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1. Risk factors and prediction of hypoglycaemia using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials

Author

Mellor, Joseph, Kuznetsov, Dmitry, Heller, Simon, Gall, Mari-Anne, Rosilio, Myriam, Amiel, Stephanie A., Ibberson, Mark, McGurnaghan, Stuart, Blackbourn, Luke, Berthon, William, Salem, Adel, Qu, Yongming, McCrimmon, Rory J., de Galan, Bastiaan E., Pedersen-Bjergaard, Ulrik, Leaviss, Joanna, McKeigue, Paul M., and Colhoun, Helen M.

Published
2024
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2. Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials

Author

Mellor, Joseph, Kuznetsov, Dmitry, Heller, Simon, Gall, Mari-Anne, Rosilio, Myriam, Amiel, Stephanie A., Ibberson, Mark, McGurnaghan, Stuart, Blackbourn, Luke, Berthon, William, Salem, Adel, Qu, Yongming, McCrimmon, Rory J., de Galan, Bastiaan E., Pedersen-Bjergaard, Ulrik, Leaviss, Joanna, McKeigue, Paul M., and Colhoun, Helen M.

Published
2024
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5. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Author

Rivellese, Felice, Surace, Anna E. A., Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R., Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E., Hudson, Briana M., Warren, Sarah E., McKeigue, Paul M., Humby, Frances, Bombardieri, Michele, Barnes, Michael R., Lewis, Myles J., and Pitzalis, Costantino

Published
2022
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7. Flash monitor initiation is associated with improvements in HbA1c levels and DKA rates among people with type 1 diabetes in Scotland: a retrospective nationwide observational study

Author

Jeyam, Anita, Gibb, Fraser W., McKnight, John A., O’Reilly, Joseph E., Caparrotta, Thomas M., Höhn, Andreas, McGurnaghan, Stuart J., Blackbourn, Luke A. K., Hatam, Sara, Kennon, Brian, McCrimmon, Rory J., Leese, Graham, Philip, Sam, Sattar, Naveed, McKeigue, Paul M., and Colhoun, Helen M.

Published
2022
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9. Impact of COVID-19 and Non-COVID-19 Hospitalized Pneumonia on Longer-Term Cardiovascular Mortality in People With Type 2 Diabetes: A Nationwide Prospective Cohort Study From Scotland.

Author

McGurnaghan, Stuart J., McKeigue, Paul M., Blackbourn, Luke A.K., Mellor, Joseph, Caparrotta, Thomas M., Sattar, Naveed, Kennon, Brian, McAllister, David, Wild, Sarah H., and Colhoun, Helen M.

Subjects
*TYPE 2 diabetes, *CARDIOVASCULAR diseases, *COVID-19, *PNEUMONIA, *COVID-19 pandemic, *COHORT analysis
Abstract

OBJECTIVE: In this study we examine whether hospitalized coronavirus disease 2019 (COVID-19) pneumonia increases long-term cardiovascular mortality more than other hospitalized pneumonias in people with type 2 diabetes and aim to quantify the relative cardiovascular disease (CVD) mortality risks associated with COVID-19 versus non-COVID-19 pneumonia. RESEARCH DESIGN AND METHODS: With use of the SCI-Diabetes register, two cohorts were identified: individuals with type 2 diabetes in 2016 and at the 2020 pandemic onset. Hospital and death records were linked for determination of pneumonia exposure and CVD deaths. Poisson regression estimated rate ratios (RRs) for CVD death associated with both pneumonia types, with adjustment for confounders. Median follow-up durations were 1,461 days (2016 cohort) and 700 days (2020 cohort). RESULTS: The adjusted RR for CVD death following non-COVID-19 pneumonia was 5.51 (95% CI 5.31–5.71) prepandemic and 7.3 (6.86–7.76) during the pandemic. For COVID-19 pneumonia, the RR was 9.13 (8.55–9.75). Beyond 30 days post pneumonia, the RRs converged, to 4.24 (3.90–4.60) for non-COVID-19 and 3.35 (3.00–3.74) for COVID-19 pneumonia, consistent even with exclusion of prior CVD cases. CONCLUSIONS: Hospitalized pneumonia, irrespective of causal agent, marks an increased risk for CVD death immediately and over the long-term. COVID-19 pneumonia poses a higher CVD death risk than other pneumonias in the short-term, but this distinction diminishes over time. These insights underscore the need for including pneumonia in CVD risk assessments, with particular attention to the acute impact of COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Deep learning detection of diabetic retinopathy in Scotland's diabetic eye screening programme.

Author

Fleming, Alan D., Mellor, Joseph, McGurnaghan, Stuart J., Blackbourn, Luke A. K., Goatman, Keith A., Styles, Caroline, Storkey, Amos J., McKeigue, Paul M., and Colhoun, Helen M.

