Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis
| Autor: | Jeremy Chataway, Ferran Prados, Rogier A. Kievit, Richard Nicholas, Alan J. Thompson, John Greenwood, M. Jorge Cardoso, Jennifer M. Nicholas, Dennis Chan, Olga Ciccarelli, Carole H. Sudre, Sebastien Ourselin, Daniel C. Alexander, Frederik Barkhof, Arman Eshaghi |
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| Přispěvatelé: | Eshaghi, Arman [0000-0002-6652-3512], Kievit, Rogier A [0000-0003-0700-4568], Apollo - University of Cambridge Repository, Radiology and nuclear medicine, Amsterdam Neuroscience - Neuroinfection & -inflammation, University College London, University of Cambridge, Universitat Oberta de Catalunya (UOC), King's College London, Imperial College London, London School of Hygiene and Tropical Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Oncology
Simvastatin Esclerosi múltiple multiple sclerosis chemistry.chemical_compound 0302 clinical medicine Medicine 10. No inequality 0303 health sciences Clinical Trials as Topic Multidisciplinary models d'equacions estructurals Brain clinical trial Biological Sciences Middle Aged Multiple Sclerosis Chronic Progressive 3. Good health Clinical trial Causality Cholesterol PNAS Plus Disease Progression modelatge causal lipids (amino acids peptides and proteins) medicine.drug Adult medicine.medical_specialty esclerosis múltiple causal modeling Placebo structural equation modeling 03 medical and health sciences Atrophy Internal medicine ensayos clínicos Humans modelos de ecuaciones estructurales EM progresiva 030304 developmental biology clinical trials Expanded Disability Status Scale Models Statistical business.industry Multiple sclerosis modelado causal assaigs clínics medicine.disease EM progressiva chemistry Block design test progressive MS business 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, 166(22), 11020-11027. National Academy of Sciences O2, repositorio institucional de la UOC Universitat Oberta de Catalunya (UOC) Eshaghi, A, Kievit, R A, Prados, F, Sudre, C H, Nicholas, J, Cardoso, M J, Chan, D, Nicholas, R, Ourselin, S, Greenwood, J, Thompson, A J, Alexander, D C, Barkhof, F, Chataway, J & Ciccarelli, O 2019, ' Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis ', Proceedings of the National Academy of Sciences of the United States of America, vol. 166, no. 22, pp. 11020-11027 . https://doi.org/10.1073/pnas.1818978116 Proceedings of the National Academy of Sciences of the United States of America Eshaghi, A, Kievit, R A, Prados, F, Sudre, C H, Nicholas, J, Cardoso, M J, Chan, D, Nicholas, R, Ourselin, S, Greenwood, J, Thompson, A J, Alexander, D C, Barkhof, F, Chataway, J & Ciccarelli, O 2019, ' Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis ', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 22, pp. 11020-11027 . https://doi.org/10.1073/pnas.1818978116 |
| ISSN: | 0027-8424 |
| DOI: | 10.1073/pnas.1818978116 |
| Popis: | Significance Traditional analysis of clinical trials precludes a mechanistic understanding of drug actions. This is further compounded by the use of outcome measures in clinical trials not directly related to the mechanism of action of the medication under study. Here, we applied structural equation models to the double-blind randomized controlled trial of simvastatin in secondary progressive multiple sclerosis to investigate causal associations that underlie treatment effects. Our results suggest that beneficial effects of simvastatin on reducing the rate of brain atrophy and slowing the deterioration of disability are independent of serum cholesterol reduction. Our work demonstrates that structural models can elucidate the statistical pathways underlying treatment effects in clinical trials of poorly understood neurodegenerative disorders, such as progressive multiple sclerosis. Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [β = −0.037; 95% credible interval (CI) = −0.075, −0.010]. This suggests that simvastatin’s beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS. |
| Databáze: | OpenAIRE |
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