30 results on '"Kiddle, Steven J."'
Search Results
2. Modelling local and general quantum mechanical properties with attention-based pooling
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Buterez, David, Janet, Jon Paul, Kiddle, Steven J., Oglic, Dino, and Liò, Pietro
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- 2023
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3. Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers
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Bakardjian, Hovagim, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Boukerrou, Nadia, Cavedo, Enrica, Chiesa, Patrizia, Colliot, Olivier, Dubois, Bruno, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Hampel, Harald, Houot, Marion, Kas, Aurélie, Lamari, Foudil, Levy, Marcel, Lista, Simone, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Andrade, Katia Santos, Sole, Marine, Surtee, Mohmed, de Schotten, Michel Thiebaut, Vergallo, Andrea, Younsi, Nadjia, Afshar, Mohammad, Aguilar, Lisi Flores, Akman-Anderson, Leyla, Arenas, Joaquín, Ávila, Jesús, Babiloni, Claudio, Baldacci, Filippo, Batrla, Richard, Benda, Norbert, Black, Keith L., Bokde, Arun L.W., Bonuccelli, Ubaldo, Broich, Karl, Cacciola, Francesco, Caraci, Filippo, Caruso, Giuseppe, Castrillo†, Juan, Ceravolo, Roberto, Chiesa, Patrizia A., Corbo, Massimo, Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L., Depypere, Herman, Duggento, Andrea, Emanuele, Enzo, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A., Garaci, Francesco, Geerts, Hugo, Giacobini, Ezio, Giorgi, Filippo S., Goetzl, Edward J., Graziani, Manuela, Haberkamp, Marion, Hänisch, Britta, Herholz, Karl, Hernandez, Felix, Imbimbo, Bruno P., Kapogiannis, Dimitrios, Karran, Eric, Kiddle, Steven J., Kim, Seung H., Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehéricy, Stéphane, Lemercier, Pablo, Llavero, Francisco, Lorenceau, Jean, Lucía, Alejandro, Mango, Dalila, Mapstone, Mark, Neri, Christian, Nisticò, Robert, O’bryant, Sid E., Palermo, Giovanni, Perry, George, Ritchie, Craig, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S., Sporns, Olaf, Toschi, Nicola, Valenzuela, Pedro L., Vellas, Bruno, Verdooner, Steven R., Villain, Nicolas, Giudici, Kelly Virecoulon, Watling, Mark, Welikovitch, Lindsay A., Woodcock, Janet, Younesi, Erfan, Zugaza, José L., Zetterberg, Henrik, and Blennow, Kaj
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- 2020
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4. Urate‐lowering therapy in patients with hyperuricemia and heart failure: A retrospective cohort study using the UK Clinical Practice Research Datalink.
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Kiddle, Steven J., Sundell, Karolina Andersson, Perl, Shira, Nolan, Stephen, and Bjursell, Magnus
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HEART failure patients ,MEDICAL research ,PROPORTIONAL hazards models ,COHORT analysis ,HOSPITAL statistics - Abstract
Background: Elevated serum uric acid (sUA) is associated with heart failure (HF). Hypothesis: Urate‐lowering therapy (ULT) in HF is associated with lower risk of HF hospitalization (hHF) and mortality. Methods: Data on patients with HF and gout or hyperuricemia in the Clinical Practice Research Datalink database linked to the Hospital Episode Statistics and the Office for National Statistics in the United Kingdom were analyzed. Risks of hHF and all‐cause mortality or cardiovascular‐related mortality by ULT exposure (ULT initiated within ≤6 months of gout or hyperuricemia diagnosis) were analyzed in a propensity score‐matched cohort using adjusted Cox proportional hazards regression models. Results: Of 2174 propensity score‐matched pairs, patients were predominantly male, aged >70 years, with mean ± standard deviation sUA 9.3 ± 1.8 (ULT‐exposed) and 9.4 ± 1.9 mg/dL (ULT‐unexposed). At 5 years, ULT‐exposed patients had a 43% lower risk of hHF or all‐cause mortality (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.51–0.65) and a 19% lower risk of hHF or cardiovascular‐related mortality (adjusted HR: 0.81; 95% CI: 0.71–0.92) versus no ULT exposure. Conclusion: ULT was associated with reduced risk of adverse clinical outcomes in patients with HF and gout or hyperuricemia over 5 years. Practitioner points: Raised serum uric acid is strongly associated with heart failure (HF); however, it is unknown whether urate‐lowering therapy (ULT) could help patients with HF.We assessed the relationship between ULT and HF outcomes using UK patient data, and found that the risk of the composite of hospital admission for HF or death was lower with ULT than with no ULT.These results support further investigation into the potential benefit of ULT in HF. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD
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Bakardjian, H., Benali, H., Bertin, H., Bonheur, J., Boukadida, L., Boukerrou, N., Cavedo, E., Chiesa, P., Colliot, O., Dubois, B., Dubois, M., Epelbaum, S., Gagliardi, G., Genthon, R., Habert, M.O., Hampel, H., Houot, M., Kas, A., Lamari, F., Levy, M., Lista, S., Metzinger, C., Mochel, F., Nyasse, F., Poisson, C., Potier, M.C., Revillon, M., Santos, A., Andrade, K.S., Sole, M., Surtee, M., Thiebaud de Schotten, M., Vergallo, A., Younsi, N., Afshar, Mohammad, Flores Aguilar, Lisi, Akman-Anderson, Leyla, Arenas, Joaquín, Avila, Jesus, Babiloni, Claudio, Baldacci, Filippo, Batrla, Richard, Benda, Norbert, Black, Keith L., Bokde, Arun L.W., Bonuccelli, Ubaldo, Broich, Karl, Cacciola, Francesco, Caraci, Filippo, Castrillo, Juan, Cavedo, Enrica, Ceravolo, Roberto, Chiesa, Patrizia A., Corvol, Jean-Christophe, Claudio Cuello, Augusto, Cummings, Jeffrey L., Depypere, Herman, Dubois, Bruno, Duggento, Andrea, Emanuele, Enzo, Escott-Price, Valentina, Federoff, Howard, Teresa Ferretti, Maria, Fiandaca, Massimo, Frank, Richard A., Garaci, Francesco, Geerts, Hugo, Giorgi, Filippo S., Goetzl, Edward J., Graziani, Manuela, Haberkamp, Marion, Marie-Odile, Habert, Hampel, Harald, Herholz, Karl, Hernandez, Felix, Kapogiannis, Dimitrios, Karran, Eric, Kiddle, Steven J., Kim, Seung H., Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehéricy, Stéphane, Lucía, Alejandro, Lista, Simone, Lorenceau, Jean, Mango, Dalila, Mapstone, Mark, Neri, Christian, Nisticò, Robert, O'Bryant, Sid E., Palermo, Giovanni, Perry, George, Ritchie, Craig, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S., Sporns, Olaf, Toschi, Nicola, Verdooner, Steven R., Vergallo, Andrea, Villain, Nicolas, Welikovitch, Lindsay A., Woodcock, Janet, Younesi, Erfan, Houot, Marion, Lemercier, Pablo, Vanmechelen, Eugeen, De Vos, Ann, Habert, Marie-Odile, and Potier, Marie-Claude
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- 2019
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6. Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease
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Bakardjian, Hovagim, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Boukerrou, Nadia, Cavedo, Enrica, Chiesa, Patrizia, Colliot, Olivier, Dubois, Bruno, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Hampel, Harald, Houot, Marion, Kas, Aurélie, Lamari, Foudil, Levy, Marcel, Lista, Simone, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Andrade, Katia Santos, Sole, Marine, Surtee, Mohmed, de Schotten, Michel Thiebaud, Vergallo, Andrea, Younsi, Nadjia, Afshar, Mohammad, Aguilar, Lisi Flores, Akman-Anderson, Leyla, Arenas, Joaquín, Avila, Jesus, Babiloni, Claudio, Baldacci, Filippo, Batrla, Richard, Benda, Norbert, Black, Keith L., Bokde, Arun L.W., Bonuccelli, Ubaldo, Broich, Karl, Cacciola, Francesco, Caraci, Filippo, Castrillo, Juan, Ceravolo, Roberto, Chiesa, Patrizia A., Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L., Depypere, Herman, Duggento, Andrea, Emanuele, Enzo, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A., Garaci, Francesco, Geerts, Hugo, Giorgi, Filippo S., Goetzl, Edward J., Graziani, Manuela, Haberkamp, Marion, Herholz, Karl, Hernandez, Felix, Kapogiannis, Dimitrios, Karran, Eric, Kiddle, Steven J., Kim, Seung H., Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehéricy, Stéphane, Lucía, Alejandro, Lorenceau, Jean, Mango, Dalila, Mapstone, Mark, Neri, Christian, Nisticó, Robert, O’Bryant, Sid E., Palermo, Giovanni, Perry, George, Ritchie, Craig, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S., Sporns, Olaf, Toschi, Nicola, Verdooner, Steven R., Villain, Nicolas, Welikovitch, Lindsay A., Woodcock, Janet, Younesi, Erfan, and Thiebaut de Schotten, Michel
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- 2019
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7. Effect of COVID-19 on Bronchiectasis Exacerbation Rates: A Retrospective U.S. Insurance Claims Study.