Abstract

Background/Aims Support vector machine-based automated grading (known as iGradingM) has been shown to be safe, cost-effective and robust in the diabetic retinopathy (DR) screening (DES) programme in Scotland. It triages screening episodes as gradable with no DR versus manual grading required. The study aim was to develop a deep learning-based autograder using images and gradings from DES and to compare its performance with that of iGradingM. Methods Retinal images, quality assurance (QA) data and routine DR grades were obtained from national datasets in 179 944 patients for years 2006-2016. QA grades were available for 744 images. We developed a deep learning-based algorithm to detect whether either eye contained ungradable images or any DR. The sensitivity and specificity were evaluated against consensus QA grades and routine grades. Results Images used in QA which were ungradable or with DR were detected by deep learning with better specificity compared with manual graders (p<0.001) and with iGradingM (p<0.001) at the same sensitivities. Any DR according to the DES final grade was detected with 89.19% (270 392/303 154) sensitivity and 77.41% (500 945/647 158) specificity. Observable disease and referable disease were detected with sensitivities of 96.58% (16 613/17 201) and 98.48% (22 600/22 948), respectively. Overall, 43.84% of screening episodes would require manual grading. Conclusion A deep learning-based system for DR grading was evaluated in QA data and images from 11 years in 50% of people attending a national DR screening programme. The system could reduce the manual grading workload at the same sensitivity compared with the current automated grading system. [ABSTRACT FROM AUTHOR]

Published
2024
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11. A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Author

van Zuydam, Natalie R, Ahlqvist, Emma, Sandholm, Niina, Deshmukh, Harshal, Rayner, N William, Abdalla, Moustafa, Ladenvall, Claes, Ziemek, Daniel, Fauman, Eric, Robertson, Neil R, McKeigue, Paul M, Valo, Erkka, Forsblom, Carol, Harjutsalo, Valma, Perna, Annalisa, Rurali, Erica, Marcovecchio, M Loredana, Igo, Robert P, Salem, Rany M, Perico, Norberto, Lajer, Maria, Käräjämäki, Annemari, Imamura, Minako, Kubo, Michiaki, Takahashi, Atsushi, Sim, Xueling, Liu, Jianjun, van Dam, Rob M, Jiang, Guozhi, Tam, Claudia HT, Luk, Andrea OY, Lee, Heung Man, Lim, Cadmon KP, Szeto, Cheuk Chun, So, Wing Yee, Chan, Juliana CN, Ang, Su Fen, Dorajoo, Rajkumar, Wang, Ling, Clara, Tan Si Hua, McKnight, Amy-Jayne, Duffy, Seamus, Pezzolesi, Marcus G, Marre, Michel, Gyorgy, Beata, Hadjadj, Samy, Hiraki, Linda T, Ahluwalia, Tarunveer S, Almgren, Peter, Schulz, Christina-Alexandra, Orho-Melander, Marju, Linneberg, Allan, Christensen, Cramer, Witte, Daniel R, Grarup, Niels, Brandslund, Ivan, Melander, Olle, Paterson, Andrew D, Tregouet, David, Maxwell, Alexander P, Lim, Su Chi, Ma, Ronald CW, Tai, E Shyong, Maeda, Shiro, Lyssenko, Valeriya, Tuomi, Tiinamaija, Krolewski, Andrzej S, Rich, Stephen S, Hirschhorn, Joel N, Florez, Jose C, Dunger, David, Pedersen, Oluf, Hansen, Torben, Rossing, Peter, Remuzzi, Giuseppe, Brosnan, Mary Julia, Palmer, Colin NA, Groop, Per-Henrik, Colhoun, Helen M, Groop, Leif C, McCarthy, Mark I, Koivula, S, Uggeldahl, T, Forslund, T, Halonen, A, Koistinen, A, Koskiaho, P, Laukkanen, M, Saltevo, J, Tiihonen, M, Forsen, M, Granlund, H, Jonsson, A-C, Nyroos, B, Kinnunen, P, Orvola, A, Salonen, T, Vähänen, A, Paldanius, Kotka R, and Riihelä, M

Subjects
Diabetes, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Case-Control Studies, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Failure, Chronic, Male, Middle Aged, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, Finnish Diabetic Nephropathy Study, Hong Kong Diabetes Registry Theme-based Research Scheme Project Group, Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group, GENIE (GEnetics of Nephropathy an International Effort) Consortium, Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group, SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium, Medical and Health Sciences, Endocrinology & Metabolism
Abstract

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.

Published
2018

13. Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland

Author

Whettlock, Alice, McLeod, Allan, Gasiorowski, Andrew, Merrick, Andrew, McAuley, Andy, Went, April, Purdie, Calum, Fischbacher, Colin, Ramsey, Colin, Bailey, David, Henderson, David, McDonald, Eisin, Drennan, Genna, Gowans, Graeme, Reid, Graeme, Murdoch, Heather, Carruthers, Jade, Murray, Josie, Heatlie, Karen, Donaldson, Lorraine, Paton, Martin, Reid, Martin, Llano, Melissa, Murphy-Hall, Michelle, Hall, Ross, Cameron, Ross, Brownlie, Susan, Gaffney, Adam, Milne, Aynsley, Sullivan, Christopher, McArdle, Edward, Glass, Elaine, Young, Johanna, Malcolm, William, McCoubrey, Jodie, McGurnaghan, Stuart J, Weir, Amanda, Bishop, Jen, Kennedy, Sharon, Blackbourn, Luke A K, McAllister, David A, Hutchinson, Sharon, Caparrotta, Thomas M, Mellor, Joseph, Jeyam, Anita, O'Reilly, Joseph E, Wild, Sarah H, Hatam, Sara, Höhn, Andreas, Colombo, Marco, Robertson, Chris, Lone, Nazir, Murray, Janet, Butterly, Elaine, Petrie, John, Kennon, Brian, McCrimmon, Rory, Lindsay, Robert, Pearson, Ewan, Sattar, Naveed, McKnight, John, Philip, Sam, Collier, Andrew, McMenamin, Jim, Smith-Palmer, Alison, Goldberg, David, McKeigue, Paul M, and Colhoun, Helen M

