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1. Pharmacogenomics of clinical response to Natalizumab in multiple sclerosis: a genome-wide multi-centric association study

Author

Clarelli, Ferdinando, Corona, Andrea, Pääkkönen, Kimmo, Sorosina, Melissa, Zollo, Alen, Piehl, Fredrik, Olsson, Tomas, Stridh, Pernilla, Jagodic, Maja, Hemmer, Bernhard, Gasperi, Christiane, Harroud, Adil, Shchetynsky, Klementy, Mingione, Alessandra, Mascia, Elisabetta, Misra, Kaalindi, Giordano, Antonino, Mazzieri, Maria Laura Terzi, Priori, Alberto, Saarela, Janna, Kockum, Ingrid, Filippi, Massimo, Esposito, Federica, and Boneschi, Filippo Giovanni Martinelli

Published
2024
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2. Evidence supports a causal association between allele-specific vitamin D receptor binding and multiple sclerosis among Europeans.

Author

Adams, Cameron, Manouchehrinia, Ali, Quach, Hong, Quach, Diana, Olsson, Tomas, Kockum, Ingrid, Schaefer, Catherine, Ponting, Chris, Alfredsson, Lars, and Barcellos, Lisa

Subjects
genetics, multiple sclerosis, vitamin D, Humans, Multiple Sclerosis, Receptors, Calcitriol, Alleles, Genome-Wide Association Study, Vitamin D, Calcitriol, Polymorphism, Single Nucleotide
Abstract

Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D) serum levels, and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding in MS is unknown. Here, we leveraged previously identified variants associated with allele imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol-stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more genetic variants that serve as proxies for exposures of interest. Here, GIVs for both VDR-BVs and 25(OH)D were used in a two-sample Mendelian Randomization study to investigate the relationship between VDR binding at a locus, 25(OH)D serum levels, and MS risk. Data for 13,598 MS cases and 38,887 controls of European ancestry from Kaiser Permanente Northern California, Swedish MS studies, and the UK Biobank were included. We estimated the association between each VDR-BV GIV and MS. Significant interaction between a VDR-BV GIV and a GIV for serum 25OH(D) was evidence for a causal association between VDR-BVs and MS unbiased by pleiotropy. We observed evidence for associations between two VDR-BVs (rs2881514, rs2531804) and MS after correction for multiple tests. There was evidence of interaction between rs2881514 and a 25(OH)D GIV, providing evidence of a causal association between rs2881514 and MS. This study is the first to demonstrate evidence that variation in VDR binding at a locus contributes to MS risk. Our results are relevant to other autoimmune diseases in which vitamin D plays a role.

Published
2024

3. A genetic-epigenetic interplay at 1q21.1 locus underlies CHD1L-mediated vulnerability to primary progressive multiple sclerosis

Author

Pahlevan Kakhki, Majid, Giordano, Antonino, Starvaggi Cucuzza, Chiara, Venkata S. Badam, Tejaswi, Samudyata, Samudyata, Lemée, Marianne Victoria, Stridh, Pernilla, Gkogka, Asimenia, Shchetynsky, Klementy, Harroud, Adil, Gyllenberg, Alexandra, Liu, Yun, Boddul, Sanjaykumar, James, Tojo, Sorosina, Melissa, Filippi, Massimo, Esposito, Federica, Wermeling, Fredrik, Gustafsson, Mika, Casaccia, Patrizia, Hillert, Jan, Olsson, Tomas, Kockum, Ingrid, Sellgren, Carl M., Golzio, Christelle, Kular, Lara, and Jagodic, Maja

Published
2024
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5. Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

Author

Ollila, Hanna M, Sharon, Eilon, Lin, Ling, Sinnott-Armstrong, Nasa, Ambati, Aditya, Yogeshwar, Selina M, Hillary, Ryan P, Jolanki, Otto, Faraco, Juliette, Einen, Mali, Luo, Guo, Zhang, Jing, Han, Fang, Yan, Han, Dong, Xiao Song, Li, Jing, Zhang, Jun, Hong, Seung-Chul, Kim, Tae Won, Dauvilliers, Yves, Barateau, Lucie, Lammers, Gert Jan, Fronczek, Rolf, Mayer, Geert, Santamaria, Joan, Arnulf, Isabelle, Knudsen-Heier, Stine, Bredahl, May Kristin Lyamouri, Thorsby, Per Medbøe, Plazzi, Giuseppe, Pizza, Fabio, Moresco, Monica, Crowe, Catherine, Van den Eeden, Stephen K, Lecendreux, Michel, Bourgin, Patrice, Kanbayashi, Takashi, Martínez-Orozco, Francisco J, Peraita-Adrados, Rosa, Benetó, Antonio, Montplaisir, Jacques, Desautels, Alex, Huang, Yu-Shu, Jennum, Poul, Nevsimalova, Sona, Kemlink, David, Iranzo, Alex, Overeem, Sebastiaan, Wierzbicka, Aleksandra, Geisler, Peter, Sonka, Karel, Honda, Makoto, Högl, Birgit, Stefani, Ambra, Coelho, Fernando Morgadinho, Mantovani, Vilma, Feketeova, Eva, Wadelius, Mia, Eriksson, Niclas, Smedje, Hans, Hallberg, Pär, Hesla, Per Egil, Rye, David, Pelin, Zerrin, Ferini-Strambi, Luigi, Bassetti, Claudio L, Mathis, Johannes, Khatami, Ramin, Aran, Adi, Nampoothiri, Sheela, Olsson, Tomas, Kockum, Ingrid, Partinen, Markku, Perola, Markus, Kornum, Birgitte R, Rueger, Sina, Winkelmann, Juliane, Miyagawa, Taku, Toyoda, Hiromi, Khor, Seik-Soon, Shimada, Mihoko, Tokunaga, Katsushi, Rivas, Manuel, Pritchard, Jonathan K, Risch, Neil, Kutalik, Zoltan, O’Hara, Ruth, Hallmayer, Joachim, Ye, Chun Jimmie, and Mignot, Emmanuel J

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Biological Sciences, Prevention, Vaccine Related, Influenza, Autoimmune Disease, Immunization, Pneumonia & Influenza, Emerging Infectious Diseases, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Infection, Inflammatory and immune system, Good Health and Well Being, Humans, Autoimmunity, Influenza, Human, Influenza A Virus, H1N1 Subtype, Autoimmune Diseases, Influenza Vaccines, Narcolepsy, FinnGen
Abstract