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Åstrand, Annika, Kiddle, Steven J., Ganesh Mudedla, Rohith Siva, Porwal, Sanchita, Chafekar, Kaushik, Agrawal, Shubh, Seminario, Carlos, Chalmers, James D., and Psallidas, Ioannis
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SARS-CoV-2 ,COVID-19 pandemic ,INSURANCE claims ,BRONCHIECTASIS ,CHRONIC obstructive pulmonary disease - Abstract
Rationale: Bronchiectasis is a chronic, progressive disease of bronchial dilation, inflammation, and scarring leading to impaired mucociliary clearance and increased susceptibility to infection. Identified causes include previous severe respiratory infections. A small, single-center UK study demonstrated a reduction in bronchiectasis exacerbations during the first year of the coronavirus disease (COVID-19) pandemic. No studies have been conducted in a U.S. (commercially insured) cohort to date. Objectives: To explore the impact of the COVID-19 pandemic on the frequency of exacerbations in a large cohort of commercially insured U.S. patients with bronchiectasis by testing the hypothesis that U.S. patients with bronchiectasis had fewer exacerbations during the pandemic. Methods: This retrospective observational cohort study used health insurance claims data from Optum's de-identified Clinformatics Data Mart database, which included U.S. patients and their covered dependents. Eligible patients were >18 years of age with bronchiectasis; patients with other respiratory conditions were excluded. The main study cohort excluded patients with frequent asthma and/or chronic obstructive pulmonary disease diagnoses. The primary objective was to compare the bronchiectasis exacerbation rates before and during the COVID-19 pandemic. Results: The median number of exacerbations per patient per year decreased significantly from the year before the COVID-19 pandemic to the first year of the pandemic (1 vs. 0; P,0.01). More patients had zero exacerbations during the first year of the pandemic than the year prior (57% vs. 24%; McNemar's chi-square = 122.56; P,0.01). Conclusions: In a U.S. population-based study of patients with International Classification of Diseases codes for bronchiectasis, the rate of exacerbations during Year 1 of the COVID-19 pandemic was reduced compared with the 2-year time period preceding the pandemic. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
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Jansen, Iris E., Savage, Jeanne E., Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M., Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K., Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S., Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S., Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J., Jonsson, Palmi V., Kiddle, Steven J., Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B., Selbæk, Geir, Shoai, Maryam, Skene, Nathan G., Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D., Wang, Yunpeng, White, Linda R., Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F., van der Flier, Wiesje M., Dobson, Richard, Davis, Lea K., Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L., Ripke, Stephan, Andreassen, Ole A., and Posthuma, Danielle
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- 2019
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9. Blood protein predictors of brain amyloid for enrichment in clinical trials?
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Ashton, Nicholas J., Kiddle, Steven J., Graf, John, Ward, Malcolm, Baird, Alison L., Hye, Abdul, Westwood, Sarah, Wong, Karyuan Vivian, Dobson, Richard J., Rabinovici, Gil D., Miller, Bruce L., Rosen, Howard J., Torres, Andrew, Zhang, Zhanpan, Thurfjell, Lennart, Covin, Antonia, Hehir, Cristina Tan, Baker, David, Bazenet, Chantal, and Lovestone, Simon
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- 2015
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10. Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology
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Sattlecker, Martina, Kiddle, Steven J., Newhouse, Stephen, Proitsi, Petroula, Nelson, Sally, Williams, Stephen, Johnston, Caroline, Killick, Richard, Simmons, Andrew, Westman, Eric, Hodges, Angela, Soininen, Hilkka, Kłoszewska, Iwona, Mecocci, Patrizia, Tsolaki, Magda, Vellas, Bruno, Lovestone, Simon, and Dobson, Richard J.B.
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- 2014
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11. MF-PCBA: Multifidelity High-Throughput Screening Benchmarks for Drug Discovery and Machine Learning.
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Buterez, David, Janet, Jon Paul, Kiddle, Steven J., and Liò, Pietro
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- 2023
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12. Arabidopsis Defense against Botrytis cinerea: Chronology and Regulation Deciphered by High-Resolution Temporal Transcriptomic Analysis
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Windram, Oliver, Madhou, Priyadharshini, McHattie, Stuart, Hill, Claire, Hickman, Richard, Cooke, Emma, Jenkins, Dafyd J., Penfold, Christopher A., Baxter, Laura, Breeze, Emily, Kiddle, Steven J., Rhodes, Johanna, Atwell, Susanna, Kliebenstein, Daniel J., Kim, Youn-sung, Stegle, Oliver, Borgwardt, Karsten, Zhang, Cunjin, Tabrett, Alex, Legaie, Roxane, Moore, Jonathan, Finkenstadt, Bärbel, Wild, David L., Mead, Andrew, Rand, David, Beynon, Jim, Ott, Sascha, Buchanan-Wollaston, Vicky, and Denby, Katherine J.
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- 2012
13. Evaluating clinical outcomes and prognosis in patients with cirrhosis and portal hypertension: a retrospective observational cohort study.
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Nerissa Hoi Ching Lee, Kiddle, Steven J., Chandankhede, Shardul, Agrawal, Shubh, Bean, Daniel M., Hunt, Phillip R., Parker, Victoria E. R., Greasley, Peter J., and Ambery, Philip
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- 2023
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14. Inhaled Corticosteroid Withdrawal and Change in Lung Function in Primary Care Patients with Chronic Obstructive Pulmonary Disease in England.
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Whittaker, Hannah R., Wing, Kevin, Douglas, Ian, Kiddle, Steven J., and Quint, Jennifer K.