Published
2021
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14. Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

Author

Postmus, Iris, Warren, Helen R, Trompet, Stella, Arsenault, Benoit J, Avery, Christy L, Bis, Joshua C, Chasman, Daniel I, de Keyser, Catherine E, Deshmukh, Harshal A, Evans, Daniel S, Feng, QiPing, Li, Xiaohui, Smit, Roelof AJ, Smith, Albert V, Sun, Fangui, Taylor, Kent D, Arnold, Alice M, Barnes, Michael R, Barratt, Bryan J, Betteridge, John, Boekholdt, S Matthijs, Boerwinkle, Eric, Buckley, Brendan M, Chen, Y-D Ida, de Craen, Anton JM, Cummings, Steven R, Denny, Joshua C, Dubé, Marie Pierre, Durrington, Paul N, Eiriksdottir, Gudny, Ford, Ian, Guo, Xiuqing, Harris, Tamara B, Heckbert, Susan R, Hofman, Albert, Hovingh, G Kees, Kastelein, John JP, Launer, Leonore J, Liu, Ching-Ti, Liu, Yongmei, Lumley, Thomas, McKeigue, Paul M, Munroe, Patricia B, Neil, Andrew, Nickerson, Deborah A, Nyberg, Fredrik, O'Brien, Eoin, O'Donnell, Christopher J, Post, Wendy, Poulter, Neil, Vasan, Ramachandran S, Rice, Kenneth, Rich, Stephen S, Rivadeneira, Fernando, Sattar, Naveed, Sever, Peter, Shaw-Hawkins, Sue, Shields, Denis C, Slagboom, P Eline, Smith, Nicholas L, Smith, Joshua D, Sotoodehnia, Nona, Stanton, Alice, Stott, David J, Stricker, Bruno H, Stürmer, Til, Uitterlinden, André G, Wei, Wei-Qi, Westendorp, Rudi GJ, Whitsel, Eric A, Wiggins, Kerri L, Wilke, Russell A, Ballantyne, Christie M, Colhoun, Helen M, Cupples, L Adrienne, Franco, Oscar H, Gudnason, Vilmundur, Hitman, Graham, Palmer, Colin NA, Psaty, Bruce M, Ridker, Paul M, Stafford, Jeanette M, Stein, Charles M, Tardif, Jean-Claude, Caulfield, Mark J, Jukema, J Wouter, Rotter, Jerome I, and Krauss, Ronald M

Subjects
Atherosclerosis, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Stroke, Good Health and Well Being, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Female, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Treatment Outcome, White People, Genome-wide association study, HDL-cholesterol, Statins, pharmacogenetics, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

BackgroundIn addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.Methods and resultsWe performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p

Published
2016

17. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

Author

Postmus, Iris, Trompet, Stella, Deshmukh, Harshal A, Barnes, Michael R, Li, Xiaohui, Warren, Helen R, Chasman, Daniel I, Zhou, Kaixin, Arsenault, Benoit J, Donnelly, Louise A, Wiggins, Kerri L, Avery, Christy L, Griffin, Paula, Feng, QiPing, Taylor, Kent D, Li, Guo, Evans, Daniel S, Smith, Albert V, de Keyser, Catherine E, Johnson, Andrew D, de Craen, Anton JM, Stott, David J, Buckley, Brendan M, Ford, Ian, Westendorp, Rudi GJ, Slagboom, P Eline, Sattar, Naveed, Munroe, Patricia B, Sever, Peter, Poulter, Neil, Stanton, Alice, Shields, Denis C, O'Brien, Eoin, Shaw-Hawkins, Sue, Chen, Y-D Ida, Nickerson, Deborah A, Smith, Joshua D, Dubé, Marie Pierre, Boekholdt, S Matthijs, Hovingh, G Kees, Kastelein, John JP, McKeigue, Paul M, Betteridge, John, Neil, Andrew, Durrington, Paul N, Doney, Alex, Carr, Fiona, Morris, Andrew, McCarthy, Mark I, Groop, Leif, Ahlqvist, Emma, Welcome Trust Case Control Consortium, Bis, Joshua C, Rice, Kenneth, Smith, Nicholas L, Lumley, Thomas, Whitsel, Eric A, Stürmer, Til, Boerwinkle, Eric, Ngwa, Julius S, O'Donnell, Christopher J, Vasan, Ramachandran S, Wei, Wei-Qi, Wilke, Russell A, Liu, Ching-Ti, Sun, Fangui, Guo, Xiuqing, Heckbert, Susan R, Post, Wendy, Sotoodehnia, Nona, Arnold, Alice M, Stafford, Jeanette M, Ding, Jingzhong, Herrington, David M, Kritchevsky, Stephen B, Eiriksdottir, Gudny, Launer, Leonore J, Harris, Tamara B, Chu, Audrey Y, Giulianini, Franco, MacFadyen, Jean G, Barratt, Bryan J, Nyberg, Fredrik, Stricker, Bruno H, Uitterlinden, André G, Hofman, Albert, Rivadeneira, Fernando, Emilsson, Valur, Franco, Oscar H, Ridker, Paul M, Gudnason, Vilmundur, Liu, Yongmei, Denny, Joshua C, Ballantyne, Christie M, Rotter, Jerome I, Adrienne Cupples, L, Psaty, Bruce M, Palmer, Colin NA, Tardif, Jean-Claude, and Colhoun, Helen M