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Published
2023

7. Publisher Correction: Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Author

Oddsson, Asmundur, Sulem, Patrick, Sveinbjornsson, Gardar, Arnadottir, Gudny A., Steinthorsdottir, Valgerdur, Halldorsson, Gisli H., Atlason, Bjarni A., Oskarsson, Gudjon R., Helgason, Hannes, Nielsen, Henriette Svarre, Westergaard, David, Karjalainen, Juha M., Katrinardottir, Hildigunnur, Fridriksdottir, Run, Jensson, Brynjar O., Tragante, Vinicius, Ferkingstad, Egil, Jonsson, Hakon, Gudjonsson, Sigurjon A., Beyter, Doruk, Moore, Kristjan H. S., Thordardottir, Helga B., Kristmundsdottir, Snaedis, Stefansson, Olafur A., Rantapää-Dahlqvist, Solbritt, Sonderby, Ida Elken, Didriksen, Maria, Stridh, Pernilla, Haavik, Jan, Tryggvadottir, Laufey, Frei, Oleksandr, Walters, G. Bragi, Kockum, Ingrid, Hjalgrim, Henrik, Olafsdottir, Thorunn A., Selbaek, Geir, Nyegaard, Mette, Erikstrup, Christian, Brodersen, Thorsten, Saevarsdottir, Saedis, Olsson, Tomas, Nielsen, Kaspar Rene, Haraldsson, Asgeir, Bruun, Mie Topholm, Hansen, Thomas Folkmann, Steingrimsdottir, Thora, Jacobsen, Rikke Louise, Lie, Rolv T., Djurovic, Srdjan, Alfredsson, Lars, Lopez de Lapuente Portilla, Aitzkoa, Brunak, Soren, Melsted, Pall, Halldorsson, Bjarni V., Saemundsdottir, Jona, Magnusson, Olafur Th., Padyukov, Leonid, Banasik, Karina, Rafnar, Thorunn, Askling, Johan, Klareskog, Lars, Pedersen, Ole Birger, Masson, Gisli, Havdahl, Alexandra, Nilsson, Bjorn, Andreassen, Ole A., Daly, Mark, Ostrowski, Sisse Rye, Jonsdottir, Ingileif, Stefansson, Hreinn, Holm, Hilma, Helgason, Agnar, Thorsteinsdottir, Unnur, Stefansson, Kari, and Gudbjartsson, Daniel F.

Published
2023
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8. Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Author

Oddsson, Asmundur, Sulem, Patrick, Sveinbjornsson, Gardar, Arnadottir, Gudny A., Steinthorsdottir, Valgerdur, Halldorsson, Gisli H., Atlason, Bjarni A., Oskarsson, Gudjon R., Helgason, Hannes, Nielsen, Henriette Svarre, Westergaard, David, Karjalainen, Juha M., Katrinardottir, Hildigunnur, Fridriksdottir, Run, Jensson, Brynjar O., Tragante, Vinicius, Ferkingstad, Egil, Jonsson, Hakon, Gudjonsson, Sigurjon A., Beyter, Doruk, Moore, Kristjan H. S., Thordardottir, Helga B., Kristmundsdottir, Snaedis, Stefansson, Olafur A., Rantapää-Dahlqvist, Solbritt, Sonderby, Ida Elken, Didriksen, Maria, Stridh, Pernilla, Haavik, Jan, Tryggvadottir, Laufey, Frei, Oleksandr, Walters, G. Bragi, Kockum, Ingrid, Hjalgrim, Henrik, Olafsdottir, Thorunn A., Selbaek, Geir, Nyegaard, Mette, Erikstrup, Christian, Brodersen, Thorsten, Saevarsdottir, Saedis, Olsson, Tomas, Nielsen, Kaspar Rene, Haraldsson, Asgeir, Bruun, Mie Topholm, Hansen, Thomas Folkmann, Steingrimsdottir, Thora, Jacobsen, Rikke Louise, Lie, Rolv T., Djurovic, Srdjan, Alfredsson, Lars, Lopez de Lapuente Portilla, Aitzkoa, Brunak, Soren, Melsted, Pall, Halldorsson, Bjarni V., Saemundsdottir, Jona, Magnusson, Olafur Th., Padyukov, Leonid, Banasik, Karina, Rafnar, Thorunn, Askling, Johan, Klareskog, Lars, Pedersen, Ole Birger, Masson, Gisli, Havdahl, Alexandra, Nilsson, Bjorn, Andreassen, Ole A., Daly, Mark, Ostrowski, Sisse Rye, Jonsdottir, Ingileif, Stefansson, Hreinn, Holm, Hilma, Helgason, Agnar, Thorsteinsdottir, Unnur, Stefansson, Kari, and Gudbjartsson, Daniel F.

Published
2023
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12. Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease

Author

Ossenkoppele, Rik, Smith, Ruben, Mattsson-Carlgren, Niklas, Groot, Colin, Leuzy, Antoine, Strandberg, Olof, Palmqvist, Sebastian, Olsson, Tomas, Jögi, Jonas, Stormrud, Erik, Cho, Hanna, Ryu, Young Hoon, Choi, Jae Yong, Boxer, Adam L, Gorno-Tempini, Maria L, Miller, Bruce L, Soleimani-Meigooni, David, Iaccarino, Leonardo, La Joie, Renaud, Baker, Suzanne, Borroni, Edilio, Klein, Gregory, Pontecorvo, Michael J, Devous, Michael D, Jagust, William J, Lyoo, Chul Hyoung, Rabinovici, Gil D, and Hansson, Oskar

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Clinical Research, Acquired Cognitive Impairment, Alzheimer's Disease, Clinical Trials and Supportive Activities, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Behavioral and Social Science, Aging, Brain Disorders, Neurodegenerative, Biomedical Imaging, Dementia, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Neurological, Aged, Alzheimer Disease, Amyloid beta-Peptides, Apolipoproteins E, Carbolines, Cerebral Cortex, Female, Follow-Up Studies, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mental Status and Dementia Tests, Middle Aged, Neuroimaging, Positron-Emission Tomography, Predictive Value of Tests, Prodromal Symptoms, Prognosis, Radiopharmaceuticals, Treatment Outcome, tau Proteins
Abstract

ImportanceTau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear.ObjectiveTo examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers.Design, setting, and participantsThis prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ).Exposures[18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation.Main outcomes and measuresBaseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations.ResultsAmong 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P

Published
2021

13. COVID-19–Related Enhancement for the COMBAT-MS Study

Author

Piehl, Fredrik, primary, Fogdell-Hahn, Anna, additional, Englund, Simon, additional, Asplund Högelin, Klara, additional, Smith, Jessica, additional, Li, Bonnie, additional, Burman, Joachim, additional, Fink, Katharina, additional, Gunnarsson, Martin, additional, Hillert, Jan, additional, Lycke, Jan, additional, Nilsson, Petra, additional, Salzer, Jonatan, additional, Svenningsson, Anders, additional, Vrethem, Magnus, additional, Olsson, Tomas, additional, Kockum, Ingrid, additional, Al Nimer, Faiez, additional, Longinetti, Elisa, additional, and Frisell, Thomas, additional