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COMBINATION drug therapy ,ADRENOCORTICAL hormones ,LUNGS ,PRIMARY health care ,BRONCHODILATOR agents ,OBSTRUCTIVE lung diseases ,INHALATION administration - Abstract
Rationale: In chronic obstructive pulmonary disease (COPD), inhaled corticosteroids (ICS) are associated with pneumonia, highlighting the importance of investigating subgroups of patients who may benefit from prolonged ICS use. Despite this, the WISDOM (Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management) trial found a greater decline in forced expiratory volume in 1 second (FEV1) in patients with COPD who withdrew from ICS compared with patients who remained on triple therapy. Objectives: We investigated the association between ICS withdrawal and the rate of FEV1 decline in patients with COPD using routinely collected electronic healthcare records. Methods: Using CPRD (Clinical Practice Research Datalink) Aurum and Hospital episode statistics, we included patients with COPD who had been on triple therapy for at least 4 months. Patients were categorized into those who withdrew from ICS and those who remained on triple therapy during follow-up. Three cohorts were created: 1) patients meeting the WISDOM trial eligibility criteria; 2) patients with COPD not restricted by the WISDOM trial eligibility criteria; and 3) patients who would have been excluded from the WISDOM trial on the basis of their comorbidities. Mixed linear regression was used to model the association between ICS withdrawal and the rate of FEV1 decline (ml/year) adjusted for baseline characteristics. Results: A total of 6,008 patients with COPD met the WISDOM eligibility criteria, of which 9.0% withdrew from ICS. Mean rates of FEV1 declined -7.8 ml/year (95% confidence interval [CI], -19.7 to 4.1) for withdrawers and -15.2 ml/year (95% CI, -18.7 to -11.8) for those who remained on triple therapy (difference, P = 0.264). A total of 60,645 patients with COPD were not restricted by the WISDOM eligibility criteria. The mean rate of FEV1 decline was -32.6 ml/year (95% CI, -33.6 to -31.5) for withdrawers and -36.4 ml/year (95% CI, -39.4 to -33.4) for those who remained on triple therapy. A total of 32,882 patients with COPD were included in the last population representing those who would have been excluded from the WISDOM trial because of their comorbidities. The mean rate of FEV1 decline was -29.4 ml/year (95% CI, -30 to -28.1) in withdrawers and -31.3 ml/year (95% CI, -35 to -27.5) in those who remained on triple therapy. Conclusions: The rate of FEV1 decline was similar between patients on triple therapy and patients who withdrew from ICS regardless of the specific COPD population studied. In routine clinical practice, few patients with COPD meet WISDOM eligibility criteria, and few patients are withdrawn from ICS. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Wigwams: identifying gene modules co-regulated across multiple biological conditions
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Polanski, Krzysztof, Rhodes, Johanna, Hill, Claire, Zhang, Peijun, Jenkins, Dafyd J., Kiddle, Steven J., Jironkin, Aleksey, Beynon, Jim, Buchanan-Wollaston, Vicky, Ott, Sascha, and Denby, Katherine J.
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- 2014
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16. Temporal clustering by affinity propagation reveals transcriptional modules in Arabidopsis thaliana
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Kiddle, Steven J., Windram, Oliver P., McHattie, Stuart, Mead, Andrew, Beynon, Jim, Buchanan-Wollaston, Vicky, Denby, Katherine J., and Mukherjee, Sach
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- 2010
17. Challenges and Pitfalls of Using Repeat Spirometry Recordings in Routine Primary Care Data to Measure FEV1 Decline in a COPD Population.
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Whittaker, Hannah R, Kiddle, Steven J, and Quint, Jennifer K
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CHRONIC obstructive pulmonary disease , *MEASUREMENT errors , *FORCED expiratory volume , *PRIMARY care , *SPIROMETRY - Abstract
Background: Electronic healthcare records (EHR) are increasingly used in epidemiological studies but are often viewed as lacking quality compared to randomised control trials and prospective cohorts. Studies of patients with chronic obstructive pulmonary disease (COPD) often use the rate of forced expiratory volume in 1 second (FEV1) decline as an outcome; however, its definition and robustness in EHR have not been investigated. We aimed to investigate how the rate of FEV1 decline differs by the criteria used in an EHR database. Methods: Clinical Practice Research Datalink and Hospital Episode Statistics were used. Patient populations were defined using 8 sets of criteria around repeated FEV1 measurements. At a minimum, patients had a diagnosis of COPD, were ≥ 35 years old, were current or ex-smokers, and had data recorded from 2004. FEV1 measurements recorded during follow-up were identified. Thereafter, eight populations were defined based on criteria around: i) the exclusion of patients or individual measurements with potential measurement error; ii) minimum number of FEV1 measurements; iii) minimum time interval between measurements; iv) specific timing of measurements; v) minimum follow-up time; and vi) the use of linked data. For each population, the rate of FEV1 decline was estimated using mixed linear regression. Results: For 7/8 patient populations, rates of FEV1 decline (age and sex adjusted) were similar and ranged from − 18.7mL/year (95% CI − 19.2 to − 18.2) to − 16.5mL/year (95% CI − 17.3 to − 15.7). Rates of FEV1 decline in populations that excluded patients with potential measurement error ranged from − 79.4mL/year (95% CI − 80.7 to − 78.2) to − 46.8mL/year (95% CI − 47.6 to − 46.0). Conclusion: FEV1 decline remained similar in a COPD population regardless of number of FEV1 measurements, time intervals between measurements, follow-up period, exclusion of specific FEV1 measurements, and linkage to HES. However, exclusion of individuals with questionable data led to selection bias and faster rates of decline. [ABSTRACT FROM AUTHOR]
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- 2021
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18. Characteristics Associated with Accelerated Lung Function Decline in a Primary Care Population with Chronic Obstructive Pulmonary Disease.
