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3. Development and validation of a machine learning-supported strategy of patient selection for osteoarthritis clinical trials: the IMI-APPROACH study

Author

Widera, Paweł, Welsing, Paco M.J., Danso, Samuel O., Peelen, Sjaak, Kloppenburg, Margreet, Loef, Marieke, Marijnissen, Anne C., van Helvoort, Eefje M., Blanco, Francisco J., Magalhães, Joana, Berenbaum, Francis, Haugen, Ida K., Bay-Jensen, Anne-Christine, Mobasheri, Ali, Ladel, Christoph, Loughlin, John, Lafeber, Floris P.J.G., Lalande, Agnès, Larkin, Jonathan, Weinans, Harrie, and Bacardit, Jaume

Published
2023
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4. Initial direct cost and deferred rent under FASB ASC 842: Topic 842 requires that initial direct costs be added to the right-of-use asset and included in its subsequent amortization

Author

Singer, Robert, Bosnick, James, Hays, Bailey, and Loughlin, John

Subjects
Deferred income (Business) -- Laws, regulations and rules -- Taxation, Leases -- Laws, regulations and rules -- Taxation, Government regulation, Banking, finance and accounting industries, Business, Law
Abstract

FASB Accounting Standards Codification (ASC) Topic 842, Leases, issued in February 2016, marked a significant overhaul in the financial reporting of long-term leases. Its adoption created many challenges for public [...]

Published
2023

5. Research priorities to reduce the impact of musculoskeletal disorders: a priority setting exercise with the child health and nutrition research initiative method

Author

Paskins, Zoe, Farmer, Clare E, Manning, Fay, Andersson, David A, Barlow, Tim, Bishop, Felicity L, Brown, Christopher A, Clark, Amanda, Clark, Emma M, Dulake, Debra, Gulati, Malvika, Le Maitre, Christine L, Jones, Richard K, Loughlin, John, Mason, Deborah J, McCarron, Maura, Millar, Neil L, Pandit, Hemant, Peat, George, Richardson, Stephen M, Salt, Emma J, Taylor, E Jane, Troeberg, Linda, Wilcox, Ruth K, Wise, Elspeth, Wilkinson, Colin, and Watt, Fiona E

Published
2022
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13. Common genetic variation in the Estrogen Receptor Beta (ESR2) gene and osteoarthritis: results of a meta-analysis

Author

Kerkhof, Hanneke JM, Meulenbelt, Ingrid, Carr, Andrew, Gonzalez, Antonio, Hart, Deborah, Hofman, Albert, Kloppenburg, Margreet, Lane, Nancy E, Loughlin, John, Nevitt, Michael C, Pols, Huibert AP, Rivadeneira, Fernando, Slagboom, Eline P, Spector, Tim D, Stolk, Lisette, Tsezou, Aspasia, Uitterlinden, André G, Valdes, Ana M, and van Meurs, Joyce BJ

Abstract

Abstract Background The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis. Methods In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls. Results The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05). Conclusion This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase.

Published
2010

20. Publisher Correction: GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures

Author

Styrkarsdottir, Unnur, Stefansson, Olafur A., Gunnarsdottir, Kristbjorg, Thorleifsson, Gudmar, Lund, Sigrun H., Stefansdottir, Lilja, Juliusson, Kristinn, Agustsdottir, Arna B., Zink, Florian, Halldorsson, Gisli H., Ivarsdottir, Erna V., Benonisdottir, Stefania, Jonsson, Hakon, Gylfason, Arnaldur, Norland, Kristjan, Trajanoska, Katerina, Boer, Cindy G., Southam, Lorraine, Leung, Jason C. S., Tang, Nelson L. S., Kwok, Timothy C. Y., Lee, Jenny S. W., Ho, Suzanne C., Byrjalsen, Inger, Center, Jacqueline R., Lee, Seung Hun, Koh, Jung-Min, Lohmander, L. Stefan, Ho-Pham, Lan T., Nguyen, Tuan V., Eisman, John A., Woo, Jean, Leung, Ping-C., Loughlin, John, Zeggini, Eleftheria, Christiansen, Claus, Rivadeneira, Fernando, van Meurs, Joyce, Uitterlinden, Andre G., Mogensen, Brynjolfur, Jonsson, Helgi, Ingvarsson, Thorvaldur, Sigurdsson, Gunnar, Benediktsson, Rafn, Sulem, Patrick, Jonsdottir, Ingileif, Masson, Gisli, Holm, Hilma, Norddahl, Gudmundur L., Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F., and Stefansson, Kari