Published
2023
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14. Comparing the Safety and Effectiveness of Different Medicines to Treat Multiple Sclerosis – The COMBAT-MS Study

Author

Piehl, Fredick, primary, Fogdell-Hahn, Anna, additional, Smith, Jessica, additional, Englund, Simon, additional, Virtanen, Suvi, additional, Alping, Peter, additional, Li, Bonnie, additional, Burman, Joachim, additional, Fink, Katharina, additional, Gunnarsson, Martin, additional, Hilert, Jan, additional, Kockum, Ingrid, additional, Lycke, Jan, additional, Nilsson, Petra, additional, Salzer, Jonatan, additional, Svenningsson, Anders, additional, Vrethem, Magnus, additional, Olsson, Tomas, additional, Longinetti, Elisa, additional, Frisell, Thomas, additional, and Langer-Gould, Annette, additional

Published
2023
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15. The impact of demographic, clinical, genetic, and imaging variables on tau PET status

Author

Ossenkoppele, Rik, Leuzy, Antoine, Cho, Hanna, Sudre, Carole H, Strandberg, Olof, Smith, Ruben, Palmqvist, Sebastian, Mattsson-Carlgren, Niklas, Olsson, Tomas, Jögi, Jonas, Stormrud, Erik, Ryu, Young Hoon, Choi, Jae Yong, Boxer, Adam L, Gorno-Tempini, Maria L, Miller, Bruce L, Soleimani-Meigooni, David, Iaccarino, Leonardo, La Joie, Renaud, Borroni, Edilio, Klein, Gregory, Pontecorvo, Michael J, Devous, Michael D, Villeneuve, Sylvia, Lyoo, Chul Hyoung, Rabinovici, Gil D, and Hansson, Oskar

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Biomedical Imaging, Aging, Alzheimer's Disease, Dementia, Brain Disorders, Neurodegenerative, Clinical Research, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Cognitive Dysfunction, Demography, Humans, Positron-Emission Tomography, tau Proteins, PET, Tau, A&#946, Alzheimer&#8217, s disease, MCI, Alzheimer’s Disease Neuroimaging Initiative, PREVENT-AD research group, Alzheimer’s disease, Aβ, Other Physical Sciences, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

PurposeA substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI) are tau PET-negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET-positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status.MethodsWe included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model.ResultsTau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan.ConclusionWe identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.

Published
2021

18. Comparison of Machine Learning’s- and Humans’- Ability to Consistently Classify Anomalies in Cylinder Locks

Author

Andersson, Tim, Bohlin, Markus, Olsson, Tomas, Ahlskog, Mats, Rannenberg, Kai, Editor-in-Chief, Soares Barbosa, Luís, Editorial Board Member, Goedicke, Michael, Editorial Board Member, Tatnall, Arthur, Editorial Board Member, Neuhold, Erich J., Editorial Board Member, Stiller, Burkhard, Editorial Board Member, Tröltzsch, Fredi, Editorial Board Member, Pries-Heje, Jan, Editorial Board Member, Kreps, David, Editorial Board Member, Reis, Ricardo, Editorial Board Member, Furnell, Steven, Editorial Board Member, Mercier-Laurent, Eunika, Editorial Board Member, Winckler, Marco, Editorial Board Member, Malaka, Rainer, Editorial Board Member, Kim, Duck Young, editor, von Cieminski, Gregor, editor, and Romero, David, editor

Published
2022
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19. Chapter Machine Learning Models for Industrial Applications

Author

Olsson, Tomas, Ramentol, Enislay, and Barua, Shaibal

Subjects
Automatic control engineering, thema EDItEUR::T Technology, Engineering, Agriculture, Industrial processes::TJ Electronics and communications engineering::TJF Electronics engineering::TJFM Automatic control engineering
Abstract

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Published
2021
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20. The genetic history of Scandinavia from the Roman Iron Age to the present

Author

Rodríguez-Varela, Ricardo, Moore, Kristjan H.S., Ebenesersdóttir, S. Sunna, Kilinc, Gulsah Merve, Kjellström, Anna, Papmehl-Dufay, Ludvig, Alfsdotter, Clara, Berglund, Birgitta, Alrawi, Loey, Kashuba, Natalija, Sobrado, Verónica, Lagerholm, Vendela Kempe, Gilbert, Edmund, Cavalleri, Gianpiero L., Hovig, Eivind, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Hansen, Thomas F., Werge, Thomas, Munters, Arielle R., Bernhardsson, Carolina, Skar, Birgitte, Christophersen, Axel, Turner-Walker, Gordon, Gopalakrishnan, Shyam, Daskalaki, Eva, Omrak, Ayça, Pérez-Ramallo, Patxi, Skoglund, Pontus, Girdland-Flink, Linus, Gunnarsson, Fredrik, Hedenstierna-Jonson, Charlotte, Gilbert, M. Thomas P., Lidén, Kerstin, Jakobsson, Mattias, Einarsson, Lars, Victor, Helena, Krzewińska, Maja, Zachrisson, Torun, Storå, Jan, Stefánsson, Kári, Helgason, Agnar, and Götherström, Anders

Published
2023
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22. Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Author

Madireddy, Lohith, Patsopoulos, Nikolaos A, Cotsapas, Chris, Bos, Steffan D, Beecham, Ashley, McCauley, Jacob, Kim, Kicheol, Jia, Xiaoming, Santaniello, Adam, Caillier, Stacy J, Andlauer, Till FM, Barcellos, Lisa F, Berge, Tone, Bernardinelli, Luisa, Martinelli-Boneschi, Filippo, Booth, David R, Briggs, Farren, Celius, Elisabeth G, Comabella, Manuel, Comi, Giancarlo, Cree, Bruce AC, D'Alfonso, Sandra, Dedham, Katrina, Duquette, Pierre, Dardiotis, Efthimios, Esposito, Federica, Fontaine, Bertrand, Gasperi, Christiane, Goris, An, Dubois, Benedicte, Gourraud, Pierre-Antoine, Hadjigeorgiou, Georgios, Haines, Jonathan, Hawkins, Clive, Hemmer, Bernhard, Hintzen, Rogier, Horakova, Dana, Isobe, Noriko, Kalra, Seema, Kira, Jun-ichi, Khalil, Michael, Kockum, Ingrid, Lill, Christina M, Lincoln, Matthew R, Luessi, Felix, Martin, Roland, Oturai, Annette, Palotie, Aarno, Pericak-Vance, Margaret A, Henry, Roland, Saarela, Janna, Ivinson, Adrian, Olsson, Tomas, Taylor, Bruce V, Stewart, Graeme J, Harbo, Hanne F, Compston, Alastair, Hauser, Stephen L, Hafler, David A, Zipp, Frauke, De Jager, Philip, Sawcer, Stephen, Oksenberg, Jorge R, and Baranzini, Sergio E

