S

tat
istica
l Methodsfor Analys
isof
St
ruc tu
ral Magnet
ic Resonance
Imagingin Pat
ientswith Multip
le
Sc
lero
sis

by

E
lizabe
th M
.Sw
eeney

Ad
isse
rta
tionsubm
ittedto TheJohn
s Hopk
ins Un
ive
rsi
ty

incon
form
ity w
iththerequ
iremen
tsfo
rthedeg
reeo
f

Doc
toro
f Ph
ilo
sophy

Ba
ltimo
re, Ma
ryland

F
ebrua
ry22
,2016

Copy
righ
t2016by E
lizabe
th M
.Sw
eeney

A
llr
igh
tsre
serv
ed
Ab
strac
t

Mu
lt
ipl
esc
ler
osi
s(MS
)isaninfl
amm
ato
ryd
ise
aseo
fth
ebr
ainandsp
ina
lco
rd

ch
ara
cte
riz
edb
ydem
yel
ina
tin
gle
sion
s.S
tru
ctu
ralm
agn
eti
cre
son
anc
eim
ag-
in
g(sMR
I)i
sa m
edi
calim
agin
gte
chn
iqu
eth
ati
ssen
sit
ivet
oth
esel
esi
ons
.

Qu
ant
it
ivean
aly
seso
f MR
I,su
cha
sth
enumb
erandv
olum
eof MSl
esi
ons
,ar
e

e
ssen
tia
lfo
rdi
agn
osin
gth
edi
sea
seand m
oni
tor
ingi
tsp
rog
res
sion
.Inadd
it
ion
,

th
efo
rma
tiono
fth
esel
esi
ons
,ac
omp
lexp
roc
essin
volv
inginfl
amm
ati
on,t
is
-

su
edam
age
,andr
epa
ir
,isa
lsoimpo
rtan
tfo
rdi
agn
osin
gand m
oni
tor
ingth
e

d
ise
ase
. Wh
il
esMR
Iiss
ens
it
ivet
ole
siona
ctiv
ity
,th
erei
ssu
rpr
is
ing
lypoo
r

a
sso
cia
tionb
etw
eenc
lin
ica
lfind
ing
sandth
erad
iol
ogi
calex
ten
tofin
volv
emen
t

on MR
Ius
ingt
rad
it
ion
alv
olum
etr
icm
easu
res
. Th
isph
enom
enoni
sre
fer
redt
o

a
sth
ecl
ini
co-
rad
iol
ogi
calp
arad
ox.

Th
ewo
rkinth
isth
esi
sisaneff
ortt
obr
idg
eth
isc
lin
ico
-rad
iol
ogi
calp
arad
ox

andl
inkth
elon
gitud
ina
lfind
ing
sons
tru
ctu
ral MR
Iinp
ati
ent
swi
th MSt
o

d
ise
ase
-mod
ify
ingt
rea
tmen
tando
the
rcl
ini
calin
form
ati
on. Ch
apt
er2o
fth
e

th
esi
sisanin
trodu
cti
ont
osMR
Ida
ta. Ch
apt
er3and4o
fth
eth
esi
sde
al

w
ith MSl
esi
ons
egm
ent
ati
onu
sin
g mu
lt
i-
sequ
enc
est
ruc
tur
al MR
I.Ch
apt
er5

i
sacu
lmin
ati
ono
fth
isw
ork
. Th
ele
sions
egm
ent
ati
ont
echn
iqu
eexp
lor
edin

Ch
apt
er3and4i
sex
tend
edt
obu
ildap
ipe
lin
etoex
tra
ctl
ong
itud
ina
lin
ten
sit
y

in
form
ati
on,o
rle
sionp
rofi
les
,fr
oml
esi
onsin mu
lt
i-
sequ
enc
esMR
I. A PCA

r
egr
ess
ion m
ode
listh
enin
trodu
cedt
ore
lat
eth
elon
gitud
ina
lle
sionp
rofi
lest
o

d
ise
ase
-mod
ify
ingt
rea
tmen
tando
the
rcl
ini
calin
form
ati
oninana
ttemp
tto

l
inkth
ein
form
ati
onf
romsMR
Itoc
lin
ica
lin
form
ati
on. Inadd
res
sin
gth
ese
c
lin
ica
lis
sue
,th
isth
esi
sal
soc
ont
ain
sanumb
ero
fbi
ost
ati
sti
calc
ont
ribu
tion
s:

i
i
th
ede
signandan
aly
siso
fexp
ertr
ate
rtr
ial
s,d
atar
edu
cti
ont
echn
iqu
esf
orh
igh
d
imen
sion
alandl
ong
itud
ina
lda
tath
rou
ghp
rin
cip
alc
ompon
entan
aly
sis(PCA
)

r
egr
ess
ion m
ode
ls
,andth
ecomp
ari
sono
fsup
erv
isedl
earn
inga
lgo
rithm
s.