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Whittaker, Hannah R, Pimenta, Jeanne M, Jarvis, Deborah, Kiddle, Steven J, and Quint, Jennifer K
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- 2020
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19. Prediction of five-year mortality after COPD diagnosis using primary care records.
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Kiddle, Steven J., Whittaker, Hannah R., Seaman, Shaun R., and Quint, Jennifer K.
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OBSTRUCTIVE lung diseases , *FORECASTING , *PRIMARY care , *BODY mass index , *INHALERS - Abstract
Accurate prognosis information after a diagnosis of chronic obstructive pulmonary disease (COPD) would facilitate earlier and better informed decisions about the use of prevention strategies and advanced care plans. We therefore aimed to develop and validate an accurate prognosis model for incident COPD cases using only information present in general practitioner (GP) records at the point of diagnosis. Incident COPD patients between 2004–2012 over the age of 35 were studied using records from 396 general practices in England. We developed a model to predict all-cause five-year mortality at the point of COPD diagnosis, using 47,964 English patients. Our model uses age, gender, smoking status, body mass index, forced expiratory volume in 1-second (FEV1) % predicted and 16 co-morbidities (the same number as the Charlson Co-morbidity Index). The performance of our chosen model was validated in all countries of the UK (N = 48,304). Our model performed well, and performed consistently in validation data. The validation area under the curves in each country varied between 0.783–0.809 and the calibration slopes between 0.911–1.04. Our model performed better in this context than models based on the Charlson Co-morbidity Index or Cambridge Multimorbidity Score. We have developed and validated a model that outperforms general multimorbidity scores at predicting five-year mortality after COPD diagnosis. Our model includes only data routinely collected before COPD diagnosis, allowing it to be readily translated into clinical practice, and has been made available through an online risk calculator (https://skiddle.shinyapps.io/incidentcopdsurvival/). [ABSTRACT FROM AUTHOR]
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- 2020
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20. Inhaled corticosteroids, blood eosinophils, and FEV1 decline in patients with COPD in a large UK primary health care setting.
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Whittaker, Hannah R, Müllerova, Hana, Jarvis, Deborah, Barnes, Neil C, Jones, Paul W, Compton, Chris H, Kiddle, Steven J, and Quint, Jennifer K
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- 2019
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21. Genetic Risk as a Marker of Amyloid-β and Tau Burden in Cerebrospinal Fluid.
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Voyle, Nicola, Patel, Hamel, Folarin, Amos, Newhouse, Stephen, Johnston, Caroline, Dobson, Richard J. B., Kiddle, Steven J., Visser, Pieter Jelle, and EDAR and DESCRIPA study groups and the Alzheimer’s Disease Neuroimaging Initiative
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ALZHEIMER'S disease ,GENETIC disorders ,POSITRON emission tomography ,CEREBROSPINAL fluid ,BRAIN imaging ,DISEASE risk factors ,APOLIPOPROTEINS ,DATABASES ,GENETIC polymorphisms ,LONGITUDINAL method ,NERVE tissue proteins ,PEPTIDES ,RESEARCH funding ,LOGISTIC regression analysis ,EARLY diagnosis ,OLIGONUCLEOTIDE arrays - Abstract
Background: The search for a biomarker of Alzheimer's disease (AD) pathology (amyloid-β (Aβ) and tau) is ongoing, with the best markers currently being measurements of Aβ and tau in cerebrospinal fluid (CSF) and via positron emission tomography (PET) scanning. These methods are relatively invasive, costly, and often have high screening failure rates. Consequently, research is aiming to elucidate blood biomarkers of Aβ and tau.Objective: This study aims to investigate a case/control polygenic risk score (PGRS) as a marker of tau and investigate blood markers of a combined Aβ and tau outcome for the first time. A sub-study also considers plasma tau as markers of Aβ and tau pathology in CSF.Methods: We used data from the EDAR*, DESCRIPA**, and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts in a logistic regression analysis to investigate blood markers of Aβ and tau in CSF. In particular, we investigated the extent to which a case/control PGRS is predictive of CSF tau, CSF amyloid, and a combined amyloid and tau outcome. The predictive ability of models was compared to that of age, gender, and APOE genotype ('basic model').Results: In EDAR and DESCRIPA test data, inclusion of a case/control PGRS was no more predictive of Aβ, and a combined Aβ and tau endpoint than the basic models (accuracies of 66.0%, and 73.3% respectively). The tau model saw a small increase in accuracy compared to basic models (59.6%). ADNI 2 test data also showed a slight increase in accuracy for the Aβ model when compared to the basic models (61.4%).Conclusion: We see some evidence that a case/control PGRS is marginally more predictive of Aβ and tau pathology than the basic models. The search for predictive factors of Aβ and tau pathologies, above and beyond demographic information, is still ongoing. Better understanding of AD risk alleles, development of more sensitive assays, and studies of larger sample size are three avenues that may provide such factors. However, the clinical utility of possible predictors of brain Aβ and tau pathologies must also be investigated.*'Beta amyloid oligomers in the early diagnosis of AD and as marker for treatment response'**'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease'. [ABSTRACT FROM AUTHOR]- Published
- 2017
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22. Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly.