Subjects
International Multiple Sclerosis Genetics Consortium
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

23. A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Author

Madireddy, Lohith, Patsopoulos, Niklaos A, Cotsapas, Chris, Bos, Steffan D, Beecham, Ashley, McCauley, Jacob, Kim, Kicheol, Jia, Xiaoming, Santaniello, Adam, Caillier, Stacy J, Andlauer, Till FM, Barcellos, Lisa F, Berge, Tone, Bernardinelli, Luisa, Martinelli-Boneschi, Filippo, Booth, David R, Briggs, Farren, Celius, Elisabeth G, Comabella, Manuel, Comi, Giancarlo, Cree, Bruce AC, D'Alfonso, Sandra, Dedham, Katrina, Duquette, Pierre, Efthimios, Dardiotis, Esposito, Federica, Fontaine, Bertrand, Gasperi, Christiane, Goris, An, Dubois, Benedicte, Gourraud, Pierre-Antoine, Hadjigeorgiou, Georgios, Haines, Jonathan, Hawkins, Clive, Hemmer, Bernhard, Hintzen, Rogier, Horakova, Dana, Isobe, Noriko, Kalra, Seema, Kira, Jun-ichi, Khalil, Michael, Kockum, Ingrid, Lill, Christina M, Lincoln, Matthew R, Luessi, Felix, Martin, Roland, Oturai, Annette, Palotie, Aarno, Pericak-Vance, Margaret A, Henry, Roland, Saarela, Janna, Ivinson, Adrian, Olsson, Tomas, Taylor, Bruce V, Stewart, Graeme J, Harbo, Hanne F, Compston, Alastair, Hauser, Stephen L, Hafler, David A, Zipp, Frauke, De Jager, Philip, Sawcer, Stephen, Oksenberg, Jorge R, and Baranzini, Sergio E

Subjects
Human Genome, Autoimmune Disease, Multiple Sclerosis, Genetics, Biotechnology, Brain Disorders, Neurodegenerative, Clinical Research, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Gene Expression Regulation, Genes, Regulator, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Systems Biology, International Multiple Sclerosis Genetics Consortium
Abstract

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.

Published
2019

24. Genetic risk factors for pediatric-onset multiple sclerosis.

Author

Gianfrancesco, Milena A, Stridh, Pernilla, Shao, Xiaorong, Rhead, Brooke, Graves, Jennifer S, Chitnis, Tanuja, Waldman, Amy, Lotze, Timothy, Schreiner, Teri, Belman, Anita, Greenberg, Benjamin, Weinstock-Guttman, Bianca, Aaen, Gregory, Tillema, Jan M, Hart, Janace, Caillier, Stacy, Ness, Jayne, Harris, Yolanda, Rubin, Jennifer, Candee, Meghan, Krupp, Lauren, Gorman, Mark, Benson, Leslie, Rodriguez, Moses, Mar, Soe, Kahn, Ilana, Rose, John, Roalstad, Shelly, Casper, T Charles, Shen, Ling, Quach, Hong, Quach, Diana, Hillert, Jan, Hedstrom, Anna, Olsson, Tomas, Kockum, Ingrid, Alfredsson, Lars, Schaefer, Catherine, Barcellos, Lisa F, Waubant, Emmanuelle, and Network of Pediatric Multiple Sclerosis Centers

Subjects
Network of Pediatric Multiple Sclerosis Centers, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, Logistic Models, Risk Factors, Polymorphism, Single Nucleotide, Sweden, Female, Male, Genetic Testing, HLA-DRB1 Chains, Multiple sclerosis, epidemiology, genetics, pediatrics, Brain Disorders, Human Genome, Autoimmune Disease, Genetics, Prevention, Neurosciences, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundStrong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology.ObjectiveWe comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS.MethodsCases with onset

Published
2018

26. Quantifying and estimating additive measures of interaction from case-control data

Author

Hössjer, Ola, Alfredsson, Lars, Hedström, Anna Karin, Lekman, Magnus, Kockum, Ingrid, and Olsson, Tomas

Subjects
Statistics - Methodology
Abstract

In this paper we develop a general framework for quantifying how binary risk factors jointly influence a binary outcome. Our key result is an additive expansion of odds ratios as a sum of marginal effects and interaction terms of varying order. These odds ratio expansions are used for estimating the excess odds ratio, attributable proportion and synergy index for a case-control dataset by means of maximum likelihood from a logistic regression model. The confidence intervals associated with these estimates of joint effects and interaction of risk factors rely on the delta method. Our methodology is illustrated with a large Nordic meta dataset for multiple sclerosis. It combines four studies, with a total of 6265 cases and 8401 controls. It has three risk factors (smoking and two genetic factors) and a number of other confounding variables., Comment: Published at http://dx.doi.org/10.15559/17-VMSTA77 in the Modern Stochastics: Theory and Applications (https://www.i-journals.org/vtxpp/VMSTA) by VTeX (http://www.vtex.lt/)

Published
2017
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27. Plasma protein profiling reveals dynamic immunomodulatory changes in multiple sclerosis patients during pregnancy.

Author

Lingehed, Georgia Papapavlou, Hellberg, Sandra, Huang, Jesse, Khademi, Mohsen, Kockum, Ingrid, Carlsson, Hanna, Tjernberg, Ivar, Svenvik, Maria, Lind, Jonas, Blomberg, Marie, Vrethem, Magnus, Mellergård, Johan, Gustafsson, Mika, Jenmalm, Maria C., Olsson, Tomas, and Ernerudh, Jan

Subjects
PREGNANCY proteins, TUMOR necrosis factors, BLOOD proteins, FALSE discovery rate, NEUROLOGICAL disorders
Abstract

Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory and neurodegenerative disorder of the central nervous system. Pregnancy represents a natural modulation of the disease course, where the relapse rate decreases, especially in the 3rd trimester, followed by a transient exacerbation after delivery. Although the exact mechanisms behind the pregnancy-induced modulation are yet to be deciphered, it is likely that the immune tolerance established during pregnancy is involved. In this study, we used the highly sensitive and specific proximity extension assay technology to perform protein profiling analysis of 92 inflammation-related proteins in MS patients (n=15) and healthy controls (n=10), longitudinally sampled before, during, and after pregnancy. Differential expression analysis was performed using linear models and p-values were adjusted for false discovery rate due to multiple comparisons. Our findings reveal gradual dynamic changes in plasma proteins that are most prominent during the 3rd trimester while reverting post-partum. Thus, this pattern reflects the disease activity of MS during pregnancy. Among the differentially expressed proteins in pregnancy, several proteins with known immunoregulatory properties were upregulated, such as PD-L1, LIF-R, TGF-b1, and CCL28. On the other hand, inflammatory chemokines such as CCL8, CCL13, and CXCL5, as well as members of the tumor necrosis factor family, TRANCE and TWEAK, were downregulated. Further in-depth studies will reveal if these proteins can serve as biomarkers in MS and whether they are mechanistically involved in the disease amelioration and worsening. A deeper understanding of the mechanisms involved may identify new treatment strategies mimicking the pregnancy milieu. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Genetics of immune response to Epstein-Barr virus: prospects for multiple sclerosis pathogenesis.

