colin, Hunt, Sarah E, Edkins, Sarah, Gray, Emma, Booth, David R, Potter, Simon C, Goris, An, Band, Gavin, Oturai, Annette Bang, Strange, Amy, Saarela, Janna, Bellenguez, Celine, Fontaine, Bertrand, Gillman, Matthew, Hemmer, Bernhard, Gwilliam, Rhian, Zipp, Frauke, Jayakumar, Alagurevathi, Martin, Roland, Leslie, Stephen, Hawkins, Stanley, Giannoulatou, Eleni, D'alfonso, Sandra, Blackburn, Hannah, Boneschi, Filippo Martinelli, Liddle, Jennifer, Harbo, Hanne F, Perez, Marc L, Spurkland, Anne, Waller, Matthew J, Mycko, Marcin P, Ricketts, Michelle, Comabella, Manuel, Hammond, Naomi, Kockum, Ingrid, McCann, Owen T, Ban, Maria, Whittaker, Pamela, Kemppinen, Anu, Weston, Paul, Hawkins, Clive, Widaa, Sara, Zajicek, John, Dronov, Serge, Robertson, Neil, Bumpstead, Suzannah J, Barcellos, Lisa F, Ravindrarajah, Rathi, Abraham, Roby, Alfredsson, Lars, Ardlie, Kristin, Aubin, Cristin, Baker, Amie, Baker, Katharine, Baranzini, Sergio E, Bergamaschi, Laura, Bergamaschi, Roberto, Bernstein, Allan, Berthele, Achim, Boggild, Mike, Bradfield, Jonathan P, Brassat, David, Broadley, Simon A, Buck, Dorothea, Butzkueven, Helmut, Capra, Ruggero, Carroll, William M, Cavalla, Paola, Celius, Elisabeth G, Cepok, Sabine, Chiavacci, Rosetta, Clerget-Darpoux, Francoise, Clysters, Katleen, Comi, Giancarlo, Cossburn, Mark, Cournu-Rebeix, Isabelle, Cox, Mathew B, Cozen, Wendy, Cree, Bruce AC, Cross, Anne H, Cusi, Daniele, Daly, Mark J, Davis, Emma, de Bakker, Paul IW, Debouverie, Marc, D'hooghe, Marie Beatrice, Dixon, Katherine, Dobosi, Rita, Dubois, Benedicte, Ellinghaus, David, Elovaara, Irina, and Esposito, Federica

Subjects
Neurosciences, Prevention, Multiple Sclerosis, Biotechnology, Autoimmune Disease, Genetics, Brain Disorders, Human Genome, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Inflammatory and immune system, Alleles, Cell Differentiation, Europe, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, HLA-A Antigens, HLA-DR Antigens, HLA-DRB1 Chains, Humans, Immunity, Cellular, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, Sample Size, T-Lymphocytes, Helper-Inducer, International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, General Science & Technology
Abstract

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2011

13. Chronic widespread pain is associated with worsening frailty in European men

Author

Wade, Katie Fredrika, Lee, David M., McBeth, John, Ravindrarajah, Rathi, Gielen, Evelien, Pye, Stephen R., Vanderschueren, Dirk, Pendleton, Neil, Finn, Joseph D., Bartfai, György, Casanueva, Felipe F., Forti, Gianni, Giwercman, Aleksander, Huhtaniemi, Ilpo T., Kula, Krzysztof, Punab, Margus, Wu, Frederick C. W., and OʼNeill, Terence W.

Published
2016
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14. Association of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone with mortality among middle-aged and older European men

Author

Lee, David M., Vanderschueren, Dirk, Boonen, Steven, OʼNeill, Terence W., Pendleton, Neil, Pye, Stephen R., Ravindrarajah, Rathi, Gielen, Evelien, Claessens, Frank, Bartfai, György, Casanueva, Felipe F., Finn, Joseph D., Forti, Gianni, Giwercman, Aleksander, Han, Thang S., Huhtaniemi, Ilpo T., Kula, Krzysztof, Lean, Michael E. J., Punab, Margus, and Wu, Frederick C. W.