Subjects
Welcome Trust Case Control Consortium, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, Polymorphism, Single Nucleotide, Cholesterol, LDL, Genome-Wide Association Study, Cholesterol, LDL, Polymorphism, Single Nucleotide
Abstract

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

Published
2014

21. Glycaemic control trends in people with type 1 diabetes in Scotland 2004–2016

Author

Mair, Colette, Wulaningsih, Wahyu, Jeyam, Anita, McGurnaghan, Stuart, Blackbourn, Luke, Kennon, Brian, Leese, Graham, Lindsay, Robert, McCrimmon, Rory J., McKnight, John, Petrie, John R., Sattar, Naveed, Wild, Sarah H., Conway, Nicholas, Craigie, Ian, Robertson, Kenneth, Bath, Louise, McKeigue, Paul M., Colhoun, Helen M., and on behalf of the Scottish Diabetes Research Network (SDRN) Epidemiology Group

Published
2019
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22. The effect of dapagliflozin on glycaemic control and other cardiovascular disease risk factors in type 2 diabetes mellitus: a real-world observational study

Author

McGurnaghan, Stuart J., Brierley, Liam, Caparrotta, Thomas M., McKeigue, Paul M., Blackbourn, Luke A. K., Wild, Sarah H., Leese, Graham P., McCrimmon, Rory J., McKnight, John A., Pearson, Ewan R., Petrie, John R., Sattar, Naveed, Colhoun, Helen M., and on behalf of the Scottish Diabetes Research Network Epidemiology Group

Published
2019
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23. Serum kidney injury molecule 1 and β2-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes

Author

Colombo, Marco, Looker, Helen C., Farran, Bassam, Hess, Sibylle, Groop, Leif, Palmer, Colin N. A., Brosnan, Mary Julia, Dalton, R. Neil, Wong, Max, Turner, Charles, Ahlqvist, Emma, Dunger, David, Agakov, Felix, Durrington, Paul, Livingstone, Shona, Betteridge, John, McKeigue, Paul M., Colhoun, Helen M., and on behalf of the SUMMIT Investigators

Published
2019
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24. SLC24A5, a Putative Cation Exchanger, Affects Pigmentation in Zebrafish and Humans

Author

Lamason, Rebecca L., Mest, Jason R., Wong, Andrew C., Norton, Heather L., Aros, Michele C., Jurynec, Michael J., Mao, Xianyun, Humphreville, Vanessa R., Humbert, Jasper E., Sinha, Soniya, Moore, Jessica L., Jagadeeswaran, Pudur, Zhao, Wei, Ning, Gang, Makalowska, Izabela, McKeigue, Paul M., O'Donnell, David, Kittles, Rick, Parra, Esteban J., Mangini, Nancy J., Grunwald, David J., Shriver, Mark D., Canfield, Victor A., and Cheng, Keith C.

Published
2005

27. Incidence of Type 1 Diabetes in Children Has Fallen to Pre–COVID-19 Pandemic Levels: A Population-Wide Analysis From Scotland.

Author

Berthon, William, McGurnaghan, Stuart J., Blackbourn, Luke A.K., Bath, Louise E., McAllister, David A., Stockton, Diane, Wild, Sarah H., McKeigue, Paul M., and Colhoun, Helen M.

Subjects
TYPE 1 diabetes, DIABETES in children, PEOPLE with diabetes, PANDEMICS, COVID-19 pandemic
Abstract

The article informs about the decline in the incidence of type 1 diabetes among children in Scotland to pre-COVID-19 pandemic levels, contrasting with the previously observed rise. Topic include Analyzing data from 2015 to 2022, the study found a regression in incidence, particularly among children aged 6–14 years, indicating a reversal of the earlier upward trend.

Published
2024
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28. Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes

Author

McKeigue, Paul M., Spiliopoulou, Athina, McGurnaghan, Stuart, Colombo, Marco, Blackbourn, Luke, McDonald, Timothy J., Onengut-Gomuscu, Suna, Rich, Stephen S., A. Palmer, Colin N., McKnight, John A., J. Strachan, Mark W., Patrick, Alan W., Chalmers, John, Lindsay, Robert S., Petrie, John R., Thekkepat, Sandeep, Collier, Andrew, MacRury, Sandra, and Colhoun, Helen M.