Author

Huang, Jesse, Tengvall, Katarina, Lima, Izaura Bomfim, Hedström, Anna Karin, Butt, Julia, Brenner, Nicole, Gyllenberg, Alexandra, Stridh, Pernilla, Khademi, Mohsen, Ernberg, Ingemar, Nimer, Faiez Al, Manouchehrinia, Ali, Hillert, Jan, Alfredsson, Lars, Andersen, Oluf, Sundström, Peter, Waterboer, Tim, Olsson, Tomas, and Kockum, Ingrid

Abstract

Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 [EBNA-1, truncated = amino acids (aa) (325–641), peptide = aa(385–420)] and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched control subjects. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 [odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.60–1.88] and EBNA-1, particularly the peptide (OR = 3.13, 95% CI = 2.93–3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to 12× the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g. DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01 , which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defence against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defence against EBV. Last, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility. [ABSTRACT FROM AUTHOR]

Published
2024
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29. Rubella virus seropositivity after infection or vaccination as a risk factor for multiple sclerosis.

Author

Ingvarsson, Jens, Grut, Viktor, Biström, Martin, Berg, Linn Persson, Stridh, Pernilla, Huang, Jesse, Hillert, Jan, Alfredsson, Lars, Kockum, Ingrid, Olsson, Tomas, Waterboer, Tim, Nilsson, Staffan, and Sundström, Peter

Subjects
MOLECULAR mimicry, DEMYELINATION, RUBELLA virus, DISEASE risk factors, CENTRAL nervous system, CHICKENPOX
Abstract

Background: Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein–Barr virus (EBV) and human herpesvirus 6A (HHV‐6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting. Methods: In this nested case–control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead‐based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression. Results: Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV‐6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8–8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0–2.9). Conclusions: To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Enhanced and cross-reactive in vitro memory B cell response against Epstein-Barr virus nuclear antigen 1 in multiple sclerosis.

Author

Marti, Zoe, Ruder, Josefine, Thomas, Olivia G., Bronge, Mattias, De La Parra Soto, Lorenzo, Grönlund, Hans, Olsson, Tomas, and Martin, Roland

Subjects
IMMUNOLOGIC memory, CELL adhesion molecules, HEMATOPOIETIC stem cell transplantation, MYELIN basic protein, MOLECULAR mimicry
Abstract

Multiple sclerosis (MS) is a prototypical autoimmune disease of the central nervous system (CNS). In addition to CD4+ T cells, memory B cells are now recognized as a critical cell type in the disease. This is underlined by the fact that the best-characterized environmental risk factor for MS is the Epstein-Barr virus (EBV), which can infect and persist in memory B cells throughout life. Several studies have identified changes in anti-EBV immunity in patients with MS. Examples include elevated titers of anti-EBV nuclear antigen 1 (EBNA1) antibodies, interactions of these with the MS-associated HLA-DR15 haplotype, and molecular mimicry with MS autoantigens like myelin basic protein (MBP), anoctamin-2 (ANO2), glial cell adhesion molecule (GlialCAM), and alpha-crystallin B (CRYAB). In this study, we employ a simple in vitro assay to examine the memory B cell antibody repertoire in MS patients and healthy controls. We replicate previous serological data from MS patients demonstrating an increased secretion of anti-EBNA1380-641 IgG in cell culture supernatants, as well as a positive correlation of these levels with autoantibodies against GlialCAM262-416 and ANO21-275. For EBNA1380-641 and ANO21-275, we provide additional evidence suggesting antibody cross-reactivity between the two targets. Further, we show that two efficacious MS treatments - natalizumab (NAT) and autologous hematopoietic stem cell transplantation (aHSCT) - are associated with distinct changes in the EBNA1- directed B cell response and that these alterations can be attributed to the unique mechanisms of action of these therapies. Using an in vitro system, our study confirms MS-associated changes in the anti-EBNA1 memory B cell response, EBNA1380-641 antibody cross-reactivity with ANO21-275, and reveals treatment-associated changes in the immunoglobulin repertoire in MS. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Interactions between High Seroreactivity to Human Herpes Virus 6A and Epstein–Barr Virus in MS Development: A Presymptomatic Case–Control Study.

Author

Grut, Viktor, Biström, Martin, Salzer, Jonatan, Stridh, Pernilla, Jons, Daniel, Gustafsson, Rasmus, Huang, Jesse, Bergström, Tomas, Kockum, Ingrid, Waterboer, Tim, Olsson, Tomas, and Sundström, Peter

Subjects
EPSTEIN-Barr virus, VIRAL antigens, CASE-control method, VIRAL antibodies, MULTIPLE sclerosis, JOHN Cunningham virus
Abstract

Synergistic interactions between human herpesvirus 6A (HHV‐6A) and Epstein–Barr virus (EBV) are hypothesized in the etiopathogenesis of multiple sclerosis (MS). This study investigated if HHV‐6A and EBV seroreactivities interact regarding the risk of developing MS. Antibodies against viral antigens were analyzed in biobank samples from 670 individuals who later developed MS and matched controls. Additive interactions were analyzed. A significant interaction between HHV‐6A and EBNA‐1 seroreactivities was observed in study participants above the median age of 24.9 years (attributable proportion due to interaction = 0.45). This finding supports the hypothesis that HHV‐6A and EBV infections interact in MS development. ANN NEUROL 2024;96:302–305 [ABSTRACT FROM AUTHOR]

Published
2024
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33. Comparing the Safety of Medicines to Treat MS during the COVID-19 Pandemic

Author

Piehl, Fredrick, primary, Fogdell-Hahn, Anna, additional, Englund, Simon, additional, Asplund Högelin, Klara, additional, Smith, Jessica, additional, Li, Bonnie, additional, Burman, Joachim, additional, Fink, Katharina, additional, Gunnarsson, Martin, additional, Hillert, Jan, additional, Lycke, Jan, additional, Nilsson, Petra, additional, Salzer, Jonatan, additional, Svenningsson, Anders, additional, Vrethem, Magnus, additional, Olsson, Tomas, additional, Kockum, Ingrid, additional, Al Nimer, Faiez, additional, Longinetti, Elisa, additional, Frisell, Thomas, additional, and Langer-Gould, Annette, additional

Published
2023
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34. The genetic structure of Norway

Author

Mattingsdal, Morten, Ebenesersdóttir, S. Sunna, Moore, Kristjan H. S., Andreassen, Ole A., Hansen, Thomas F., Werge, Thomas, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Helgason, Agnar, Stefánsson, Kári, and Hovig, Eivind