Published
2014
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15. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Author

Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Ferrier, I. Nicol, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Mohiuddin, M. Khalid, Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]

Published
2007
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16. Linkage of monogenic infantile hypertrophic pyloric stenosis to chromosome 16p12-p13 and evidence for genetic heterogeneity

Author

Capon, Francesca, Reece, Ashley, Ravindrarajah, Rathi, and Chung, Eddie

Subjects
Single nucleotide polymorphisms -- Research, Pyloric stenosis -- Genetic aspects, Genetic research, Biological sciences
Abstract

A 3-generation family with infantile hypertrophic pyloric stenosis (IHPS) is analyzed and a single-nucleotide polymorphism-based genomewide scan is sued t o map the underlying disease locus to chromosome 16p12-p13. The analysis has yielded negative or nonsignificant LOD scores, indicating the presence of locus heterogeneity, and the sequence analysis of candidate genes from the chromosome 16 disease intervals has excluded the presence of pathogenic mutations in the GRIN2A and MYH11 genes.

Published
2006

17. Frailty and Sexual Health in Older European Men

Author

Lee, David M., Tajar, Abdelouahid, Ravindrarajah, Rathi, Pye, Stephen R., O’Connor, Daryl B., Corona, Giovanni, O’Connell, Matthew, Gielen, Evelien, Boonen, Steven, Vanderschueren, Dirk, Pendleton, Neil, Finn, Joseph D., Bartfai, György, Casanueva, Felipe F., Forti, Gianni, Giwercman, Aleksander, Han, Thang S., Huhtaniemi, Ilpo T., Kula, Krzysztof, Lean, Michael E. J., Punab, Margus, Wu, Frederick C. W., and O’Neill, Terence W.

Published
2013
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18. The association of frailty with serum 25-hydroxyvitamin D and parathyroid hormone levels in older European men

Author

Tajar, Abdelouahid, Lee, David M., Pye, Stephen R., OʼConnell, Matthew D. L., Ravindrarajah, Rathi, Gielen, Evelien, Boonen, Steven, Vanderschueren, Dirk, Pendleton, Neil, Finn, Joseph D., Bartfai, György, Casanueva, Felipe F., Forti, Gianni, Giwercman, Aleksander, Han, Thang S., Huhtaniemi, Ilpo T., Kula, Krzysztof, Lean, Michael E. J., Punab, Margus, Wu, Frederick C. W., and OʼNeill, Terence W.

Published
2013
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19. Epidemiology and determinants of non-diabetic hyperglycaemia and its conversion to type 2 diabetes mellitus, 2000–2015: cohort population study using UK electronic health records

Author

Ravindrarajah, Rathi, primary, Reeves, David, additional, Howarth, Elizabeth, additional, Meacock, Rachel, additional, Soiland-Reyes, Claudia, additional, Cotterill, Sarah, additional, Whittaker, William, additional, Heller, Simon, additional, Sutton, Matt, additional, Bower, Peter, additional, and Kontopantelis, Evangelos, additional

Published
2020
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23. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Author

Nejentsev, Sergey, Howson, Joanna M. M., Walker, Neil M., Szeszko, Jeffrey, Field, Sarah F., Stevens, Helen E., Reynolds, Pamela, Hardy, Matthew, King, Erna, Masters, Jennifer, Hulme, John, Maier, Lisa M., Smyth, Deborah, Bailey, Rebecca, Cooper, Jason D., Ribas, Gloria, Campbell, R. Duncan, Clayton, David G., Todd, John A., Burton, Paul R., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Taylor, Niall C., Walters, Graham R., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Nicol Ferrier, I., Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Khalid Mohiuddin, M., Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Braga, Carolina A., Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bryan, Claire, Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Jilur, Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingeleif B., Howie, Bryan N., Su, Zhan, Ying Teo, Yik, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Sergey Nejentsev [1, 57]; Joanna M. M. Howson (corresponding author) [1, 57]; Neil M. Walker [1]; Jeffrey Szeszko [1]; Sarah F. Field [1]; Helen E. Stevens [1]; Pamela Reynolds [...]

Published
2007
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27. Frailty and bone health in European men

Author

Cook, Michael J., primary, Oldroyd, Alexander, additional, Pye, Stephen R., additional, Ward, Kate A., additional, Gielen, Evelien, additional, Ravindrarajah, Rathi, additional, Adams, Judith E., additional, Lee, David M., additional, Bartfai, Gyorgy, additional, Boonen, Steven, additional, Casanueva, Felipe, additional, Forti, Gianni, additional, Giwercman, Aleksander, additional, Han, Thang S., additional, Huhtaniemi, Ilpo T., additional, Kula, Krzysztof, additional, Lean, Michael E., additional, Pendleton, Neil, additional, Punab, Margus, additional, Vanderschueren, Dirk, additional, Wu, Frederick C., additional, and O'Neill, Terence W., additional

Published
2016
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29. Chronic widespread pain is associated with worsening frailty in European men

Author

Wade, Katie Fredrika, primary, Lee, David M., additional, McBeth, John, additional, Ravindrarajah, Rathi, additional, Gielen, Evelien, additional, Pye, Stephen R., additional, Vanderschueren, Dirk, additional, Pendleton, Neil, additional, Finn, Joseph D., additional, Bartfai, György, additional, Casanueva, Felipe F., additional, Forti, Gianni, additional, Giwercman, Aleksander, additional, Huhtaniemi, Ilpo T., additional, Kula, Krzysztof, additional, Punab, Margus, additional, Wu, Frederick C. W., additional, and O'Neill, Terence W., additional

Published
2015
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30. Trajectory of Total Cholesterol in the Last Years of Life Over Age 80 Years: Cohort Study of 99,758 Participants.