Published
2019
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29. Rapid Epidemiological Analysis of Comorbidities and Treatments as risk factors for COVID-19 in Scotland (REACT-SCOT): A population-based case-control study

Author

McKeigue, Paul M., Weir, Amanda, Bishop, Jen, McGurnaghan, Stuart J., Kennedy, Sharon, McAllister, David, Robertson, Chris, Wood, Rachael, Lone, Nazir, Murray, Janet, Caparrotta, Thomas M., Smith-Palmer, Alison, Goldberg, David, McMenamin, Jim, Ramsay, Colin, Hutchinson, Sharon, Colhoun, Helen M., Stone, Clare, and Veitch, Emma

Subjects
Risk factors (Health) -- Identification and classification, Comorbidity -- Complications and side effects -- Identification and classification, Biological sciences
Abstract

Background The objectives of this study were to identify risk factors for severe coronavirus disease 2019 (COVID-19) and to lay the basis for risk stratification based on demographic data and health records. Methods and findings The design was a matched case-control study. Severe COVID-19 was defined as either a positive nucleic acid test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the national database followed by entry to a critical care unit or death within 28 days or a death certificate with COVID-19 as underlying cause. Up to 10 controls per case matched for sex, age, and primary care practice were selected from the national population register. For this analysis-based on ascertainment of positive test results up to 6 June 2020, entry to critical care up to 14 June 2020, and deaths registered up to 14 June 2020-there were 36,948 controls and 4,272 cases, of which 1,894 (44%) were care home residents. All diagnostic codes from the past 5 years of hospitalisation records and all drug codes from prescriptions dispensed during the past 240 days were extracted. Rate ratios for severe COVID-19 were estimated by conditional logistic regression. In a logistic regression using the age-sex distribution of the national population, the odds ratios for severe disease were 2.87 for a 10-year increase in age and 1.63 for male sex. In the case-control analysis, the strongest risk factor was residence in a care home, with rate ratio 21.4 (95% CI 19.1-23.9, p = 8 x 10.sup.-644). Univariate rate ratios for conditions listed by public health agencies as conferring high risk were 2.75 (95% CI 1.96-3.88, p = 6 x 10.sup.-9) for type 1 diabetes, 1.60 (95% CI 1.48-1.74, p = 8 x 10.sup.-30) for type 2 diabetes, 1.49 (95% CI 1.37-1.61, p = 3 x 10.sup.-21) for ischemic heart disease, 2.23 (95% CI 2.08-2.39, p = 4 x 10.sup.-109) for other heart disease, 1.96 (95% CI 1.83-2.10, p = 2 x 10.sup.-78) for chronic lower respiratory tract disease, 4.06 (95% CI 3.15-5.23, p = 3 x 10.sup.-27) for chronic kidney disease, 5.4 (95% CI 4.9-5.8, p = 1 x 10.sup.-354) for neurological disease, 3.61 (95% CI 2.60-5.00, p = 2 x 10.sup.-14) for chronic liver disease, and 2.66 (95% CI 1.86-3.79, p = 7 x 10.sup.-8) for immune deficiency or suppression. Seventy-eight percent of cases and 52% of controls had at least one listed condition (51% of cases and 11% of controls under age 40). Severe disease was associated with encashment of at least one prescription in the past 9 months and with at least one hospital admission in the past 5 years (rate ratios 3.10 [95% CI 2.59-3.71] and 2.75 [95% CI 2.53-2.99], respectively) even after adjusting for the listed conditions. In those without listed conditions, significant associations with severe disease were seen across many hospital diagnoses and drug categories. Age and sex provided 2.58 bits of information for discrimination. A model based on demographic variables, listed conditions, hospital diagnoses, and prescriptions provided an additional 1.07 bits (C-statistic 0.804). A limitation of this study is that records from primary care were not available. Conclusions We have shown that, along with older age and male sex, severe COVID-19 is strongly associated with past medical history across all age groups. Many comorbidities beyond the risk conditions designated by public health agencies contribute to this. A risk classifier that uses all the information available in health records, rather than only a limited set of conditions, will more accurately discriminate between low-risk and high-risk individuals who may require shielding until the epidemic is over., Author(s): Paul M. McKeigue 1,2,*, Amanda Weir 2, Jen Bishop 2, Stuart J. McGurnaghan 3, Sharon Kennedy 4, David McAllister 2,5, Chris Robertson 6, Rachael Wood 4, Nazir Lone 1, [...]

