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Title: Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis
Author: Eshaghi, Arman
Kievit, Rogier A.
Prados Carrasco, Ferran
Sudre, Carole H.
Nicholas, Jennifer
Cardoso, Manuel Jorge
Chan, Dennis
Nicholas, Richard
Ourselin, Sebastien
Greenwood, John
Thompson, Alan J.
Alexander, Daniel C.
Barkhof, Frederik
Chataway, Jeremy
Ciccarelli, Olga
Others: 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
Keywords: causal modeling
multiple sclerosis
clinical trials
structural equation modeling
progressive MS
Issue Date: 28-May-2019
Publisher: Proceedings of the National Academy of Sciences
Citation: 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, 166(22), 11020-11027. doi: 10.1073/pnas.1818978116
Project identifier: info:eu-repo/grantAgreement/M020533
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Abstract: 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 [B = -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.
Language: English
ISSN: 1091-6490MIAR
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