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    FMRI Group Analysis

    GLM

    Design matrix

    Effect size subject-series

    Voxel-wise group analysis

    Group

    effect size

    statistics

    Subject

    groupings

    1

    1

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    1

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    1

    0

    0

    0

    0

    0

    0

    0

    0

    0

    0

    0

    0

    1

    1

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    1

    Standard-space

    brain atlas

    subjects

    Single-subject

    effect size

    statistics

    Single-subject

    effect sizestatistics

    Single-subject

    effect size

    statistics

    Single-subjecteffect size

    statistics

    subjects

    Register

    subjects into

    a standard

    space

    Effect size

    statistics

    Statistic ImageSignificant

    voxels/clustersContrast

    Thresholding

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    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

    HannaJosephine 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?

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    Does the group activate on average?

    A simple example

    Group

    Mark Steve Karl Will Tom Andrew

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    Does the group activate on average?

    0 effect size

    A simple example

    Group

    Mark Steve Karl Will Tom Andrew

    Yk = Xk k + k

    First-level GLMon Marks 4D FMRI

    data set

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    Does the group activate on average?

    0 effect size

    A simple example

    Group

    Mark Steve Karl Will Tom Andrew

    Yk = Xk k + k

    Marks

    within-subject

    variance

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    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

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    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 asstraight-forward meanacross lower-level estimates

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    Do these exact 6 subjects activate on average?

    Fixed-Effects Analysis

    Group

    Mark Steve Karl Will Tom Andrew

    0 effect size

    YK= XKK+ K

    K = Xgg

    g =1

    6

    6

    k=1

    kXg =

    1

    1

    1

    1

    1

    1

    Group

    mean

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    Do these exact 6 subjects activate on average?

    Fixed-Effects Analysis

    Group

    Mark Steve Karl Will Tom Andrew

    0 effect size

    K = Xgg

    Xg =

    1

    1

    1

    1

    1

    1

    Group

    mean

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    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

    YK= XKK+ KK = Xgg

    Fixed Effects Analysis:

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    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

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    0 effect size

    Does the population activate on average?

    Mixed-Effects Analysis

    Group

    Mark Steve Karl Keith Tom Andrew

    0 effect size

    YK= XK K+ K

    gk

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

    2

    g is the between-subject variance

    g

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    0 effect size

    Does the population activate on average?

    Mixed-Effects Analysis

    Group

    Mark Steve Karl Keith Tom Andrew

    YK= XK K+ K

    gk

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

    2

    g is the between-subject variance

    g

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    Does the population activate on average?

    Mixed-Effects Analysis

    Group

    Mark Steve Karl Keith Tom Andrew

    YK= XKK+ K

    0 effect sizeg

    k

    gK= Xgg + g

    Xg =

    1

    1

    1

    1

    1

    1

    Population

    mean

    between-subject

    variation

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    Does the population activate on average?

    Mixed-Effects Analysis

    Group

    Mark Steve Karl Keith Tom Andrew

    0 effect sizeg

    k

    gK= Xgg + g

    Xg =

    1

    1

    1

    1

    1

    1

    Population

    mean

    between-subject

    variation

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    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

    YK= XKK+ K

    Mixed-Effects Analysis:

    K= Xgg + g

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    All-in-One Approach

    Could use one (huge) GLM to infer group difference

    difficult to ask sub-questions in isolation

    computationally demanding

    need to process again when new data is acquired

    Group 2

    HannaJosephine 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?

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    Summary Statistics Approach

    At each level:

    Inputs are summary stats from levels

    below (or FMRI data at the lowestlevel)

    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

    Groupdifference

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    FLAME

    Fully Bayesian framework

    use non-central t-distributions:

    Input COPES, VARCOPES & DOFsfrom 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

    Groupdifference

    COPES

    VARCOPESDOFs

    Z-Stats

    COPES

    VARCOPESDOFs

    COPESVARCOPES

    DOFs

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    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

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    Choosing Inference Approach

    1. Fixed Effects

    Use for intermediate/top levels

    2. Mixed Effects - OLSUse 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

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    FLAME vs. OLS

    allow different within-levelvariances (e.g. patients vs.

    controls)

    allow non-balanced designs

    (e.g. containing behaviouralscores)

    allow un-equal group sizes

    solve the negative varianceproblem

    0 effect size

    pat ctl

    GroupSubjectSession

    < 0

    >0?