Published
2019
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21. GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures

Author

Styrkarsdottir, Unnur, Stefansson, Olafur A., Gunnarsdottir, Kristbjorg, Thorleifsson, Gudmar, Lund, Sigrun H., Stefansdottir, Lilja, Juliusson, Kristinn, Agustsdottir, Arna B., Zink, Florian, Halldorsson, Gisli H., Ivarsdottir, Erna V., Benonisdottir, Stefania, Jonsson, Hakon, Gylfason, Arnaldur, Norland, Kristjan, Trajanoska, Katerina, Boer, Cindy G., Southam, Lorraine, Leung, Jason C. S., Tang, Nelson L. S., Kwok, Timothy C. Y., Lee, Jenny S. W., Ho, Suzanne C., Byrjalsen, Inger, Center, Jacqueline R., Lee, Seung Hun, Koh, Jung-Min, Lohmander, L. Stefan, Ho-Pham, Lan T., Nguyen, Tuan V., Eisman, John A., Woo, Jean, Leung, Ping-C., Loughlin, John, Zeggini, Eleftheria, Christiansen, Claus, Rivadeneira, Fernando, van Meurs, Joyce, Uitterlinden, Andre G., Mogensen, Brynjolfur, Jonsson, Helgi, Ingvarsson, Thorvaldur, Sigurdsson, Gunnar, Benediktsson, Rafn, Sulem, Patrick, Jonsdottir, Ingileif, Masson, Gisli, Holm, Hilma, Norddahl, Gudmundur L., Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F., and Stefansson, Kari

Published
2019
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24. Mediation of the Same Epigenetic and Transcriptional Effect by Independent Osteoarthritis Risk–Conferring Alleles on a Shared Target Gene, COLGALT2.

Author

Kehayova, Yulia S., Wilkinson, J. Mark, Rice, Sarah J., and Loughlin, John

Subjects
CARTILAGE analysis, DNA analysis, CARTILAGE cells, SEQUENCE analysis, DNA demethylation, ALLELES, RISK assessment, OSTEOARTHRITIS, GENES, GENOTYPES, TRANSCRIPTION factors, EPIGENOMICS, DISEASE risk factors
Abstract

Objective: Over 100 DNA variants have been associated with osteoarthritis (OA), including rs1046934, located within a linkage disequilibrium block encompassing part of COLGALT2 and TSEN15. The present study was undertaken to determine the target gene(s) and the mechanism of action of the OA locus using human fetal cartilage, cartilage from OA and femoral neck fracture arthroplasty patients, and a chondrocyte cell model. Methods: Genotyping and methylation array data of DNA from human OA cartilage samples (n = 87) were used to determine whether the rs1046934 genotype is associated with differential DNA methylation at proximal CpGs. Results were replicated in DNA from human arthroplasty (n = 132) and fetal (n = 77) cartilage samples using pyrosequencing. Allelic expression imbalance (AEI) measured the effects of genotype on COLGALT2 and TSEN15 expression. Reporter gene assays and epigenetic editing determined the functional role of regions harboring differentially methylated CpGs. In silico analyses complemented these experiments. Results: Three differentially methylated CpGs residing within regulatory regions were detected in the human OA cartilage array data, and 2 of these were replicated in human arthroplasty and fetal cartilage. AEI was detected for COLGALT2 and TSEN15, with associations between expression and methylation for COLGALT2. Reporter gene assays confirmed that the CpGs are in chondrocyte enhancers, with epigenetic editing results directly linking methylation with COLGALT2 expression. Conclusion: COLGALT2 is a target of this OA locus. We previously characterized another OA locus, marked by rs11583641, that independently targets COLGALT2. The genotype of rs1046934, like rs11583641, mediates its effect by modulating expression of COLGALT2 via methylation changes to CpGs located in enhancers. Although the single‐nucleotide polymorphisms, CpGs, and enhancers are distinct between the 2 independent OA risk loci, their effect on COLGALT2 is the same. COLGALT2 is the target of independent OA risk loci sharing a common mechanism of action. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Genome-wide association study of developmental dysplasia of the hip identifies an association with GDF5

