Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis

Arman Eshaghi, Rogier A. Kievit, Ferran Prados, Carole H. Sudre, Jennifer Nicholas, M. Jorge Cardoso, Dennis Chan, Richard Nicholas, Sebastien Ourselin, John Greenwood, Alan J. Thompson, Daniel C. Alexander, Frederik Barkhof, Jeremy Chataway, Olga Ciccarelli

Research output: Contribution to journalArticleAcademicpeer-review

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 [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.
Original languageEnglish
Pages (from-to)11020-11027
JournalProceedings of the National Academy of Sciences of the United States of America
Volume166
Issue number22
DOIs
Publication statusPublished - 2019

Cite this

Eshaghi, Arman ; Kievit, Rogier A. ; Prados, Ferran ; Sudre, Carole H. ; Nicholas, Jennifer ; Cardoso, M. Jorge ; Chan, Dennis ; Nicholas, Richard ; Ourselin, Sebastien ; Greenwood, John ; Thompson, Alan J. ; Alexander, Daniel C. ; Barkhof, Frederik ; Chataway, Jeremy ; Ciccarelli, Olga. / Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 166, No. 22. pp. 11020-11027.
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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 [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.",
author = "Arman Eshaghi and Kievit, {Rogier A.} and Ferran Prados and Sudre, {Carole H.} and Jennifer Nicholas and Cardoso, {M. Jorge} and Dennis Chan and Richard Nicholas and Sebastien Ourselin and John Greenwood and Thompson, {Alan J.} and Alexander, {Daniel C.} and Frederik Barkhof and Jeremy Chataway and Olga Ciccarelli",
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doi = "10.1073/pnas.1818978116",
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Eshaghi, A, Kievit, RA, Prados, F, Sudre, CH, Nicholas, J, Cardoso, MJ, Chan, D, Nicholas, R, Ourselin, S, Greenwood, J, Thompson, AJ, Alexander, DC, 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

Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis. / Eshaghi, Arman; Kievit, Rogier A.; Prados, Ferran; Sudre, Carole H.; Nicholas, Jennifer; Cardoso, M. Jorge; Chan, Dennis; Nicholas, Richard; Ourselin, Sebastien; Greenwood, John; Thompson, Alan J.; Alexander, Daniel C.; Barkhof, Frederik; Chataway, Jeremy; Ciccarelli, Olga.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 166, No. 22, 2019, p. 11020-11027.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis

AU - Eshaghi, Arman

AU - Kievit, Rogier A.

AU - Prados, Ferran

AU - Sudre, Carole H.

AU - Nicholas, Jennifer

AU - Cardoso, M. Jorge

AU - Chan, Dennis

AU - Nicholas, Richard

AU - Ourselin, Sebastien

AU - Greenwood, John

AU - Thompson, Alan J.

AU - Alexander, Daniel C.

AU - Barkhof, Frederik

AU - Chataway, Jeremy

AU - Ciccarelli, Olga

PY - 2019

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N2 - 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.

AB - 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.

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