FMRI Group Analysis

GLM
Design matrix
Effect size subject-series
Voxel-wise group analysis
Group
effect size
statistics
Subject
groupings
1
1
1
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
Standard-space
brain atlas
subjects
Single-subject
effect size
statistics
Single-subject
effect size
statistics
Single-subject
effect size
statistics
Single-subject
effect size
statistics
subjects
Register
subjects into
a standard
space
Effect size
statistics
Statistic Image
Significant
voxels/clusters
Contrast
Thresholding

uses GLM at both lower and higher levels

typically need to infer across multiple subjects,

sometimes multiple groups and/or multiple sessions

questions of interest involve comparisons at the

highest level
Multi-Level FMRI analysis
Group 2
Hanna
Josephine
Anna Sebastian Lydia Elisabeth
Group 1
Mark Steve Karl
Will Tom Andrew
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 4
Difference?
Does the group activate on average?
A simple example
Group
Mark Steve Karl Will Tom Andrew
Does the group activate on average?
0 effect size
A simple example
Group
Mark Steve Karl Will Tom Andrew
Y
k
= X
k

k
+
k
First-level GLM
on Marks 4D FMRI
data set
Does the group activate on average?
0 effect size
A simple example
Group
Mark Steve Karl Will Tom Andrew
Y
k
= X
k

k
+
k
Marks
effect size
Does the group activate on average?
0 effect size
A simple example
Group
Mark Steve Karl Will Tom Andrew
Y
k
= X
k

k
+
k
Marks
within-subject
variance
Does the group activate on average?
0 effect size
A simple example
Group
Mark Steve Karl Will Tom Andrew
All rst-level GLMs
on 6 FMRI data set
Y
K
= X
K

K
+
K
Does the group activate on average?
What group mean are we after? Is it:
1. The group mean for those exact 6 subjects?
Fixed-Effects (FE) Analysis
2. The group mean for the population from which
these 6 subjects were drawn?
Mixed-Effects (ME) analysis
A simple example
Group
Mark Steve Karl Will Tom Andrew
Do these exact 6 subjects activate on average?
Fixed-Effects Analysis
Group
Mark Steve Karl Will Tom Andrew
0 effect size

g
=
1
6
6

k=1

k
estimate group effect size as
straight-forward mean
across lower-level estimates
Do these exact 6 subjects activate on average?
Fixed-Effects Analysis
Group
Mark Steve Karl Will Tom Andrew
0 effect size
Y
K
= X
K

K
+
K

K
= X
g

g
=
1
6
6

k=1

k
X
g
=

1
1
1
1
1
1

Group
mean
Do these exact 6 subjects activate on average?
Fixed-Effects Analysis
Group
Mark Steve Karl Will Tom Andrew
0 effect size
Y
K
= X
K

K
+
K

K
= X
g

g
=
1
6
6

k=1

k
X
g
=

1
1
1
1
1
1

Group
mean
Do these exact 6 subjects activate on average?

Consider only these 6 subjects

estimate the mean across these subject

only variance is within-subject variance

Fixed-Effects Analysis
Group
Mark Steve Karl Will Tom Andrew
Y
K
= X
K

K
+
K

K
= X
g

g
Fixed Effects Analysis:
Does the group activate on average?
What group mean are we after? Is it:
1. The group mean for those exact 6 subjects?
Fixed-Effects (FE) Analysis
2. The group mean for the population from which
these 6 subjects were drawn?
Mixed-Effects (ME) analysis
A simple example
Group
Mark Steve Karl Keith Tom Andrew
0 effect size
Does the population activate on average?
Mixed-Effects Analysis
Group
Mark Steve Karl Keith Tom Andrew
0 effect size
Y
K
= X
K

K
+
K

k
Consider the distribution over the
population from which our 6
subjects were sampled:

2
g
is the between-subject variance

g
0 effect size
Does the population activate on average?
Mixed-Effects Analysis
Group
Mark Steve Karl Keith Tom Andrew
Y
K
= X
K

K
+
K

k
Consider the distribution over the
population from which our 6
subjects were sampled:

2
g
is the between-subject variance

g
Does the population activate on average?
Mixed-Effects Analysis
Group
Mark Steve Karl Keith Tom Andrew
Y
K
= X
K

K
+
K
0 effect size

K
= X
g

g
+
g
X
g
=

1
1
1
1
1
1

Population
mean
between-
subject
variation
Does the population activate on average?
Mixed-Effects Analysis
Group
Mark Steve Karl Keith Tom Andrew
Y
K
= X
K

K
+
K
0 effect size

K
= X
g

g
+
g
X
g
=

1
1
1
1
1
1

Population
mean
between-
subject
variation
Does the population activate on average?