Published
2020
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30. Cohort profile: the Scottish Diabetes Research Network national diabetes cohort – a population-based cohort of people with diabetes in Scotland

Author

McGurnaghan, Stuart J., primary, Blackbourn, Luke A. K., additional, Caparrotta, Thomas M., additional, Mellor, Joseph, additional, Barnett, Anna, additional, Collier, Andy, additional, Sattar, Naveed, additional, McKnight, John, additional, Petrie, John, additional, Philip, Sam, additional, Lindsay, Robert, additional, Hughes, Katherine, additional, McAllister, David, additional, Leese, Graham P, additional, Pearson, Ewan R, additional, Wild, Sarah, additional, McKeigue, Paul M, additional, and Colhoun, Helen M, additional

Published
2022
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31. Association of Genetic Loci for Human Plasma Proteins with Response to Treatment in People with Rheumatoid Arthritis

Author

Iakovliev, Andrii, Ling, Stephanie, Colombo, Marco, Plant, Darren, Lewis, Myles J., Pitzalis, Costantino, Barton, Anne, McKeigue, Paul M, and Spiliopoulou, Athina

Abstract

We used locus-specific genotypic scores for human plasma proteins (pQTLs), gene expression (eQTLs), and gene methylation (mQTLs) to detect effects of these intermediate variables on response to Tumor Necrosis Factor inhibitors (TNFi) in over 3,000 people with Rheumatoid Arthritis (RA). Change in erythrocyte sedimentation rate (ΔESR) and in Swollen 28-Joint Count (ΔSJC) were used to quantify TNFi response. Associations were adjusted for false discovery rate. Significant loci were further explored by Mendelian randomisation (MR) and colocalization analyses. One cis pQTL score on chromosome 10 for the ENTPD1 protein and five trans pQTL scores on chromosome 3 for the ARHGAP30, APOM, EHMT2, BGN, and FURIN proteins were associated with TNFi response. Validation using SWATH-MS protein expression data in 180 people confirmed that APOM expression was significantly associated with TNFi response. Signals on chromosome 3 occurred within butyrylcholinesterase (BCHE) locus. The eQTL and mQTL cis scores for the BCHE gene were associated with TNFi response (P < 0.05) and the genetic signals colocalized with the trans pQTLs suggesting common causal variants. MR analysis using two independent instruments for the butyrylcholinesterase enzyme indicated a positive causal effect on TNFi response (β = 0.13, P = 0.033). We have detected a strong genetic signal for TNFi response at the BCHE locus and provided evidence of a weak causal effect of the butyrylcholinesterase enzyme. BCHE has not been previously associated with TNFi response. The apparent pleiotropy in this locus, indicated by five trans pQTLs makes it difficult to identify the most likely causal pathway.

Published
2022

32. Use of personalised risk-based screening schedules to optimise workload and sojourn time in screening programmes for diabetic retinopathy: A retrospective cohort study

Author

Ochs, Andreas, McGurnaghan, Stuart, Black, Mike W., Leese, Graham P., Philip, Sam, Sattar, Naveed, Styles, Caroline, Wild, Sarah H., McKeigue, Paul M., and Colhoun, Helen M.

Subjects
Health screening -- Usage, Diabetic retinopathy -- Usage, Type 2 diabetes -- Usage, Type 1 diabetes -- Usage, Retirement benefits, Biological sciences
Abstract

Background National guidelines in most countries set screening intervals for diabetic retinopathy (DR) that are insufficiently informed by contemporary incidence rates. This has unspecified implications for interval disease risks (IDs) of referable DR, disparities in ID between groups or individuals, time spent in referable state before screening (sojourn time), and workload. We explored the effect of various screening schedules on these outcomes and developed an open-access interactive policy tool informed by contemporary DR incidence rates. Methods and findings Scottish Diabetic Retinopathy Screening Programme data from 1 January 2007 to 31 December 2016 were linked to diabetes registry data. This yielded 128,606 screening examinations in people with type 1 diabetes (T1D) and 1,384,360 examinations in people with type 2 diabetes (T2D). Among those with T1D, 47% of those without and 44% of those with referable DR were female, mean diabetes duration was 21 and 23 years, respectively, and mean age was 26 and 24 years, respectively. Among those with T2D, 44% of those without and 42% of those with referable DR were female, mean diabetes duration was 9 and 14 years, respectively, and mean age was 58 and 52 years, respectively. Individual probability of developing referable DR was estimated using a generalised linear model and was used to calculate the intervals needed to achieve various IDs across prior grade strata, or at the individual level, and the resultant workload and sojourn time. The current policy in Scotland-screening people with no or mild disease annually and moderate disease every 6 months-yielded large differences in ID by prior grade (13.2%, 3.6%, and 0.6% annually for moderate, mild, and no prior DR strata, respectively, in T1D) and diabetes type (2.4% in T1D and 0.6% in T2D overall). Maintaining these overall risks but equalising risk across prior grade strata would require extremely short intervals in those with moderate DR (1-2 months) and very long intervals in those with no prior DR (35-47 months), with little change in workload or average sojourn time. Changing to intervals of 12, 9, and 3 months in T1D and to 24, 9, and 3 months in T2D for no, mild, and moderate DR strata, respectively, would substantially reduce disparity in ID across strata and between diabetes types whilst reducing workload by 26% and increasing sojourn time by 2.3 months. Including clinical risk factor data gave a small but significant increment in prediction of referable DR beyond grade (increase in C-statistic of 0.013 in T1D and 0.016 in T2D, both p < 0.001). However, using this model to derive personalised intervals did not have substantial workload or sojourn time benefits over stratum-specific intervals. The main limitation is that the results are pertinent only to countries that share broadly similar rates of retinal disease and risk factor distributions to Scotland. Conclusions Changing current policies could reduce disparities in ID and achieve substantial reductions in workload within the range of IDs likely to be deemed acceptable. Our tool should facilitate more rational policy setting for screening., Author(s): Andreas Ochs 1, Stuart McGurnaghan 1, Mike W. Black 2, Graham P. Leese 3, Sam Philip 4, Naveed Sattar 5, Caroline Styles 6, Sarah H. Wild 7, Paul M. [...]