Author

Charlton, Judith, Ravindrarajah, Rathi, Hamada, Shota, Gulliford, Martin C., and Jackson, Stephen H.

Subjects
*STATINS (Cardiovascular agents), *BLOOD pressure, *MORTALITY, CHOLESTEROL testing
Abstract

Background: Epidemiological studies suggest that lower total cholesterol (TC) may be associated with higher mortality. This study aimed to evaluate whether a decline in TC before death might account for the association of TC with mortality over age 80 years.Methods: Cohort study using primary care electronic health records of 99,758 participants aged 80-105 years from the UK Clinical Practice Research Datalink. Hazard ratios for all-cause mortality were adjusted for age, gender, frailty, comorbidity, blood pressure, and smoking. Fractional polynomial models were fitted to evaluate longitudinal trends in TC before death or end-of-study. Adjusted odds ratios were estimated using generalized estimating equations.Results: There were 63,630 women and 36,128 men, mean age 86 years, with 29,200 deaths. There were 41,164 treated with statins at cohort entry. Compared with TC values of 4.5-5.4 mmol/L, TC values <3.0 mmol/L were associated with higher mortality (statin treated hazard ratios 1.53, 95% confidence interval 1.43-1.64, p < .001; not treated, 1.41, 1.29-1.54, p < .001). A secular decline in TC values accelerated in the last 2 years of life. In the last quarter of follow-up, the adjusted odds of TC < 3.0 mmol/L for those who died, compared with surviving participants, were 3.33 (2.84-3.91, p < .001) for untreated and 1.88 (1.68-2.11, p < .001) for statin-treated participants.Conclusions: TC values show a terminal decline in the last years of life. Reverse causation may contribute to the association of lower TC with higher mortality in nonrandomized studies. [ABSTRACT FROM AUTHOR]

Published
2018
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31. Frailty and bone health in European men.

Author

COOK, MICHAEL J., OLDROYD, ALEXANDER, PYE, STEPHEN R., WARD, KATE A., GIELEN, EVELIEN, RAVINDRARAJAH, RATHI, ADAMS, JUDITH E., LEE, DAVID M., BARTFAI, GYORGY, BOONEN, STEVEN, CASANUEVA, FELIPE, FORTI, GIANNI, GIWERCMAN, ALEKSANDER, THANG S. HAN, HUHTANIEMI, ILPO T., KULA, KRZYSZTOF, LEAN, MICHAEL E., PENDLETON, NEIL, PUNAB, MARGUS, and VANDERSCHUEREN, DIRK

Subjects
RISK factors of fractures, AGING, DATABASES, EPIDEMIOLOGICAL research, FRAIL elderly, HEALTH status indicators, MEDICAL information storage & retrieval systems, MEN'S health, PROBABILITY theory, REGRESSION analysis, PHENOTYPES, BONE density, BODY mass index, INDEPENDENT living, HEEL (Anatomy), DESCRIPTIVE statistics, PHOTON absorptiometry
Abstract

Background: frailty is associated with an increased risk of fragility fractures. Less is known, however, about the association between frailty and bone health. Methods: men aged 40-79 years were recruited from population registers in eight European centres for participation in the European Male Aging Study. Subjects completed a comprehensive assessment which included quantitative ultrasound (QUS) scan of the heel (Hologic-SAHARA) and in two centres, dual-energy bone densitometry (dual-energy x-ray absorptiometry, DXA). Frailty was defined based on an adaptation of Fried's phenotype criteria and a frailty index (FI) was constructed. The association between frailty and the QUS and DXA parameters was determined using linear regression, with adjustments for age, body mass index and centre. Results: in total, 3,231 subjects contributed data to the analysis. Using the Fried categorisation of frailty, pre-frail and frail men had significantly lower speed of sound (SOS), broadband ultrasound attenuation (BUA) and quantitative ultrasound index (QUI) compared to robust men (P < 0.05). Similar results were seen using the FI after categorisation into 'high', 'medium' and 'low' levels of frailty. Using the Fried categorisation, frail men had lower femoral neck bone mineral density (BMD) compared to robust men (P < 0.05), but not lower lumbar spine BMD. Using the FI categorisation, a 'high' level of frailty (FI > 0.35) was associated with lower lumbar spine BMD (P < 0.05) when compared to those with low (FI < 0.2), but not lower femoral neck BMD. When analysed as a continuous variable, higher FI was linked with lower SOS, BUA and QUI (P < 0.05). Conclusions: optimisation of bone health as well as prevention of falls should be considered as strategies to reduce fractures in frail older people. [ABSTRACT FROM AUTHOR]