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Westwood, Sarah, Leoni, Emanuela, Hye, Abdul, Lynham, Steven, Khondoker, Mizanur R., Ashton, Nicholas J., Kiddle, Steven J., Baird, Alison L., Sainz-Fuertes, Ricardo, Leung, Rufina, Graf, John, Hehir, Cristina Tan, Baker, David, Cereda, Cristina, Bazenet, Chantal, Ward, Malcolm, Thambisetty, Madhav, and Lovestone, Simon
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ALZHEIMER'S disease diagnosis ,BIOMARKERS ,AMYLOID ,PROTEOMICS ,BLOOD plasma ,PROTEIN analysis ,ALZHEIMER'S disease ,BIOCHEMISTRY ,BLOOD proteins ,BRAIN ,GLOBULINS ,MASS spectrometry ,PHENOMENOLOGY ,RESEARCH funding ,THIAZOLES ,POSITRON emission tomography - Abstract
Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p < 0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q < 0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature. [ABSTRACT FROM AUTHOR]
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- 2016
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23. Alzheimer's disease: are blood and brain markers related? A systematic review.
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Khan, Ali T., Dobson, Richard J. B., Sattlecker, Martina, and Kiddle, Steven J.
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ALZHEIMER'S disease ,BLOOD-brain barrier ,BIOMARKERS ,EARLY diagnosis ,HEAT shock proteins - Abstract
Objective Peripheral protein biomarkers of Alzheimer's disease ( AD) may help identify novel treatment avenues by allowing early diagnosis, recruitment to clinical trials, and treatment initiation. The purpose of this review was to determine which proteins have been found to be differentially expressed in the AD brain and whether these proteins are also found within the blood of AD patients. Methods A two-stage approach was conducted. The first stage involved conducting a systematic search to identify discovery-based brain proteomic studies of AD. The second stage involved comparing whether proteins found to be differentially expressed in AD brain were also differentially expressed in the blood. Results Across 11 discovery based brain proteomic studies 371 proteins were at different levels in the AD brain. Nine proteins were frequently found, defined as appearing in at least three separate studies. Of these proteins heat-shock cognate 71 kDa, ubiquitin carboxyl-terminal hydrolase isozyme L1, and 2′,3′-cyclic nucleotide 3′ phosphodiesterase alone were found to share a consistent direction of change, being consistently upregulated in studies they appeared in. Eighteen proteins seen as being differentially expressed within the AD brain were present in blood proteomic studies of AD. Only complement C4a was seen multiple times within both the blood and brain proteomic studies. Interpretation We report a number of proteins appearing in both the blood and brain of AD patients. Of these proteins, C4a may be a good candidate for further follow-up in large-scale replication efforts. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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24. A Subset of Cerebrospinal Fluid Proteins from a Multi-Analyte Panel Associated with Brain Atrophy, Disease Classification and Prediction in Alzheimer’s Disease.
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Khan, Wasim, Aguilar, Carlos, Kiddle, Steven J., Doyle, Orla, Thambisetty, Madhav, Muehlboeck, Sebastian, Sattlecker, Martina, Newhouse, Stephen, Lovestone, Simon, Dobson, Richard, Giampietro, Vincent, Westman, Eric, Simmons, Andrew, and null, null
- Subjects
CEREBROSPINAL fluid proteins ,CEREBRAL atrophy ,ALZHEIMER'S disease ,BRAIN imaging ,MAGNETIC resonance imaging - Abstract
In this exploratory neuroimaging-proteomic study, we aimed to identify CSF proteins associated with AD and test their prognostic ability for disease classification and MCI to AD conversion prediction. Our study sample consisted of 295 subjects with CSF multi-analyte panel data and MRI at baseline downloaded from ADNI. Firstly, we tested the statistical effects of CSF proteins (n = 83) to measures of brain atrophy, CSF biomarkers, ApoE genotype and cognitive decline. We found that several proteins (primarily CgA and FABP) were related to either brain atrophy or CSF biomarkers. In relation to ApoE genotype, a unique biochemical profile characterised by low CSF levels of Apo E was evident in ε4 carriers compared to ε3 carriers. In an exploratory analysis, 3/83 proteins (SGOT, MCP-1, IL6r) were also found to be mildly associated with cognitive decline in MCI subjects over a 4-year period. Future studies are warranted to establish the validity of these proteins as prognostic factors for cognitive decline. For disease classification, a subset of proteins (n = 24) combined with MRI measurements and CSF biomarkers achieved an accuracy of 95.1% (Sensitivity 87.7%; Specificity 94.3%; AUC 0.95) and accurately detected 94.1% of MCI subjects progressing to AD at 12 months. The subset of proteins included FABP, CgA, MMP-2, and PPP as strong predictors in the model. Our findings suggest that the marker of panel of proteins identified here may be important candidates for improving the earlier detection of AD. Further targeted proteomic and longitudinal studies would be required to validate these findings with more generalisability. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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25. Circulating Proteomic Signatures of Chronological Age.