Published
2019
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33. Large socioeconomic gap in period life expectancy and life years spent with complications of diabetes in the Scottish population with type 1 diabetes, 2013-2018

Author

Höhn, Andreas, McGurnaghan, Stuart J., Caparrotta, Thomas M., Jeyam, Anita, O'Reilly, Joseph E., Blackbourn, Luke A. K., Hatam, Sara, Dudel, Christian, Seaman, Rosie J., Mellor, Joseph, Sattar, Naveed, McCrimmon, Rory J., Kennon, Brian, Petrie, John R., Wild, Sarah, McKeigue, Paul M., Colhoun, Helen M., on behalf of the SDRN-Epi Group, and University of St Andrews. School of Geography & Sustainable Development

Subjects
Male, Scotland/epidemiology, Multidisciplinary, GF Human ecology. Anthropogeography, 3rd-DAS, Diabetes Complications/complications, Middle Aged, GF, Diabetes Complications, Diabetes Mellitus, Type 1, Life Expectancy, Scotland, SDG 3 - Good Health and Well-being, Socioeconomic Factors, RA0421, RA0421 Public health. Hygiene. Preventive Medicine, Diabetes Mellitus, Type 1/complications, Humans, Female, Aged, Retrospective Studies
Abstract

Background We report the first study to estimate the socioeconomic gap in period life expectancy (LE) and life years spent with and without complications in a national cohort of individuals with type 1 diabetes. Methods This retrospective cohort study used linked healthcare records from SCI-Diabetes, the population-based diabetes register of Scotland. We studied all individuals aged 50 and older with a diagnosis of type 1 diabetes who were alive and residing in Scotland on 1 January 2013 (N = 8591). We used the Scottish Index of Multiple Deprivation (SIMD) 2016 as an area-based measure of socioeconomic deprivation. For each individual, we constructed a history of transitions by capturing whether individuals developed retinopathy/maculopathy, cardiovascular disease, chronic kidney disease, and diabetic foot, or died throughout the study period, which lasted until 31 December 2018. Using parametric multistate survival models, we estimated total and state-specific LE at an attained age of 50. Results At age 50, remaining LE was 22.2 years (95% confidence interval (95% CI): 21.6 − 22.8) for males and 25.1 years (95% CI: 24.4 − 25.9) for females. Remaining LE at age 50 was around 8 years lower among the most deprived SIMD quintile when compared with the least deprived SIMD quintile: 18.7 years (95% CI: 17.5 − 19.9) vs. 26.3 years (95% CI: 24.5 − 28.1) among males, and 21.2 years (95% CI: 19.7 − 22.7) vs. 29.3 years (95% CI: 27.5 − 31.1) among females. The gap in life years spent without complications was around 5 years between the most and the least deprived SIMD quintile: 4.9 years (95% CI: 3.6 − 6.1) vs. 9.3 years (95% CI: 7.5 − 11.1) among males, and 5.3 years (95% CI: 3.7 − 6.9) vs. 10.3 years (95% CI: 8.3 − 12.3) among females. SIMD differences in transition rates decreased marginally when controlling for time-updated information on risk factors such as HbA1c, blood pressure, BMI, or smoking. Conclusions In addition to societal interventions, tailored support to reduce the impact of diabetes is needed for individuals from low socioeconomic backgrounds, including access to innovations in management of diabetes and the prevention of complications.

Published
2022

37. The Genetic Landscape of Renal Complications in Type 1 Diabetes

Author

Sandholm, Niina, Van Zuydam, Natalie, Ahlqvist, Emma, Juliusdottir, Thorhildur, Deshmukh, Harshal A., Rayner, N. William, Di Camillo, Barbara, Forsblom, Carol, Fadista, Joao, Ziemek, Daniel, Salem, Rany M., Hiraki, Linda T., Pezzolesi, Marcus, Trégouët, David, Dahlström, Emma, Valo, Erkka, Oskolkov, Nikolay, Ladenvall, Claes, Marcovecchio, M. Loredana, Cooper, Jason, Sambo, Francesco, Malovini, Alberto, Manfrini, Marco, McKnight, Amy Jayne, Lajer, Maria, Harjutsalo, Valma, Gordin, Daniel, Parkkonen, Maija, Lyssenko, Valeriya, McKeigue, Paul M., Rich, Stephen S., Brosnan, Mary Julia, Fauman, Eric, Bellazzi, Riccardo, Rossing, Peter, Hadjadj, Samy, Krolewski, Andrzej, Paterson, Andrew D., Hirschhorn, Joel N., Maxwell, Alexander P., Cobelli, Claudio, Colhoun, Helen M., Groop, Leif, McCarthy, Mark I., Groop, Per-Henrik, Sandholm, N., Van Zuydam, N., Ahlqvist, E., Juliusdottir, T., Deshmukh, H.A., Di Camillo, B., Forsblom, C., Fadista, J., Ziemek, D., Salem, R.M., Hiraki, L.T., Pezzolesi, M., Trégouët, D., Dahlström, E., Valo, E., Oskolkov, N., Ladenvall, C., Marcovecchio, M.L., Cooper, J., Sambo, F., Malovini, A., Manfrini, M., McKnight, A. J., Lajer, M., V, Gordin, D., Parkkonen, M., Tuomilehto, J., V, McKeigue, P.M., Rich, S.S., Brosnan, M.J., Fauman, E., Bellazzi, R., Rossing, P., Hadjadj, S., Krolewski, A., Paterson, A.D., Florez, J.C., Hirschhorn, J.N., Maxwell, A.P., Dunger, D., Cobelli, C., Colhoun, H.M., Groop, L., McCarthy, M.I., and Groop, P.-H.