Published
2017
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32. Association of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone with mortality among middle-aged and older European men

Author

Lee, David M., primary, Vanderschueren, Dirk, additional, Boonen, Steven, additional, O'Neill, Terence W., additional, Pendleton, Neil, additional, Pye, Stephen R., additional, Ravindrarajah, Rathi, additional, Gielen, Evelien, additional, Claessens, Frank, additional, Bartfai, György, additional, Casanueva, Felipe F., additional, Finn, Joseph D., additional, Forti, Gianni, additional, Giwercman, Aleksander, additional, Han, Thang S., additional, Huhtaniemi, Ilpo T., additional, Kula, Krzysztof, additional, Lean, Michael E. J., additional, Punab, Margus, additional, and Wu, Frederick C. W., additional

Published
2013
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33. The ability of three different models of frailty to predict all-cause mortality: Results from the European Male Aging Study (EMAS)

Author

Ravindrarajah, Rathi, primary, Lee, David M., additional, Pye, Stephen R., additional, Gielen, Evelien, additional, Boonen, Steven, additional, Vanderschueren, Dirk, additional, Pendleton, Neil, additional, Finn, Joseph D., additional, Tajar, Abdelouahid, additional, O’Connell, Matthew D.L., additional, Rockwood, Kenneth, additional, Bartfai, György, additional, Casanueva, Felipe F., additional, Forti, Gianni, additional, Giwercman, Aleksander, additional, Han, Thang S., additional, Huhtaniemi, Ilpo T., additional, Kula, Krzysztof, additional, Lean, Michael E.J., additional, Punab, Margus, additional, Wu, Frederick C.W., additional, and O’Neill, Terence W., additional

Published
2013
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34. Chronic widespread pain is associated with worsening frailty in European men.

Author

FREDRIKAWADE, KATIE, LEE, DAVID M., MCBETH, JOHN, RAVINDRARAJAH, RATHI, GIELEN, EVELIEN, PYE, STEPHEN R., VANDERSCHUEREN, DIRK, PENDLETON, NEIL, FINN, JOSEPH D., BARTFAI, GYÖRGY, CASANUEVA, FELIPE F., FORTI, GIANNI, GIWERCMAN, ALEKSANDER, HUHTANIEMI, ILPO T., KULA, KRZYSZTOF, PUNAB, MARGUS, WU, FREDERICK C. W., and O'NEILL, TERENCE W.

Subjects
CHRONIC pain, CONFIDENCE intervals, FRAIL elderly, HEALTH surveys, LONGITUDINAL method, MEDICAL screening, MEN, QUESTIONNAIRES, STATISTICS, T-test (Statistics), DATA analysis, DATA analysis software, DESCRIPTIVE statistics, ODDS ratio, MANN Whitney U Test, DISEASE complications
Abstract

Background: we hypothesised that chronic widespread pain (CWP), by acting as a potential stressor, may predispose to the development of, or worsening, frailty. Setting: longitudinal analysis within the European Male Ageing Study (EMAS). Participants: a total of 2,736 community-dwelling men aged 40-79. Methods: subjects completed a pain questionnaire and shaded a manikin, with the presence of CWP defined using the American College of Rheumatology criteria. Physical activity, smoking, alcohol consumption and depression were measured. Repeat assessments took place a median of 4.3 years later. A frailty index (FI) was used, with frail defined as an FI >0.35. The association between CWP at baseline and the new occurrence of frailty was examined using logistic regression; the association between CWP at baseline and change in FI was examined using negative binomial regression. Results: at baseline, 218 (8.3%) men reported CWP. Of the 2,631 men who were defined as non-frail at baseline, 112 (4.3%) were frail at follow-up; their mean FI was 0.12 (SD 0.1) at baseline and 0.15 (SD 0.1) at follow-up, with a mean change of 0.03 (SD 0.08) P ≤ 0.001. Among men who were non-frail at baseline, those with CWP were significantly more likely to develop frailty. After adjustment for age and centre, compared with those with no pain, those with CWP at baseline had a 70% higher FI at follow-up; these associations remained significant after further adjustment for smoking, body mass index, depression, physical activity and FI at baseline. Conclusion: the presence of CWP is associated with an increased risk of frailty in older European men. [ABSTRACT FROM AUTHOR]