    0

    subject

    effect size

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    Single Group Average

    We have 8 subjects - all in one group - and want themean group average:

    Does the group activate on average?

    estimate mean

    estimate std-error

    (FE or ME)

    test significance of

    mean > 0

    >0?

    0

    subject

    effect size

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    Single Group Average

    Does the group activate on average?

    0

    subject

    effect size

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    Single Group Average

    Does the group activate on average?

    0

    subject

    effect size

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    Single Group Average

    Does the group activate on average?

    0

    subject

    effect size

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    Single Group Average

    Does the group activate on average?

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    Unpaired Two-Group Difference

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

    with different between-subject variance

    Is there a significant group difference?

    estimate means

    estimate std-errors(FE or ME)

    test significance of

    difference in means

    >0?

    0

    subject

    effect size

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    Unpaired Two-Group Difference

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

    with different between-subject variance

    Is there a significant group difference?

    estimate means

    estimate std-errors(FE or ME)

    test significance of

    difference in means

    >0?

    0

    subject

    effect size

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    Unpaired Two-Group Difference

    Is there a significant group difference?

    0

    subject

    effect size

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    Unpaired Two-Group Difference

    Is there a significant group difference?

    0

    subject

    effect size

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    Unpaired Two-Group Difference

    Is there a significant group difference?

    0

    subject

    effect size

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    Unpaired Two-Group Difference

    Is there a significant group difference?

    0

    subject

    effect size

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    Unpaired Two-Group Difference

    Is there a significant group difference?

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    Unpaired Two-Group Difference

    Is there a significant group difference?

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    Paired T-Test

    8 subjects scanned under 2 conditions (A,B)

    Is there a significant difference between conditions?

    0

    subject

    effect size

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    Paired T-Test

    8 subjects scanned under 2 conditions (A,B)

    Is there a significant difference between conditions?

    0

    subject

    effect size

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    >0?

    Paired T-Test

    8 subjects scanned under 2 conditions (A,B)

    Is there a significant difference between conditions?

    0

    subject

    effect size

    try non-paired t-test

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    8 subjects scanned under 2 conditions (A,B)

    Is there a significant difference between conditions?

    data

    0

    subject

    effect size

    Paired T-Test

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    8 subjects scanned under 2 conditions (A,B)

    Is there a significant difference between conditions?

    data

    0

    subject

    effect size

    Paired T-Test

    subject meanaccounts for large prop.

    of the overall variance

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    8 subjects scanned under 2 conditions (A,B)

    Is there a significant difference between conditions?

    de-meaned data

    0

    subject

    effect size

    data

    0

    subject

    effect size

    Paired T-Test

    subject meanaccounts for large prop.

    of the overall variance

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    8 subjects scanned under 2 conditions (A,B)

    Is there a significant difference between conditions?

    de-meaned data

    0

    subject

    effect size

    data

    0

    subject

    effect size

    Paired T-Test

    >0?subject mean

    accounts for large prop.

    of the overall variance

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    subject

    effect size00

    Paired T-Test

    Is there a significant difference between conditions?

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    subject

    effect size00

    Paired T-Test

    Is there a significant difference between conditions?

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    subject

    effect size00

    Paired T-Test

    Is there a significant difference between conditions?

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    subject

    effect size00

    Paired T-Test

    Is there a significant difference between conditions?

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    subject

    effect size00

    Paired T-Test

    Is there a significant difference between conditions?

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    subject

    effect size00

    Paired T-Test

    Is there a significant difference between conditions?

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    Paired T-Test

    Is there a significant difference between conditions?

    EV1models the A-B

    paired difference; EVs2-9 are confounds

    which model out eachsubjects mean

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    Paired T-Test

    Is there a significant difference between conditions?