Published
2021
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35. Identification of MS-specific serum miRNAs in an international multicenter study

Author

Regev, Keren, Healy, Brian C, Paul, Anu, Diaz-Cruz, Camilo, Mazzola, Maria Antonietta, Raheja, Radhika, Glanz, Bonnie I, Kivisäkk, Pia, Chitnis, Tanuja, Jagodic, Maja, Piehl, Fredrik, Olsson, Tomas, Khademi, Mohsen, Hauser, Stephen, Oksenberg, Jorge, Khoury, Samia J, Weiner, Howard L, and Gandhi, Roopali

Subjects
Biomedical and Clinical Sciences, Neurosciences, Genetics, Biotechnology, Neurodegenerative, Multiple Sclerosis, Clinical Research, Brain Disorders, Autoimmune Disease, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis
Abstract

ObjectiveTo identify circulating microRNAs (miRNAs) linked to disease, disease stage, and disability in MS across cohorts.MethodsSamples were obtained from the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB, Boston, MA), EPIC (San Francisco, CA), AMIR (Beirut, Lebanon) as part of the SUMMIT consortium, and Stockholm Prospective Assessment of Multiple Sclerosis (Stockholm, Sweden) cohorts. Serum miRNA expression was measured using locked nucleic acid-based quantitative PCR. Four groups were compared: (1) MS vs healthy control (HC), (2) relapsing-remitting (RR) vs HC, (3) secondary progressive (SP) vs HC, and (4) RR vs SP. A Wilcoxon rank-sum test was used for the comparisons. The association between each miRNA and the Expanded Disability Status Scale (EDSS) score was assessed using the Spearman correlation coefficient. For each comparison, the p values were corrected for multiple comparisons using the approach of Benjamini and Hochberg to control the false discovery rate.ResultsIn the CLIMB cohort, 5 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-320a, hsa-miR-486-5p, and hsa-miR-320c) showed a significant difference between patients with MS and healthy individuals; among these, miR-484 remained significant after accounting for multiple comparisons (p = 0.01). When comparing RRMS with HCs, hsa-miR-484 showed a significant difference (p = 0.004) between the groups after accounting for multiple group comparisons. When SP and HC were compared, 6 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-142-5p, hsa-miR-320a, hsa-miR-320b, and hsa-miR-320c) remained significantly different after accounting for multiple comparisons. Disability correlation analysis with miRNA provided 4 miRNAs (hsa-miR-320a, hsa-miR-337-3p, hsa-miR-199a-5p, and hsa-miR-142-5p) that correlated with the EDSS during the internal reproducibility phase. Among these, hsa-miR-337-3p was the most statistically significant miRNA that negatively correlated with the EDSS in three of the MS cohorts tested.ConclusionsThese findings further confirm the use of circulating serum miRNAs as biomarkers to diagnose and monitor disease status in MS.Classification of evidenceThis study provides Class III evidence that levels of circulating miRNAs identify patients with MS.

Published
2018

37. Genetic variation inHIF1Ais associated with smoldering inflammation and disease progression in Multiple Sclerosis

Author

Giordano, Antonino, primary, Stridh, Pernilla, additional, Preziosa, Paolo, additional, Pisa, Marco, additional, Sorosina, Melissa, additional, Mascia, Elisabetta, additional, Santoro, Silvia, additional, Misra, Kaalindi, additional, Clarelli, Ferdinando, additional, Ferrè, Laura, additional, Needhamsen, Maria, additional, Manouchehrinia, Ali, additional, Cannizzaro, Miryam, additional, Moridi, Thomas, additional, Shchetynsky, Klementy, additional, Ouellette, Russell, additional, Harroud, Adil, additional, Sandberg, Elisabeth, additional, Kuttikkatte, Subita Balaram, additional, Piehl, Fredrik, additional, Alfredsson, Lars, additional, Hillert, Jan, additional, Olsson, Tomas, additional, Fugger, Lars, additional, Attfield, Kate, additional, Granberg, Tobias, additional, Jagodic, Maja, additional, DeLuca, Gabriele Carmine, additional, Rocca, Mara, additional, Filippi, Massimo, additional, Kockum, Ingrid, additional, and Esposito, Federica, additional

Published
2024
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41. Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Author

Forstner, Andreas J., Awasthi, Swapnil, Wolf, Christiane, Maron, Eduard, Erhardt, Angelika, Czamara, Darina, Eriksson, Elias, Lavebratt, Catharina, Allgulander, Christer, Friedrich, Nina, Becker, Jessica, Hecker, Julian, Rambau, Stefanie, Conrad, Rupert, Geiser, Franziska, McMahon, Francis J., Moebus, Susanne, Hess, Timo, Buerfent, Benedikt C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Kockum, Ingrid, Olsson, Tomas, Alfredsson, Lars, Weber, Heike, Alpers, Georg W., Arolt, Volker, Fehm, Lydia, Fydrich, Thomas, Gerlach, Alexander L., Hamm, Alfons, Kircher, Tilo, Pané-Farré, Christiane A., Pauli, Paul, Rief, Winfried, Ströhle, Andreas, Plag, Jens, Lang, Thomas, Wittchen, Hans-Ulrich, Mattheisen, Manuel, Meier, Sandra, Metspalu, Andres, Domschke, Katharina, Reif, Andreas, Hovatta, Iiris, Lindefors, Nils, Andersson, Evelyn, Schalling, Martin, Mbarek, Hamdi, Milaneschi, Yuri, de Geus, Eco J. C., Boomsma, Dorret I., Penninx, Brenda W. J. H., Thorgeirsson, Thorgeir E., Steinberg, Stacy, Stefansson, Kari, Stefansson, Hreinn, Müller-Myhsok, Bertram, Hansen, Thomas Folkmann, Børglum, Anders D., Werge, Thomas, Mortensen, Preben Bo, Nordentoft, Merete, Hougaard, David M., Hultman, Christina M., Sullivan, Patrick F., Nöthen, Markus M., Woldbye, David P. D., Mors, Ole, Binder, Elisabeth B., Rück, Christian, Ripke, Stephan, Deckert, Jürgen, and Schumacher, Johannes

Published
2021
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44. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS

Author

Gianfrancesco, Milena A, Stridh, Pernilla, Rhead, Brooke, Shao, Xiaorong, Xu, Edison, Graves, Jennifer S, Chitnis, Tanuja, Waldman, Amy, Lotze, Timothy, Schreiner, Teri, Belman, Anita, Greenberg, Benjamin, Weinstock-Guttman, Bianca, Aaen, Gregory, Tillema, Jan M, Hart, Janace, Caillier, Stacy, Ness, Jayne, Harris, Yolanda, Rubin, Jennifer, Candee, Meghan, Krupp, Lauren, Gorman, Mark, Benson, Leslie, Rodriguez, Moses, Mar, Soe, Kahn, Ilana, Rose, John, Roalstad, Shelly, Casper, T Charles, Shen, Ling, Quach, Hong, Quach, Diana, Hillert, Jan, Bäärnhielm, Maria, Hedstrom, Anna, Olsson, Tomas, Kockum, Ingrid, Alfredsson, Lars, Metayer, Catherine, Schaefer, Catherine, Barcellos, Lisa F, and Waubant, Emmanuelle