Consider the 6 subjects as samples from a wider population

estimate the mean across the population

between-subject variance accounts for random sampling

Mixed-Effects Analysis
Group
Mark Steve Karl Keith Tom Andrew
Y
K
= X
K

K
+
K
Mixed-Effects Analysis:

K
= X
g

g
+
g
All-in-One Approach

Could use one (huge) GLM to infer group difference

difcult to ask sub-questions in isolation

computationally demanding

need to process again when new data is acquired

Group 2
Hanna
Josephine
Anna Sebastian Lydia Elisabeth
Group 1
Mark Steve Karl
Will Tom Andrew
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 1
session 2
session 3
session 4
session 1
session 2
session 3
session 4
Difference?
Summary Statistics Approach

At each level:

Inputs are summary stats from levels

below (or FMRI data at the lowest
level)

Outputs are summary stats or

statistic maps for inference

Need to ensure formal equivalence

between different approaches!
In FEAT estimate levels one stage at a time
Group
Subject
Session
Group
difference
FLAME

Fully Bayesian framework

use non-central t-distributions:

Input COPES, VARCOPES & DOFs
from lower-level

estimate COPES, VARCOPES &

DOFs at current level

pass these up

Infer at top level

Equivalent to All-in-One approach

FMRIBs Local Analysis of Mixed Effects
Group
Subject
Session
Group
difference
COPES
VARCOPES
DOFs
Z-Stats
COPES
VARCOPES
DOFs
COPES
VARCOPES
DOFs
FLAME Inference

Default is:

FLAME1: fast approximation for all voxels (using

marginal variance MAP estimates)

Optional slower, slightly more accurate approach:

FLAME1+2:

FLAME1 for all voxels, FLAME2 for voxels close to

threshold

FLAME2: MCMC sampling technique

Choosing Inference Approach
1. Fixed Effects
Use for intermediate/top levels
2. Mixed Effects - OLS
Use at top level: quick and less accurate
3. Mixed Effects - FLAME 1
Use at top level: less quick but more accurate
4. Mixed Effects - FLAME 1+2
Use at top level: slow but even more accurate
FLAME vs. OLS

allow different within-level

variances (e.g. patients vs.
controls)

allow non-balanced designs

(e.g. containing behavioural
scores)

allow un-equal group sizes

solve the negative variance

problem
0 effect size
pat ctl
Group Subject Session
< <
...
FLAME vs. OLS

Two ways in which FLAME can give different Z-stats

compared to OLS:

higher Z due to increased efciency from using

lower-level variance heterogeneity
O
L
S
F
L
A
M
E
FLAME vs. OLS

Two ways in which FLAME can give different Z-stats

compared to OLS:

Lower Z due to higher-level variance being

constrained to be positive (i.e. solve the implied
negative variance problem)
O
L
S
F
L
A
M
E
Multiple Group Variances

can deal with multiple group

variances

separate variance will be

estimated for each variance group (be aware of
#observations for each estimate, though!)

design matrices need to be separable, i.e. EVs only

have non-zero values for a single group
0 effect size
pat ctl
valid invalid
Examples
Single Group Average

We have 8 subjects - all in one group - and want the

mean group average:
Does the group activate on average?

estimate mean

estimate std-error
(FE or ME)

test signicance of
mean > 0
>0?
0
s
u
b
j
e
c
t
effect size
Single Group Average

We have 8 subjects - all in one group - and want the

mean group average:
Does the group activate on average?

estimate mean

estimate std-error
(FE or ME)

test signicance of
mean > 0
>0?
0
s
u
b
j
e
c
t
effect size
Single Group Average
Does the group activate on average?
0
s
u
b
j
e
c
t
effect size
Single Group Average
Does the group activate on average?
0
s
u
b
j
e
c
t
effect size
Single Group Average
Does the group activate on average?
0
s
u
b
j
e
c
t
effect size
Single Group Average
Does the group activate on average?
Unpaired Two-Group Difference

We have two groups (e.g. 9 patients, 7 controls)

with different between-subject variance
Is there a signicant group difference?

estimate means

estimate std-errors
(FE or ME)

test signicance of
difference in means
>0?
0
s
u
b
j
e
c
t
effect size
Unpaired Two-Group Difference

We have two groups (e.g. 9 patients, 7 controls)

with different between-subject variance
Is there a signicant group difference?