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    Multi-Session & Multi-Subject

    5 subjects each have three sessions.

    Does the group activate on average?

    Use three levels: in the second levelwe

    model the within-subject repeated measure

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    Multi-Session & Multi-Subject

    5 subjects each have three sessions.

    Does the group activate on average?

    Use three levels: in the third levelwe model

    the between-subjects variance

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    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 fixed effects(!)

    as #sessions are small

    in the third level we model the between subjects

    variance using fixed or mixed effects

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    Reducing variance

    Does the group activate on average?

    mean effect size small

    relative to std errormean effect size large

    relative to std error

    0

    s

    ubject

    effect size

    >0?

    0

    s

    ubject

    effect size

    >0?

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    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

    ubject

    effect size

    >0?

    0

    s

    ubject

    effect size

    >0?

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    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

    subject

    effect size

    Single Group Average & Covariates

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

    additional measurements (e.g. age; disability score;

    behavioural measures like reaction times):

    0

    subject

    effect size

    Single Group Average & Covariates

    fastRTslow

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    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

    subject

    effect size

    Single Group Average & Covariates

    fastRTslow

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    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

    subject

    effect size

    Single Group Average & Covariates

    fastRTslow

    S l G A C

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    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

    subject

    effect size

    Single Group Average & Covariates

    fastRTslow

    S l G A & C

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    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

    subject

    effect size

    Single Group Average & Covariates

    fastRTslow

    S l G A & C

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    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

    subject

    effect size

    Single Group Average & Covariates

    fastRTslow

    Si l G A & C i

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    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 toexplain variation

    estimate mean

    estimate std-error(FE or ME)

    0

    subject

    effect size

    Single Group Average & Covariates

    fastRTslow

    Si l G A & C i

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    Does the group activate on average?

    use covariates to explain variation

    need to de-mean additional covariates!

    Single Group Average & Covariates

    FEAT G A l i

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    Run FEAT on raw FMRI data to get first-level .featdirectories, 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 G A l i

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    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 first-level COPE

    each lower-level COPE generates its own .featdirectory inside the .gfeat dir

    Th t ll f lk

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    Thats all folks

    A di

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    Appendix:

    G F t t

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    Group F-tests

    Gro F tests

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    Group F-tests

    3 groups of subjects

    Group F tests

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    Group F-tests

    3 groups of subjects

    Is any of the groups activating on average?

    ANOVA: 1 factor 4 levels

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    ANOVA: 1-factor 4-levels

    ANOVA: 1 factor 4 levels

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    ANOVA: 1-factor 4-levels

    8 subjects, 1 factor at 4 levels

    ANOVA: 1 factor 4 levels

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    ANOVA: 1-factor 4-levels

    8 subjects, 1 factor at 4 levels

    Is there any effect?

    ANOVA: 1 factor 4 levels

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    ANOVA: 1-factor 4-levels

    8 subjects, 1 factor at 4 levels

    Is there any effect?

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

    ANOVA: 1 factor 4 levels

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    ANOVA: 1-factor 4-levels

    8 subjects, 1 factor at 4 levels

    Is there any effect?

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

    F-test shows any difference between levels

    ANOVA: 2 factor 2 levels

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    ANOVA: 2-factor 2-levels

    ANOVA: 2 factor 2 levels

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    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

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    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

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    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 fixed fact. is A, Fa=fstat1/fstat3

    ANOVA: 3 factor 2 levels

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    ANOVA: 3-factor 2-levels

    ANOVA: 3-factor 2-levels

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    ANOVA: 3-factor 2-levels

    16 subjects, 3 factor at 2 levels.

    ANOVA: 3-factor 2-levels

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    ANOVA: 3-factor 2-levels

    16 subjects, 3 factor at 2 levels.

    Fixed-Effects ANOVA:

    ANOVA: 3-factor 2-levels

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    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

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    Understanding FEAT dirs

    First-level analysis:

    Understanding FEAT dirs

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    Understanding FEAT dirs

    Second-level analysis:

    Thats all folks

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    That s all folks