Author

Hatzikotoulas, Konstantinos, Roposch, Andreas, The DDH Case Control Consortium, Shah, Karan M., Clark, Matthew J., Bratherton, Selina, Limbani, Vasanti, Steinberg, Julia, Zengini, Eleni, Warsame, Kaltuun, Ratnayake, Madhushika, Tselepi, Maria, Schwartzentruber, Jeremy, Loughlin, John, Eastwood, Deborah M., Zeggini, Eleftheria, and Wilkinson, J. Mark

Published
2018
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30. Predicted and actual 2-year structural and pain progression in the IMI-APPROACH knee osteoarthritis cohort.

Author

Helvoort, Eefje M van, Jansen, Mylène P, Marijnissen, Anne C A, Kloppenburg, Margreet, Blanco, Francisco J, Haugen, Ida K, Berenbaum, Francis, Bay-Jensen, Anne-Christine C, Ladel, Christoph, Lalande, Agnes, Larkin, Jonathan, Loughlin, John, Mobasheri, Ali, Weinans, Harrie H, Widera, Pawel, Bacardit, Jaume, Welsing, Paco M J, and Lafeber, Floris P J G

Subjects
KNEE osteoarthritis, DISEASE progression, EXPERIMENTAL design, BIOMARKERS, PAIN, PAIN measurement, TIME, MACHINE learning, REGRESSION analysis, JOINT pain, QUESTIONNAIRES, DESCRIPTIVE statistics, RECEIVER operating characteristic curves, PREDICTION models, DATA analysis software, LONGITUDINAL method
Abstract

Objectives The IMI-APPROACH knee osteoarthritis study used machine learning (ML) to predict structural and/or pain progression, expressed by a structural (S) and pain (P) predicted-progression score, to select patients from existing cohorts. This study evaluates the actual 2-year progression within the IMI-APPROACH, in relation to the predicted-progression scores. Methods Actual structural progression was measured using minimum joint space width (minJSW). Actual pain (progression) was evaluated using the Knee injury and Osteoarthritis Outcomes Score (KOOS) pain questionnaire. Progression was presented as actual change (Δ) after 2 years, and as progression over 2 years based on a per patient fitted regression line using 0, 0.5, 1 and 2-year values. Differences in predicted-progression scores between actual progressors and non-progressors were evaluated. Receiver operating characteristic (ROC) curves were constructed and corresponding area under the curve (AUC) reported. Using Youden's index, optimal cut-offs were chosen to enable evaluation of both predicted-progression scores to identify actual progressors. Results Actual structural progressors were initially assigned higher S predicted-progression scores compared with structural non-progressors. Likewise, actual pain progressors were assigned higher P predicted-progression scores compared with pain non-progressors. The AUC-ROC for the S predicted-progression score to identify actual structural progressors was poor (0.612 and 0.599 for Δ and regression minJSW, respectively). The AUC-ROC for the P predicted-progression score to identify actual pain progressors were good (0.817 and 0.830 for Δ and regression KOOS pain, respectively). Conclusion The S and P predicted-progression scores as provided by the ML models developed and used for the selection of IMI-APPROACH patients were to some degree able to distinguish between actual progressors and non-progressors. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov , NCT03883568. [ABSTRACT FROM AUTHOR]

Published
2023
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36. Prioritization of PLEC and GRINA as Osteoarthritis Risk Genes Through the Identification and Characterization of Novel Methylation Quantitative Trait Loci

Author

Rice, Sarah J., Tselepi, Maria, Sorial, Antony K., Aubourg, Guillaume, Shepherd, Colin, Almarza, David, Skelton, Andrew J., Pangou, Ioanna, Deehan, David, Reynard, Louise N., and Loughlin, John

Subjects
Adult, Cartilage, Articular, Male, Genotype, Quantitative Trait Loci, Membrane Proteins, DNA Methylation, Middle Aged, Polymorphism, Single Nucleotide, Receptors, N-Methyl-D-Aspartate, Biomechanical Phenomena, Risk Factors, Osteoarthritis, Humans, Plectin, Original Article, CpG Islands, Female, Genetic Predisposition to Disease, Alleles, Aged, Genome-Wide Association Study
Abstract