Published
2016
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35. Understanding variance in health outcomes in England : a study of deprivation and health inequality

Author

Murphy, Jennifer, Elliot, Mark, Whittaker, William, and Ravindrarajah, Rathi

Subjects
wellbeing, access, primary care, deprivation, health inequality, COVID-19
Abstract

In this thesis, I present a body of quantitative empirical work on the theme of deprivation and health, linking administrative and survey datasets to publicly available census data to provide insight into the factors affecting a range of health related outcomes. In the first paper, I investigate the impact of distance and deprivation on the uptake of extended hours services in Primary Care and conclude that there is evidence of geographical inequity in the service but that deprivation was not directly associated with rates of use. In the second paper, I analyse the trajectory of well-being over the course of the firstwave of the COVID-19 pandemic, and found that well-being decreased but bounced back in a similar way across all deciles of deprivation. In the third paper, I analyse the outcomes for hospitalised COVID patients in Greater Manchester during 2020 and conclude that there was a deprivation effect in risk of death but that the length of stay in hospital for any given patient was not associated with their level of deprivation. The work highlights that investigating health outcomes and inequalities therein is a complex and difficult task, and at the heart of this must be an understanding of what the researcher seeks to measure and how this relates to the lived experience of the study population.

Published
2022

37. Low testosterone in ageing men: a modifiable risk factor for frailty?

Author

O'Connell MD, Ravindrarajah R, Tajar A, and Wu FC

Subjects
Aged, Aged, 80 and over, Aging drug effects, Aging metabolism, Androgens adverse effects, Androgens therapeutic use, Animals, Frail Elderly, Hormone Replacement Therapy adverse effects, Humans, Male, Models, Biological, Receptors, Androgen chemistry, Receptors, Androgen metabolism, Risk Factors, Sarcopenia blood, Sarcopenia drug therapy, Sarcopenia epidemiology, Sarcopenia prevention & control, Signal Transduction drug effects, Testosterone adverse effects, Testosterone therapeutic use, Aging blood, Health Status, Testosterone blood
Abstract

There is substantial interest in the role of testosterone (T) in male ageing. Studies suggest that low T may be a risk factor for frailty, the vulnerable health status that occurs at advanced ages. However, T deficiency is relatively rare in ageing men and, importantly, is linked to modifiable risk factors including body weight and concurrent illnesses. These observations shift the focus away from hormone replacement and towards potential preventative strategies to help maintain T levels in ageing men. Furthermore, the effects of T on physical function remain inconsistent, and studies examining the safety of T treatment in ageing males raise concerns. Further research may usefully focus on novel pro-anabolic pharmaceutical agents, which together with other interventions will allow for optimal management of frailty., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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38. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.

Author

Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskivina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop TD, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Matthew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop MG, Connell J, Dominiczak A, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hilder SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Newport M, Sirugo G, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Davison D, Ferreira T, Pereira-Gale J, Hallgrimsdo'ttir IB, Howie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Brown MA, Compston A, Farrall M, Hall AS, Hattersley AT, Hill AV, Parkes M, Pembrey M, Stratton MR, Mitchell SL, Newby PR, Brand OJ, Carr-Smith J, Pearce SH, McGinnis R, Keniry A, Deloukas P, Reveille JD, Zhou X, Sims AM, Dowling A, Taylor J, Doan T, Davis JC, Savage L, Ward MM, Learch TL, Weisman MH, and Brown M

Subjects
Aminopeptidases genetics, Breast Neoplasms epidemiology, Case-Control Studies, Chromosome Mapping, Genetics, Population, Genotype, Haplotypes genetics, Humans, Linkage Disequilibrium, Minor Histocompatibility Antigens, Multiple Sclerosis epidemiology, North America epidemiology, Polymerase Chain Reaction, Receptors, Immunologic genetics, Receptors, Interleukin genetics, Spondylitis, Ankylosing epidemiology, Thyroiditis, Autoimmune epidemiology, Autoimmunity genetics, Breast Neoplasms genetics, Multiple Sclerosis genetics, Polymorphism, Single Nucleotide genetics, Spondylitis, Ankylosing genetics, Thyroiditis, Autoimmune genetics
Abstract

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Published
2007
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