Published
2017
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40. Protein biomarkers for the prediction of cardiovascular disease in type 2 diabetes

Author

Looker, Helen C., Colombo, Marco, Agakov, Felix, Zeller, Tanja, Groop, Leif, Thorand, Barbara, Palmer, Colin N., Hamsten, Anders, de Faire, Ulf, Nogoceke, Everson, Livingstone, Shona J., Salomaa, Veikko, Leander, Karin, Barbarini, Nicola, Bellazzi, Riccardo, van Zuydam, Natalie, McKeigue, Paul M., Colhoun, Helen M., and on behalf of the SUMMIT Investigators

Published
2015
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42. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis

Author

Levin, Daniel, Bell, Samira, Sund, Reijo, Hartikainen, Sirpa A., Tuomilehto, Jaakko, Pukkala, Eero, Keskimäki, Ilmo, Badrick, Ellena, Renehan, Andrew G., Buchan, Iain E., Bowker, Samantha L., Minhas-Sandhu, Jasjeet K., Zafari, Zafar, Marra, Carlo, Johnson, Jeffrey A., Stricker, Bruno H., Uitterlinden, Andrè G., Hofman, Albert, Ruiter, Rikje, de Keyser, Catherine E., MacDonald, Thomas M., Wild, Sarah H., McKeigue, Paul M., Colhoun, Helen M., and on behalf of the Scottish Diabetes Research Network Epidemiology Group and the Diabetes and Cancer Research Consortium

Published
2015
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44. Effect of Vaccination on Transmission of SARS-CoV-2

Author

Shah, Anoop S.V., primary, Gribben, Ciara, additional, Bishop, Jennifer, additional, Hanlon, Peter, additional, Caldwell, David, additional, Wood, Rachael, additional, Reid, Martin, additional, McMenamin, Jim, additional, Goldberg, David, additional, Stockton, Diane, additional, Hutchinson, Sharon, additional, Robertson, Chris, additional, McKeigue, Paul M., additional, Colhoun, Helen M., additional, and McAllister, David A., additional

Published
2021
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46. Marked improvements in glycaemic outcomes following insulin pump therapy initiation in people with Type 1 Diabetes - a nationwide observational study in Scotland:CSII and glycaemic outcomes in Scotland

Author

Jeyam, Anita, Gibb, Fraser W, McKnight, J., Kennon, Brian, O'Reilly, Joseph, Caparrotta, Tom, Höhn, Andreas, McGurnaghan, Stuart, Blackbourn, Luke, Hatam, Sara, McCrimmon, Rory J., Leese, Graeme, Lindsay, Robert S., Petrie, John R, Chalmers, John, Philip, Sam, Wild, Sarah H, Sattar, Naveed A., McKeigue, Paul M, Colhoun, Helen M, and on behalf of the Scottish Diabetes Research Network Epidemiology, Group

Published
2021

47. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Author

Rivellese, Felice, Surace, Anna E A, Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R, Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E, Hudson, Briana M, Warren, Sarah E, McKeigue, Paul M, Humby, Frances, Bombardieri, Michele, Barnes, Michael R, Lewis, Myles J, Pitzalis, Costantino, R4RA collaborative group, Taylor, PC, group, R4RA collaborative, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie

Subjects
Arthritis, Rheumatoid, Antirheumatic Agents, Biopsy, Antibodies, Monoclonal, Humans, General Medicine, Antibodies, Monoclonal, Humanized, Rituximab, General Biochemistry, Genetics and Molecular Biology, Biomarkers
Abstract

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

Published
2021

48. Risk of hospital admission with covid-19 among teachers compared with healthcare workers and other adults of working age in Scotland, March 2020 to July 2021: population based case-control study

Author

Fenton, Lynda, primary, Gribben, Ciara, additional, Caldwell, David, additional, Colville, Sam, additional, Bishop, Jen, additional, Reid, Martin, additional, White, Jane, additional, Campbell, Marion, additional, Hutchinson, Sharon, additional, Robertson, Chris, additional, Colhoun, Helen M, additional, Wood, Rachael, additional, McKeigue, Paul M, additional, and McAllister, David A, additional

Published
2021
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