Objective To identify methylation quantitative trait loci (mQTLs) correlating with osteoarthritis (OA) risk alleles and to undertake mechanistic characterization as a means of target gene prioritization. Methods We used genome‐wide genotyping and cartilage DNA methylation array data in a discovery screen of novel OA risk loci. This was followed by methylation, gene expression analysis, and genotyping studies in additional cartilage samples, accompanied by in silico analyses. Results We identified 4 novel OA mQTLs. The most significant mQTL contained 9 CpG sites where methylation correlated with OA risk genotype, with 5 of the CpG sites having P values

Published
2019

37. Investigation of Association Between Hip Osteoarthritis Susceptibility Loci and Radiographic Proximal Femur Shape

Author

Lindner, Claudia, Thiagarajah, Shankar, Wilkinson, Mark J., Panoutsopoulou, Kalliope, Day-Williams, Aaron G., Cootes, Timothy F., Wallis, Gillian A., Loughlin, John, Birrell, Fraser, Carr, Andrew, Chapman, Kay, Deloukas, Panos, Doherty, Michael, McCaskie, Andrew, Ollier, William E. R., Rai, Ashok, Ralston, Stuart H., Spector, Timothy D., Valdes, Ana M., and Zeggini, Eleftheria

Published
2015
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39. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

Author

Evangelou, Evangelos, Kerkhof, Hanneke J, Styrkarsdottir, Unnur, Ntzani, Evangelia E, Bos, Steffan D, Esko, Tonu, Evans, Daniel S, Metrustry, Sarah, Panoutsopoulou, Kalliope, Ramos, Yolande F M, Thorleifsson, Gudmar, Tsilidis, Konstantinos K, Arden, Nigel, Aslam, Nadim, Bellamy, Nicholas, Birrell, Fraser, Blanco, Francisco J, Carr, Andrew, Chapman, Kay, Day-Williams, Aaron G, Deloukas, Panos, Doherty, Michael, Engström, Gunnar, Helgadottir, Hafdis T, Hofman, Albert, Ingvarsson, Thorvaldur, Jonsson, Helgi, Keis, Aime, Keurentjes, Christiaan J, Kloppenburg, Margreet, Lind, Penelope A, McCaskie, Andrew, Martin, Nicholas G, Milani, Lili, Montgomery, Grant W, Nelissen, Rob G H H, Nevitt, Michael C, Nilsson, Peter M, Ollier, William ER, Parimi, Neeta, Rai, Ashok, Ralston, Stuart H, Reed, Mike R, Riancho, Jose A, Rivadeneira, Fernando, Rodriguez-Fontenla, Cristina, Southam, Lorraine, Thorsteinsdottir, Unnur, Tsezou, Aspasia, Wallis, Gillian A, Wilkinson, Mark J, Gonzalez, Antonio, Lane, Nancy E, Lohmander, Stefan L, Loughlin, John, Metspalu, Andres, Uitterlinden, Andre G, Jonsdottir, Ingileif, Stefansson, Kari, Slagboom, Eline P, Zeggini, Eleftheria, Meulenbelt, Ingrid, Ioannidis, John PA, Spector, Tim D, van Meurs, Joyce B J, and Valdes, Ana M

Published
2014
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40. Leadership at the subnational level: Mayoral and executive models

Author

Karsten, Niels, Sweeting, David, Kjær, Ulrik, Kukovič, Simona, Callanan, Mark, Loughlin, John, Innovatie in de democratische rechtsstaat, Public Law & Governance, and Tilburg Institute of Governance

Subjects
Local Government, Political leadership, Mayoralty, Mayors, local democracy, Institutionalism
Abstract

Over the last decades and across the globe, subnational government has undergone significant reform. In many of these structural changes to the systems of local, urban and metropolitan governance, the roles of leaders and positions of leadership were at the core of the reform. One of the most prominent aims has been to give expression to a new ideal type of local political leadership and to increase the legitimacy and accountability of subnational government. The further proliferation of the directly elected mayor model is but one expression of this trend. However, the academic literature continues to struggle to capture the complexity and changing nature of subnational leadership. In response, the aim of this chapter is to analyze and discuss the changes in mayoral and executive leadership against the background of the available typologies for mayoral and executive models. In addition, the authors develop an agenda for further research