estimate means

estimate std-errors
(FE or ME)

test signicance of
difference in means
>0?
0
s
u
b
j
e
c
t
effect size
Unpaired Two-Group Difference
Is there a signicant group difference?
0
s
u
b
j
e
c
t
effect size
Unpaired Two-Group Difference
Is there a signicant group difference?
0
s
u
b
j
e
c
t
effect size
Unpaired Two-Group Difference
Is there a signicant group difference?
0
s
u
b
j
e
c
t
effect size
Unpaired Two-Group Difference
Is there a signicant group difference?
0
s
u
b
j
e
c
t
effect size
Unpaired Two-Group Difference
Is there a signicant group difference?
Unpaired Two-Group Difference
Is there a signicant group difference?
Paired T-Test

8 subjects scanned under 2 conditions (A,B)

Is there a signicant difference between conditions?
0
s
u
b
j
e
c
t
effect size
Paired T-Test

8 subjects scanned under 2 conditions (A,B)

Is there a signicant difference between conditions?
0
s
u
b
j
e
c
t
effect size
>0?
Paired T-Test

8 subjects scanned under 2 conditions (A,B)

Is there a signicant difference between conditions?
0
s
u
b
j
e
c
t
effect size
try non-paired t-test

8 subjects scanned under 2 conditions (A,B)

Is there a signicant difference between conditions?
data
0
s
u
b
j
e
c
t
effect size
Paired T-Test

8 subjects scanned under 2 conditions (A,B)

Is there a signicant difference between conditions?
data
0
s
u
b
j
e
c
t
effect size
Paired T-Test
subject mean
accounts for large prop.
of the overall variance

8 subjects scanned under 2 conditions (A,B)

Is there a signicant difference between conditions?
de-meaned data
0
s
u
b
j
e
c
t
effect size
data
0
s
u
b
j
e
c
t
effect size
Paired T-Test
subject mean
accounts for large prop.
of the overall variance

8 subjects scanned under 2 conditions (A,B)

Is there a signicant difference between conditions?
de-meaned data
0
s
u
b
j
e
c
t
effect size
data
0
s
u
b
j
e
c
t
effect size
Paired T-Test
>0?
subject mean
accounts for large prop.
of the overall variance
s
u
b
j
e
c
t
effect size 00
Paired T-Test
Is there a signicant difference between conditions?
s
u
b
j
e
c
t
effect size 00
Paired T-Test
Is there a signicant difference between conditions?
s
u
b
j
e
c
t
effect size 00
Paired T-Test
Is there a signicant difference between conditions?
s
u
b
j
e
c
t
effect size 00
Paired T-Test
Is there a signicant difference between conditions?
s
u
b
j
e
c
t
effect size 00
Paired T-Test
Is there a signicant difference between conditions?
s
u
b
j
e
c
t
effect size 00
Paired T-Test
Is there a signicant difference between conditions?
Paired T-Test
Is there a signicant difference between conditions?
EV1models the A-B
paired difference; EVs
2-9 are confounds
which model out each
subjects mean
Paired T-Test
Is there a signicant difference between conditions?
Multi-Session & Multi-Subject

5 subjects each have three sessions.

Does the group activate on average?

Use three levels: in the second level we

model the within-subject repeated measure
Multi-Session & Multi-Subject

5 subjects each have three sessions.

Does the group activate on average?

Use three levels: in the third level we model

the between-subjects variance
Multi-Session & Multi-Subject

5 subjects each have three sessions.

Does the group activate on average?

Use three levels:

in the second level we model the within subject

repeated measure typically using xed effects(!)
as #sessions are small

in the third level we model the between subjects

variance using xed or mixed effects
Reducing variance
Does the group activate on average?
mean effect size small
relative to std error
mean effect size large
relative to std error
0
s
u
b
j
e
c
t
effect size
>0?
0
s
u
b
j
e
c
t
effect size
>0?
mean effect size large
relative to std error
Reducing variance
Does the group activate on average?
mean effect size large
relative to std error
0
s
u
b
j
e
c
t
effect size
>0?
0
s
u
b
j
e
c
t
effect size
>0?