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Menni, Cristina, Kiddle, Steven J, Mangino, Massimo, Viñuela, Ana, Psatha, Maria, Steves, Claire, Sattlecker, Martina, Buil, Alfonso, Newhouse, Stephen, Nelson, Sally, Williams, Stephen, Voyle, Nicola, Soininen, Hilkka, Kloszewska, Iwona, Mecocci, Patrizia, Tsolaki, Magda, Vellas, Bruno, Lovestone, Simon, Spector, Tim D, and Dobson, Richard
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- *
PROTEOMICS , *AGING , *AGE , *NUCLEOTIDE sequence , *CARDIOVASCULAR diseases risk factors , *OSTEOPOROSIS , *DISEASE risk factors - Abstract
To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis β [SE] = 0.013 [0.001], p = 3.66 × 10(-46)) and pleiotrophin (0.012 [0.005], p = 3.88 × 10(-41)). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10(-5)). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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26. Candidate Blood Proteome Markers of Alzheimer's Disease Onset and Progression: A Systematic Review and Replication Study.
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Kiddle, Steven J., Sattlecker, Martina, Proitsi, Petroula, Simmons, Andrew, Westman, Eric, Bazenet, Chantal, Nelson, Sally K., Williams, Stephen, Hodges, Angela, Johnston, Caroline, Soininen, Hilkka, Kłoszewska, Iwona, Mecocci, Patrizia, Tsolaki, Magda, Vellas, Bruno, Newhouse, Stephen, Lovestone, Simon, and Dobson, Richard J. B.
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- *
BIOMARKERS , *ALZHEIMER'S disease , *BASAL ganglia diseases , *PROTEOMICS , *MOLECULAR biology , *APOLIPOPROTEIN E - Abstract
A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of Alzheimer's disease (AD) would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (> 100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: α-1-antitrypsin, α-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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27. Dysregulated Antibody, Natural Killer Cell and Immune Mediator Profiles in Autoimmune Thyroid Diseases.
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Martin, Tiphaine C., Ilieva, Kristina M., Visconti, Alessia, Beaumont, Michelle, Kiddle, Steven J., Dobson, Richard J. B., Mangino, Massimo, Lim, Ee Mun, Pezer, Marija, Steves, Claire J., Bell, Jordana T., Wilson, Scott G., Lauc, Gordan, Roederer, Mario, Walsh, John P., Spector, Tim D., and Karagiannis, Sophia N.
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KILLER cells ,THYROID diseases ,AUTOIMMUNE diseases ,IMMUNOGLOBULIN G ,ANTIBODY-dependent cell cytotoxicity ,BLOOD cells - Abstract
The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood and the association between different immune features and the germline variants involved in AITD are yet unclear. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation in peripheral blood mononuclear cells in AITD, correlated with anti-thyroid peroxidase antibody (TPOAb) levels. Fucose depletion is known to potentiate strong antibody-mediated NK cell activation and enhanced target antigen-expressing cell killing. In autoimmunity, this may translate to autoantibody-mediated immune cell recruitment and attack of self-antigen expressing normal tissues. Hence, we investigated the crosstalk between immune cell traits, secreted proteins, genetic variants and the glycosylation patterns of serum IgG, in a multi-omic and cross-sectional study of 622 individuals from the TwinsUK cohort, 172 of whom were diagnosed with AITD. We observed associations between two genetic variants (rs505922 and rs687621), AITD status, the secretion of Desmoglein-2 protein, and the profile of two IgG N-glycan traits in AITD, but further studies need to be performed to better understand their crosstalk in AITD. On the other side, enhanced afucosylated IgG was positively associated with activatory CD335
- CD314+ CD158b+ NK cell subsets. Increased levels of the apoptosis and inflammation markers Caspase-2 and Interleukin-1α positively associated with AITD. Two genetic variants associated with AITD, rs1521 and rs3094228, were also associated with altered expression of the thyrocyte-expressed ligands known to recognize the NK cell immunoreceptors CD314 and CD158b. Our analyses reveal a combination of heightened Fc-active IgG antibodies, effector cells, cytokines and apoptotic signals in AITD, and AITD genetic variants associated with altered expression of thyrocyte-expressed ligands to NK cell immunoreceptors. Together, TPOAb responses, dysregulated immune features, germline variants associated with immunoactivity profiles, are consistent with a positive autoreactive antibody-dependent NK cell-mediated immune response likely drawn to the thyroid gland in AITD. [ABSTRACT FROM AUTHOR]- Published
- 2020
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28. Inhaled corticosteroids and FEV1 decline in chronic obstructive pulmonary disease: a systematic review.
