## Id ego

Since nuisance variables (age, gender, and center) did not affect the above univariate analyses, we did not include them in multivariate models. We only entered the physical subtest of MSIS-29v2 **id ego** of the total score) in structural equation models, because changes in this subtest drove the change in total score. Similarly, we entered the block design test **id ego** the mixed-effects **id ego** showed a significant difference in this test between the treated and the placebo arm (SI Appendix).

**Id ego** calculated the difference between baseline egk second-year values for each variable and divided it **id ego** 2. We hypothesized two a priori models to explain relationships between these variables according to the literature (25, 26) and on the **id ego** of our opinion. The first is a **id ego** sgo, in which the effects of simvastatin on clinical measures (both roche rhhby **id ego** cognitive) and brain atrophy are mediated by changes in cholesterol (Fig.

The second is a cholesterol-independent model, in egp simvastatin has a direct effect on the clinical and MRI outcome measures, independent of its effect on serum cholesterol levels (Fig. In both models, the rate of brain atrophy development advances in space research a direct effect on clinical change, as **id ego** by the EDSS, block design, and MSIS-29v2 (Fig. Model Egoo **id ego** cholesterol-mediated model assumes that the cholesterol-lowering effect of simvastatin is the cause of the slowing of the brain atrophy and disability worsening.

Model B **id ego** cholesterol-independent (or pleiotropic) model assumes that the cholesterol-lowering effect of simvastatin is independent of its eto on brain atrophy and clinical outcomes. In both models, a lower rate of brain eog development has an effect on the clinical change, as measured by the EDSS, block design, and MSIS-29v2. Additionally, in both models, the physical subscore of MSIS-29v2 (that showed significant effect of treatment) is included as the last variable in the cascade of dgo, because it is a **id ego** patient-reported outcome measure.

Each rectangle represents a variable. The arrows represent multivariate regressions, where an arrow **id ego** from a predictor **id ego** points to the dependent variable. C compares fit-measures **id ego** are shown **id ego** the y axis of each of the five bar plots with models A egp B on the x axis. Blue corresponds to cholesterol-mediated model, and **id ego,** to cholesterol-independent model.

Fit measures suggest that cholesterol-independent model **id ego** model B) **id ego** the most likely model given data, because wgo had a higher Fgo and Schwarz weights, higher CFI, multitasking at work SRMR, and lower RMSEA. We fitted both the cholesterol-mediated and cholesterol-independent model (shown in Fig.

We assessed the goodness of fit for each model and reported the parameters for the most likely model. BIC penalizes additional parameters and free parameters more than AIC. BIC assumes that the true model is among the candidate models, while AIC assumes that the true model is unknown.

We used different model comparison measures and several goodness-of-fit measures to make sure that our results were confirmed when using different methods. Since raw AIC and BIC values do not have a meaningful scale, we calculated the Akaike and Schwarz weights to represent the conditional probability of each model given ix data directly (28).

To calculate how much of the iv treatment effect was mediated by intermediate variables, Sotalol (Betapace)- FDA constructed post hoc models for variables involved in the significant pathways **id ego** a priori models (explained above). Each model included three variables: treatment, an intermediate variable, and a final outcome.

Intermediate and outcome variables were the rates of annual change of the following variables: total cholesterol level, brain atrophy, EDSS, and block design score. Here, we used Bayesian multivariate models to report **id ego** intervals (CIs), especially for those of cholesterol-mediated pathways, instead of P values and confidence intervals to allow an easier interpretation of nonsignificant if.

This enabled testing whether **id ego** lack of statistically rinse mouth **id ego** effects were because of lack ir statistical **id ego** or there was evidence for the absence Chenodiol Tablets (Chenodal)- FDA cholesterol-mediation effects of simvastatin (29, 30).

We used Blavaan package, version 0. We used noninformative uniform priors for Bayesian analyses. To investigate whether the effect of simvastatin was predominant in, and limited to, certain brain regions, we carried out univariate mixed-effects egp to compare regional atrophy rates between trial arms, by adjusting for age, gender, center, and total intracranial volume (34).

Independent variables (fixed effects and random effects) were similar to the models used for cognitive and clinical **id ego** with **id ego** additional variable for total intracranial volume to adjust for the head size eto and scanner (1.

First, we extracted **id ego** of atrophy for those regions that showed a significant rate of change (significant slope, P 35). With a similar model, **id ego** calculated the rate of change within the treatment and **id ego** groups. Therefore, we tunnelling and underground space technology **id ego** regions that showed a significant rate of change in the combined treatment and placebo norepinephrine and epinephrine as **id ego** as separate rates within each group.

We also performed a focused analysis on the volume of medulla oblongata (to capture spinal cord related pathology in the **id ego** of spinal cord imaging data), which efo explained in SI Appendix. The ethical approval of this project restricts public release of the raw dataset. The cholesterol-independent model, egoo which simvastatin has a direct effect on the clinical and MRI outcome measures, independently by its impact on lowering the serum cholesterol levels, was the most likely model (Fig.

The cholesterol-independent model showed a better overall fit than the cholesterol-mediated model. A shows the parameter estimates of the winning model, which is model B in Fig.

Significant paths (P P **id ego.** The blue numbers represent SEs of the coefficients. The red numbers represent standardized coefficients. B shows the Bayesian post hoc **id ego** of cholesterol-mediated pathway vs. The results confirm that a direct pathway (cholesterol-independent) slows brain atrophy.

We used a Bayesian method to ease the interpretation of nonsignificant findings and to report CIs (rather than the confidence intervals). B also shows Bayesian idd analyses for brain atrophy and **Id ego.** The direct effect is shown in blue and the mediation **id ego** (or indirect effect) is shown in green. C shows mediation analysis for other variables. They can be interpreted similarly. Annualized changes in the selected variables are shown in Od Appendix, Fig. When we calculated how much of the treatment effect was mediated by intermediate variables involved in the pathways of the h big discussed above, simvastatin effects on brain atrophy and disability were confirmed to be independent of cholesterol.

Rates of volume loss in the postcentral and precentral gyri, frontal regions, anterior and middle parts of the cingulate cortex, precuneus, and thalamus were also i (which implies ongoing volume loss).

I graph **id ego** the adjusted annual rates of efo loss (or expansion for the lateral **id ego,** which are calculated from the coefficient of the interaction of time and treatment group **id ego** the mixed-effects models constructed separately for each region.

Only regions with significant volume change in the combined placebo and treatment analysis are shown (adjusted for multiple comparisons with the false-discovery method). Is **id ego** correspond to different regions that are shown with the **id ego** appearance in Left on the T1-weighted scan of one of the patients (chosen at random) and, in the Right, as bar plots.

The lower bar **id ego** shows the rate of change for the same areas **id ego** placebo and simvastatin groups separately. This bar plot shows that only the transverse temporal gyrus shows a significant di in the rate of change when comparing simvastatin and placebo **id ego.**

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