Subjects
Neurosciences, Pediatric, Multiple Sclerosis, Brain Disorders, Prevention, Clinical Research, Nutrition, Genetics, Neurodegenerative, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Age of Onset, Biomarkers, Body Mass Index, Female, Genetic Predisposition to Disease, HLA-DRB1 Chains, Humans, Male, Mendelian Randomization Analysis, Risk, Sweden, United States, Vitamin D, White People, Network of Pediatric Multiple Sclerosis Centers, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS).MethodsWe constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820).ResultsMeta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model.ConclusionsWe provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.

Published
2017

45. Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility.

Author

Gianfrancesco, Milena, Glymour, M, Walter, Stefan, Rhead, Brooke, Shao, Xiaorong, Shen, Ling, Quach, Hong, Hubbard, Alan, Jónsdóttir, Ingileif, Stefánsson, Kári, Strid, Pernilla, Hillert, Jan, Hedström, Anna, Olsson, Tomas, Kockum, Ingrid, Schaefer, Catherine, Alfredsson, Lars, and Barcellos, Lisa

Subjects
Mendelian randomization, body mass index, genetic instrumental variables, multiple sclerosis, obesity, Adult, Body Mass Index, Case-Control Studies, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Multiple Sclerosis
Abstract

Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.

Published
2017

46. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, Niamh, Forstner, Andreas J., O’Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R. I., Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Børte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Bøcker Pedersen, Carsten, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Giørtz Pedersen, Marianne, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L., Kamatani, Yoichiro, Kennedy, James L., Kittel-Schneider, Sarah, Knowles, James A., Kogevinas, Manolis, Koromina, Maria, Kranz, Thorsten M., Kranzler, Henry R., Kubo, Michiaki, Kupka, Ralph, Kushner, Steven A., Lavebratt, Catharina, Lawrence, Jacob, Leber, Markus, Lee, Heon-Jeong, Lee, Phil H., Levy, Shawn E., Lewis, Catrin, Liao, Calwing, Lucae, Susanne, Lundberg, Martin, MacIntyre, Donald J., Magnusson, Sigurdur H., Maier, Wolfgang, Maihofer, Adam, Malaspina, Dolores, Maratou, Eirini, Martinsson, Lina, Mattheisen, Manuel, McCarroll, Steven A., McGregor, Nathaniel W., McGuffin, Peter, McKay, James D., Medeiros, Helena, Medland, Sarah E., Millischer, Vincent, Montgomery, Grant W., Moran, Jennifer L., Morris, Derek W., Mühleisen, Thomas W., O’Brien, Niamh, O’Donovan, Claire, Olde Loohuis, Loes M., Oruc, Lilijana, Papiol, Sergi, Pardiñas, Antonio F., Perry, Amy, Pfennig, Andrea, Porichi, Evgenia, Potash, James B., Quested, Digby, Raj, Towfique, Rapaport, Mark H., DePaulo, J. Raymond, Regeer, Eline J., Rice, John P., Rivas, Fabio, Rivera, Margarita, Roth, Julian, Roussos, Panos, Ruderfer, Douglas M., Sánchez-Mora, Cristina, Schulte, Eva C., Senner, Fanny, Sharp, Sally, Shilling, Paul D., Sigurdsson, Engilbert, Sirignano, Lea, Slaney, Claire, Smeland, Olav B., Smith, Daniel J., Sobell, Janet L., Søholm Hansen, Christine, Soler Artigas, Maria, Spijker, Anne T., Stein, Dan J., Strauss, John S., Świątkowska, Beata, Terao, Chikashi, Thorgeirsson, Thorgeir E., Toma, Claudio, Tooney, Paul, Tsermpini, Evangelia-Eirini, Vawter, Marquis P., Vedder, Helmut, Walters, James T. R., Witt, Stephanie H., Xi, Simon, Xu, Wei, Yang, Jessica Mei Kay, Young, Allan H., Young, Hannah, Zandi, Peter P., Zhou, Hang, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Babadjanova, Gulja, Backlund, Lena, Baune, Bernhard T., Bellivier, Frank, Bengesser, Susanne, Berrettini, Wade H., Blackwood, Douglas H. R., Boehnke, Michael, Børglum, Anders D., Breen, Gerome, Carr, Vaughan J., Catts, Stanley, Corvin, Aiden, Craddock, Nicholas, Dannlowski, Udo, Dikeos, Dimitris, Esko, Tõnu, Etain, Bruno, Ferentinos, Panagiotis, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gershon, Elliot S., Goes, Fernando S., Green, Melissa J., Grigoroiu-Serbanescu, Maria, Hauser, Joanna, Henskens, Frans, Hillert, Jan, Hong, Kyung Sue, Hougaard, David M., Hultman, Christina M., Hveem, Kristian, Iwata, Nakao, Jablensky, Assen V., Jones, Ian, Jones, Lisa A., Kahn, René S., Kelsoe, John R., Kirov, George, Landén, Mikael, Leboyer, Marion, Lewis, Cathryn M., Li, Qingqin S., Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, Martin, Nicholas G., Mathews, Carol A., Mayoral, Fermin, McElroy, Susan L., McIntosh, Andrew M., McMahon, Francis J., Melle, Ingrid, Michie, Patricia, Milani, Lili, Mitchell, Philip B., Morken, Gunnar, Mors, Ole, Mortensen, Preben Bo, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Neale, Benjamin M., Nievergelt, Caroline M., Nordentoft, Merete, Nöthen, Markus M., O’Donovan, Michael C., Oedegaard, Ketil J., Olsson, Tomas, Owen, Michael J., Paciga, Sara A., Pantelis, Chris, Pato, Carlos, Pato, Michele T., Patrinos, George P., Perlis, Roy H., Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Ripke, Stephan, Rouleau, Guy A., Saito, Takeo, Schall, Ulrich, Schalling, Martin, Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Stefansson, Hreinn, Stefansson, Kari, Stordal, Eystein, Streit, Fabian, Sullivan, Patrick F., Turecki, Gustavo, Vaaler, Arne E., Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas W., Werge, Thomas, Wray, Naomi R., Zwart, John-Anker, Biernacka, Joanna M., Nurnberger, John I., Cichon, Sven, Edenberg, Howard J., Stahl, Eli A., McQuillin, Andrew, Di Florio, Arianna, Ophoff, Roel A., and Andreassen, Ole A.

