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Hi Julian,

Am 11.03.2022 um 11:06 schrieb Julian Macoveanu 
<julian.macove...@gmail.com<mailto:julian.macove...@gmail.com>>:

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Dear Kersten,

Thank you for your answer, I have some follow-up questions to the
first two points before I can move on.

1) Regarding family-relation, since three random effects may not work,
did you mean that a simpler model with 2 random effects (intercept and
family ID, thus leaving out slope which I assume is time from
baseline) would work? While forgetting family ID is an option, it
would be a model that may attract criticism.

I generally like the idea of proceeding from simple to more complex models, 
assuming / checking that results do not fundamentally change when models get a 
bit more complex. In your case, I initially considered looking at a sequence 
like 1. random intercept (subject), 2. random intercept (subject) and random 
slope (time), 3. random intercept (subject), slope (time), and another, 
higher-level random intercept (family). But you are right, the two random 
intercepts (subject ID and family ID) model would also be worth checking.

In my previous response I was a bit skeptical if adding a higher-level random 
effect (ie. family ID) would work. This was because I remembered other software 
(e.g. R’s lmer package) that require a specialized syntax for nested vs. 
crossed random effects, and I did not immediately see a way how to implement in 
FreeSurfer’s lme toolbox.

However, I now think that in the end it boils down to simply checking the 
covariance matrix of the random effects (that should be stats.Dhat). If the 
program is able to construct this matrix so that it correctly captures the 
dependencies between the observations, then I see no reason not to proceed with 
a higher-level random effect. The disclaimer is that I have not tried this 
before, and that the above just reflects my current understanding.

2) Regarding multiple comparison correction, I understand how to
perform the procedure you suggested (second option) to simply
calculate the corrected p threshold using pcor = -log10(pth) and then
use pcor as threshold for the sig.mgh. However after running FDR2:
[detvtx,sided_pval,pth] =
lme_mass_FDR2(F_lhstats.pval,F_lhstats.sgn,lhcortex,0.05,0);

While detvtx is not empty (a few vertexes survived) and the pth value
is calculated to 1.00000e-30 and therefore pcor to 30. This doesn’t
seem right. What is also strange is that I saw a few times a more
reasonable pth in the range of e-5 using the exact same data and
procedure. I cannot replicate this in the same analysis in R2021, now
I only get the e-30 (I only tried left cortex thickness so far).

It’s a bit hard to tell if something went wrong without looking at the data, 
but here are two suggestions: one would be to look at the beta weights for that 
contrast, which should show a somewhat smooth and somewhat anatomically 
plausible pattern. The other would be to look at other contrasts such as the 
simple effect of time, or the group differences at baseline, and also check 
their spatial pattern and their magnitude. Both might help to judge whether or 
not something went wrong with the analysis.

Also, you mentioned before that you had issues (and possibly different 
results?) with Matlab’s R2019 release, in particular with its parallel 
processing tools; if you have a way to share the error messages, that could be 
another way to proceed.

Best regards,

Kersten


Best,
Julian

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Kersten Diers
Image Analysis Group (AG Reuter)
German Center for Neurodegenerative Diseases (DZNE)
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