We have 7 subjects - all in one group. We also have

additional measurements (e.g. age; disability score;
behavioural measures like reaction times):
Does the group activate on average?

use covariates to
explain variation

estimate mean

estimate std-error
(FE or ME)
0
s
u
b
j
e
c
t
effect size
Single Group Average & Covariates

We have 7 subjects - all in one group. We also have

additional measurements (e.g. age; disability score;
behavioural measures like reaction times):
0
s
u
b
j
e
c
t
effect size
Single Group Average & Covariates
fast RT slow

We have 7 subjects - all in one group. We also have

additional measurements (e.g. age; disability score;
behavioural measures like reaction times):
Does the group activate on average?
0
s
u
b
j
e
c
t
effect size
Single Group Average & Covariates
fast RT slow

We have 7 subjects - all in one group. We also have

additional measurements (e.g. age; disability score;
behavioural measures like reaction times):
Does the group activate on average?

use covariates to
explain variation

estimate mean

estimate std-error
(FE or ME)
0
s
u
b
j
e
c
t
effect size
Single Group Average & Covariates
fast RT slow

We have 7 subjects - all in one group. We also have

additional measurements (e.g. age; disability score;
behavioural measures like reaction times):
Does the group activate on average?

use covariates to
explain variation

estimate mean

estimate std-error
(FE or ME)
0
s
u
b
j
e
c
t
effect size
Single Group Average & Covariates
fast RT slow

We have 7 subjects - all in one group. We also have

additional measurements (e.g. age; disability score;
behavioural measures like reaction times):
Does the group activate on average?

use covariates to
explain variation

estimate mean

estimate std-error
(FE or ME)
0
s
u
b
j
e
c
t
effect size
Single Group Average & Covariates
fast RT slow

We have 7 subjects - all in one group. We also have

additional measurements (e.g. age; disability score;
behavioural measures like reaction times):
Does the group activate on average?

use covariates to
explain variation

estimate mean

estimate std-error
(FE or ME)
0
s
u
b
j
e
c
t
effect size
Single Group Average & Covariates
fast RT slow

We have 7 subjects - all in one group. We also have

additional measurements (e.g. age; disability score;
behavioural measures like reaction times):
Does the group activate on average?

use covariates to
explain variation

estimate mean

estimate std-error
(FE or ME)
0
s
u
b
j
e
c
t
effect size
Single Group Average & Covariates
fast RT slow
Does the group activate on average?

use covariates to explain variation

need to de-mean additional covariates!

Single Group Average & Covariates

Run FEAT on raw FMRI data to get rst-level .feat

directories, each one with several (consistent) COPEs

low-res copeN/varcopeN .feat/stats

when higher-level FEAT is run, highres copeN/

varcopeN .feat/reg_standard
FEAT Group Analysis
FEAT Group Analysis

Run second-level FEAT to get one .gfeat directory

Inputs can be lower-

level .feat dirs or
lower-level COPEs

the second-level GLM analysis is run separately

for each rst-level COPE

each lower-level COPE generates its own .feat

directory inside the .gfeat dir
Thats all folks
Appendix:
Group F-tests
Group F-tests

3 groups of subjects
Group F-tests

3 groups of subjects
Is any of the groups activating on average?
ANOVA: 1-factor 4-levels
ANOVA: 1-factor 4-levels

8 subjects, 1 factor at 4 levels

ANOVA: 1-factor 4-levels

8 subjects, 1 factor at 4 levels

Is there any effect?
ANOVA: 1-factor 4-levels

8 subjects, 1 factor at 4 levels

Is there any effect?

EV1 ts cond. D, EV2 ts cond A relative to D etc.

ANOVA: 1-factor 4-levels

8 subjects, 1 factor at 4 levels

Is there any effect?

EV1 ts cond. D, EV2 ts cond A relative to D etc.

F-test shows any difference between levels

ANOVA: 2-factor 2-levels
ANOVA: 2-factor 2-levels

8 subjects, 2 factor at 2 levels. FE Anova: 3 F-tests give

standard results for factor A, B and interaction
ANOVA: 2-factor 2-levels

8 subjects, 2 factor at 2 levels. FE Anova: 3 F-tests give

standard results for factor A, B and interaction

If both factors are random effects then Fa=fstat1/fstat3,

Fb=fstat2/fstat3ME
ANOVA: 2-factor 2-levels

8 subjects, 2 factor at 2 levels. FE Anova: 3 F-tests give

standard results for factor A, B and interaction

If both factors are random effects then Fa=fstat1/fstat3,

Fb=fstat2/fstat3ME

ME: if xed fact. is A, Fa=fstat1/fstat3

ANOVA: 3-factor 2-levels
ANOVA: 3-factor 2-levels

16 subjects, 3 factor at 2 levels.

ANOVA: 3-factor 2-levels

16 subjects, 3 factor at 2 levels.

Fixed-Effects ANOVA:
ANOVA: 3-factor 2-levels

16 subjects, 3 factor at 2 levels.

Fixed-Effects ANOVA:

For random/mixed effects need different Fs.

Understanding FEAT dirs

First-level analysis:
Understanding FEAT dirs

Second-level analysis:
Thats all folks