Published
2021

43. Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies

Author

Rodriguez-Fontenla, Cristina, Calaza, Manuel, Evangelou, Evangelos, Valdes, Ana M., Arden, Nigel, Blanco, Francisco J., Carr, Andrew, Chapman, Kay, Deloukas, Panos, Doherty, Michael, Esko, Tõnu, Garcés Aletá, Carlos M., Gomez-Reino Carnota, Juan J., Helgadottir, Hafdis, Hofman, Albert, Jonsdottir, Ingileif, Kerkhof, Hanneke J. M., Kloppenburg, Margreet, McCaskie, Andrew, Ntzani, Evangelia E., Ollier, William E. R., Oreiro, Natividad, Panoutsopoulou, Kalliope, Ralston, Stuart H., Ramos, Yolande F., Riancho, Jose A., Rivadeneira, Fernando, Slagboom, Eline P., Styrkarsdottir, Unnur, Thorsteinsdottir, Unnur, Thorleifsson, Gudmar, Tsezou, Aspasia, Uitterlinden, André G., Wallis, Gillian A., Wilkinson, Mark J., Zhai, Guangju, Zhu, Yanyan, Felson, David T., Ioannidis, John P. A., Loughlin, John, Metspalu, Andres, Meulenbelt, Ingrid, Stefansson, Kari, van Meurs, Joyce B., Zeggini, Eleftheria, Spector, Timothy D., and Gonzalez, Antonio

Published
2014
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44. Genome-wide association scan identifies a prostaglandin-endoperoxide synthase 2 variant involved in risk of knee osteoarthritis

Author

Valdes, Ana M., Loughlin, John, Timms, Kirsten M., van Meurs, Joyce J.B., Southam, Lorraine, Wilson, Scott G, Doherty, Sally, Lories, Rik J., Luyten, Frank P., Gutin, Alexander, Abkevich, Victor, Dongliang Ge, Hofman, Albert, Uitterlinden, Andre G., Hart, Deborah J., Feng Zhang, Zhai, Guangju, Spector, Tim D., Lanchbury, Jerry, Doherty, Michael, and Egli, Rainer J.

Subjects
Osteoarthritis -- Genetic aspects, Single nucleotide polymorphisms -- Analysis, Genomics -- Research, Gene expression -- Analysis, Biological sciences
Abstract

A large-coverage pooled genome-wide association scan (GWAS) of knee osteoarthritis (OA) and the results from successive test of individual most highly associated single-nucleotide polymorphisms (SNPs) in five case-control studies are reported. Findings show that polymorphism in LD with variants affecting the expression of the PTGS2 gene are associated with susceptibility to knee OA in five independent populations and highlight the importance of inflammatory pathways in OA pathogenesis.

Published
2008

49. The Europe factor: how the EU influenced changes in Scotland, Wales and Northern Ireland

Author

Loughlin, John

Subjects
Political reform -- Analysis, Social sciences, European Union -- Political activity, European Union -- Influence
Abstract

IN 1998, TWO SETS OF POLITICAL EVENTS OCCURRED IN THE UNITED Kingdom that would have seemed improbable, even impossible, 20 years before. First, the Good Friday Agreement was reached in [...]

Published
2004

50. The 'transformation' of governance: new directions in policy and politics

Author

Loughlin, John

Subjects
Political systems -- Analysis, Representative government and representation -- Analysis, History, Political science, Regional focus/area studies
Abstract

The terms transformation and governance are used increasingly in the academic literature but often in a confused way. This article attempts to define both terms. It argues that there are three kinds of transformation: pseudo-change; incremental evolutionary transformation (IET), which is the most common form; and revolutionary transformation (RT). It applies this model of change to three paradigm shifts in developed countries since 1945: the Welfare State; the neo-liberal state; and the so-called Third Way. It argues that each of these paradigms involves a particular dominant mode of governance: statist; pluralist; and network respectively. It examines both the causes and consequences of these transformations for politics and policy.

Published
2004

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