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Whittaker, Hannah R., Jarvis, Debbie, Sheikh, Mohamed R., Kiddle, Steven J., and Quint, Jennifer K.
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OBSTRUCTIVE lung diseases ,META-analysis - Abstract
Rate of FEV1 decline in COPD is heterogeneous and the extent to which inhaled corticosteroids (ICS) influence the rate of decline is unclear. The majority of previous reviews have investigated specific ICS and non-ICS inhalers and have consisted of randomised control trials (RCTs), which have specific inclusion and exclusion criteria and short follow up times. We aimed to investigate the association between change in FEV1 and ICS-containing medications in COPD patients over longer follow up times.MEDLINE and EMBASE were searched and literature comparing change in FEV1 in COPD patients taking ICS-containing medications with patients taking non-ICS-containing medications were identified. Titles, abstract, and full texts were screened and information extracted using the PICO checklist. Risk of bias was assessed using the Cochrane Risk of Bias tool and a descriptive synthesis of the literature was carried out due to high heterogeneity of included studies.Seventeen studies met our inclusion criteria. We found that the difference in change in FEV1 in people using ICS and non-ICS containing medications depended on the study follow-up time. Shorter follow-up studies (1 year or less) were more likely to report an increase in FEV1 from baseline in both patients on ICS and in patients on non-ICS-containing medications, with the majority of these studies showing a greater increase in FEV1 in patients on ICS-containing medications. Longer follow-up studies (greater than 1 year) were more likely to report a decline in FEV1 from baseline in patients on ICS and in patients on non-ICS containing medications but rates of FEV1 decline were similar.Further studies are needed to better understand changes in FEV1 when ICS-containing medications are prescribed and to determine whether ICS-containing medications influence rate of decline in FEV1 in the long term. Results from inclusive trials and observational patient cohorts may provide information more generalisable to a population of COPD patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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29. A Blood Test for Alzheimer's Disease: Progress, Challenges, and Recommendations.
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Voyle, Nicola, Kiddle, Steven J., and Dobson, Richard J.B.
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ALZHEIMER'S disease diagnosis , *BLOOD testing , *COHORT analysis , *GENE expression , *METABOLOMICS , *ALZHEIMER'S disease , *COMPARATIVE studies , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *RESEARCH funding , *EVALUATION research - Abstract
Ever since the discovery of APOEɛ4 around 25 years ago, researchers have been excited about the potential of a blood test for Alzheimer's disease (AD). Since then researchers have looked for genetic, protein, metabolite, and/or gene expression markers of AD and related phenotypes. However, no blood test for AD is yet being used in the clinical setting. We first review the trends and challenges in AD blood biomarker research, before giving our personal recommendations to help researchers overcome these challenges. While some degree of consistency and replication has been seen across independent studies, several high-profile studies have seemingly failed to replicate. Partly due to academic incentives, there is a reluctance in the field to report predictive ability, to publish negative findings, and to independently replicate the work of others. If this can be addressed, then we will know sooner whether a blood test for AD or related phenotypes with clinical utility can be developed. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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30. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic.
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Hampel, Harald, O’Bryant, Sid E., Molinuevo, José L., Zetterberg, Henrik, Masters, Colin L., Lista, Simone, Kiddle, Steven J., Batrla, Richard, Blennow, Kaj, and O'Bryant, Sid E
- Subjects
- *
BIOMARKERS , *ALZHEIMER'S disease , *INDIVIDUALIZED medicine , *CEREBROSPINAL fluid , *TAU proteins , *ALZHEIMER'S disease treatment , *RESEARCH funding , *EARLY diagnosis - Abstract
Biomarker discovery and development for clinical research, diagnostics and therapy monitoring in clinical trials have advanced rapidly in key areas of medicine - most notably, oncology and cardiovascular diseases - allowing rapid early detection and supporting the evolution of biomarker-guided, precision-medicine-based targeted therapies. In Alzheimer disease (AD), breakthroughs in biomarker identification and validation include cerebrospinal fluid and PET markers of amyloid-β and tau proteins, which are highly accurate in detecting the presence of AD-associated pathophysiological and neuropathological changes. However, the high cost, insufficient accessibility and/or invasiveness of these assays limit their use as viable first-line tools for detecting patterns of pathophysiology. Therefore, a multistage, tiered approach is needed, prioritizing development of an initial screen to exclude from these tests the high numbers of people with cognitive deficits who do not demonstrate evidence of underlying AD pathophysiology. This Review summarizes the efforts of an international working group that aimed to survey the current landscape of blood-based AD biomarkers and outlines operational steps for an effective academic-industry co-development pathway from identification and assay development to validation for clinical use. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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