Published
2021
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47. Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis

Author

Grut, Viktor, Biström, Martin, Salzer, Jonatan, Stridh, Pernilla, Jons, Daniel, Gustafsson, Rasmus, Fogdell-Hahn, Anna, Huang, Jesse, Butt, Julia, Lindam, Anna, Alonso-Magdalena, Lucia, Bergström, Tomas, Kockum, Ingrid, Waterboer, Tim, Olsson, Tomas, Zetterberg, Henrik, Blennow, Kaj, Andersen, Oluf, Nilsson, Staffan, Sundström, Peter, Grut, Viktor, Biström, Martin, Salzer, Jonatan, Stridh, Pernilla, Jons, Daniel, Gustafsson, Rasmus, Fogdell-Hahn, Anna, Huang, Jesse, Butt, Julia, Lindam, Anna, Alonso-Magdalena, Lucia, Bergström, Tomas, Kockum, Ingrid, Waterboer, Tim, Olsson, Tomas, Zetterberg, Henrik, Blennow, Kaj, Andersen, Oluf, Nilsson, Staffan, and Sundström, Peter

Abstract

Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before t

Published
2024
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48. Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage

Author

Jons, Daniel, Grut, Viktor, Bergström, Tomas, Zetterberg, Henrik, Biström, Martin, Gunnarsson, Martin, Vrethem, Magnus, Brenner, Nicole, Butt, Julia, Blennow, Kaj, Nilsson, Staffan, Kockum, Ingrid, Olsson, Tomas, Waterboer, Tim, Sundström, Peter, Andersen, Oluf, Jons, Daniel, Grut, Viktor, Bergström, Tomas, Zetterberg, Henrik, Biström, Martin, Gunnarsson, Martin, Vrethem, Magnus, Brenner, Nicole, Butt, Julia, Blennow, Kaj, Nilsson, Staffan, Kockum, Ingrid, Olsson, Tomas, Waterboer, Tim, Sundström, Peter, and Andersen, Oluf

Abstract

BACKGROUND: Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens. METHODS: We performed a case-control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury. RESULTS: EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15-20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001-0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001).With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10-5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026). CONCLUSIONS: Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS., DJ was supported by grants from the Swedish State under the ALF agreement between the Swedish Government and County Councils (ALFGBG- 772071), as well as by grants from the Research Foundation of the Gothenburg MS Society, Bjornsson Research Foundation, Gothenburg, Sweden, and The Gothenburg Society of Medicine. VG was supported by the Visare Norr Fund, Northern County Councils' Regional Federation, the Research and Development Unit, Region Jaemtland Haerjedalen, the Research Fund for Clinical Neuroscience at the University Hospital of Northern Sweden, Oskarfonden, and NEURO Sweden. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018- 02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG- 71320), the Alzheimer Drug Discovery Foundation-USA (#201809- 2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF- 21- 831376- C, #ADSF- 21- 831381- C and #ADSF- 21- 831377- C), the Olav Thon Foundation, the Erling- Persson Family Foundation, Stiftelsen foer Gamla Tjaenarinnor, Hjaernfonden-Sweden (#FO2019- 0228), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska- Curie grant agreement No. 860197 (MIRIADE), the European Union Joint Programme-Neurodegenerative Disease Research (JPND2021- 00694), and the UK Dementia Research Institute at University College London (UKDRI- 1003). KB is supported by the Swedish Research Council (#2017- 00915), the Alzheimer Drug Discovery Foundation-USA (#RDAPB- 201809- 2016615), the Swedish Alzheimer Foundation (#AF- 742881), Hjarnfonden, Sweden (#FO2017- 0243), the Swedish state under the agreement between the Swedish Government and the County Councils, the ALF agreement (#ALFGBG- 715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019- 466- 236), the US National Institutes of Health (grant EBV before MS- induced neuronal damage #1R01AG068398- 01), and the Alzh

Published
2024
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49. Trajectories of cognitive processing speed and physical disability over 11 years following initiation of a first multiple sclerosis disease-modulating therapy

Author

Longinetti, Elisa, Englund, Simon, Burman, Joachim, Fink, Katharina, Fogdell-Hahn, Anna, Gunnarsson, Martin, Hillert, Jan, Langer-Gould, Annette Magdalene, Lycke, Jan, Nilsson, Petra, Salzer, Jonatan, Svenningsson, Anders, Mellergård, Johan, Olsson, Tomas, Piehl, Fredrik, Frisell, Thomas, Longinetti, Elisa, Englund, Simon, Burman, Joachim, Fink, Katharina, Fogdell-Hahn, Anna, Gunnarsson, Martin, Hillert, Jan, Langer-Gould, Annette Magdalene, Lycke, Jan, Nilsson, Petra, Salzer, Jonatan, Svenningsson, Anders, Mellergård, Johan, Olsson, Tomas, Piehl, Fredrik, and Frisell, Thomas

Abstract

Background We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start. Methods Using a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011-2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories. Results We identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories. Conclusions In this cohort of actively treated RRMS, patients processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start., Funding Agencies|Patient -Centered Outcomes Research Institute (PCORI) Award [MS- 1511-33196]; Swedish Research Council for Health, Working Life, and Welfare [2020-0115]; Swedish Research Council [2021-01418]; Swedish Brain foundation

Published
2024
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50. Interpretable ML model for quality control of locks using counterfactual explanations

Author

Andersson, Tim, Bohlin, Markus, Ahlskog, Mats, Olsson, Tomas, Andersson, Tim, Bohlin, Markus, Ahlskog, Mats, and Olsson, Tomas

Abstract

This paper presents an interpretable machinelearning model for anomaly detection in door locks using torque data. The model aims to replace the human tactile sense in the quality control process, reducing repetitive tasks and improving reliability. The model achieved an accuracy of 96%, however, to gain social acceptance and operators' trust, interpretability of the model is crucial. The purpose of this study was to evaluate anapproach that can improve interpretability of anomalousclassifications obtained from an anomaly detection model. Weevaluate four instance-based counterfactual explanators, three of which, employ optimization techniques and one uses, a less complex, weighted nearest neighbor approach, which serve as ourbaseline. The former approaches, leverage a latent representation of the data, using a weighted principal component analysis, improving plausibility of the counter factual explanations andreduces computational cost. The explanations are presentedtogether with the 5-50-95th percentile range of the training data, acting as a frame of reference to improve interpretability. All approaches successfully presented valid and plausible counterfactual explanations. However, instance-based approachesemploying optimization techniques yielded explanations withgreater similarity to the observations and was therefore concluded to be preferable despite the higher execution times (4-16s) compared to the baseline approach (0.1s). The findings of this study hold significant value for the lock industry and can potentially be extended to other industrial settings using timeseries data, serving as a valuable point of departure for further research., In press

Published
2024

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