i
ii
The
sis Comm
ittee

P
rima
ry Reade
rs

P
ete
rCa
labres
i
D
ire
ctor
,D ivi
sionofN eu
roimmuno
logy
,
P
rofe
ssorofN eur
ology
,
J
ohnsH opkinsSchoolofM ed
ic
ine

M
ich
el
leC a
rlson
A
ssoc
iatePro
fes
sorofMent
alHea
lth
,
J
ohnsH opk
insBloomb
ergSch
oolofPub
li
cHe
alth

C
ipr
ianCra
inic
e anu(Adviso
r)
Pro
fes
soro fBios
tati
sti
cs,
JohnsH opkin
sB loombergS
choo
lofPub
li
cHe
alth

Ru
sse
llShinoha
ra(Co-advi
sor)
As
sis
tantPro
fesso
ro fBiost
ati
sti
cs,
Pe
relmanSchoolofM ed
icine
,
Un
ivers
ityo
fP ennsy
lvania

A
lte
rna
te Reade
rs

B
rianC
aff o
Pro
fess
oro fBi
ost
ati
sti
cs,
JohnsH opk
insBloombergS
choo
lofPub
li
cHe
alth

A
ldenG
r o
ss
A
s s
ist
antPr
ofe
sso
rofEp
idemi
ology
,
JohnsHopk
insBl
oombe
rgSchoo
lofPub
li
cHe
alth

iv
Acknow
ledgmen
ts

Iw
ouldfi
rstl
iket
oth
ankth
ememb
erso
fmyth
esi
scomm
itt
ee,D
r. M
ich
el
le
C
arl
sonandD
r.P
ete
rCa
lab
res
i,a
swe
lla
smyth
esi
scomm
itt
eea
lte
rna
tes
,Dr
.

B
rianC
affoand D
r.A
lden G
ros
s. Th
anky
ouf
ort
akin
gth
etim
etor
ead m
y

th
esi
sandf
ory
ours
erv
iceon m
ycomm
itt
ee. Th
anky
oua
lsot
oth
ewond
erfu
l
c
oau
tho
rsf
romth
isth
esi
s(w
ith
out wh
omth
isw
ork w
ouldn
otex
ist
!)
: m
y

adv
iso
rDr
.Cip
rianC
rain
ice
anu
,myc
o-adv
iso
rDr
. Ru
sse
ll(T
aki
)Sh
inoh
ara
,

D
r. D
ani
elR
eich
,Dr
. An
iEl
oyan
,Dr
. D
zun
gPh
am,D
r. N
avidSh
iee
,Dr
.

F
arr
ah M
ate
en,D
r.P
ete
rCa
lab
res
i,D
r.J
oshu
aVo
gel
ste
in,D
r. Avn
iChud
gar
,
B
lak
eDew
ey,M
atth
ewS
chind
ler
,andJ
enn
ife
rCu
zzo
cre
o.A
lsoth
aty
out
oth
e

Ep
idem
iol
ogyandB
ios
tat
ist
icso
fAg
ingT
rain
ingP
rog
ramth
atsuppo
rted m
y

th
esi
swo
rkand m
ymen
tor
sfr
omth
isp
rog
ramD
r.K
arenB
and
een
-Ro
cheand

D
r.M
ich
el
leC
arl
son
.

Th
anky
out
omyadv
iso
rCip
rianC
rain
ice
anuf
oren
cou
rag
ingand m
otiv
at-
in
gmet
oach
iev
emo
reth
anIev
erth
ough
tpo
ssib
lef
orm
yse
lf
. W
ork
ingw
ith

y
ouf
orth
ela
stfiv
eye
arsh
asb
eenat
rulyam
azin
gexp
eri
enc
e.Is
ti
llr
ememb
er

th
eda
ywh
eny
ousu
gge
stedth
atIsh
ouldr
eapp
lyt
oth
ePhDp
rog
ram
.Il
eft

y
ouroffi
cec
omp
let
elyo
verwh
elm
edandth
ough
titw
ouldb
eimpo
ssib
lef
orm
e
t
oea
rnaPhD
,bu
tyougu
idedm
eth
rou
ghth
een
tir
epr
oce
ss. Th
eca
rin
g,c
om-

p
ass
ion
,andund
ers
tand
ingth
aty
oug
avem
edu
rin
gth
eha
rde
stt
ime
softh
e

PhDw
ereabo
vea
llwh
atm
adeth
ediff
eren
ceth
ist
ime
. Th
anky
ouf
ora
lwa
ys

b
eli
evin
gin m
e,in
ves
tin
gso mu
chin m
e,andd
isc
ove
rin
gandnu
rtu
rin
gth
e

po
ten
tia
lth
atIc
ouldn
ots
eein m
yse
lf
. Wh
aty
ouh
aved
oneh
ast
rulych
ang
ed

m
yli
fe.

v
 Th
anky
out
omyc
o-adv
iso
rTak
iSh
inoh
araf
ory
ourp
ati
enc
eandb
ein
ga
c
ons
tan
tsou
rceo
fin
spi
rat
ionandsuppo
rt. Th
anky
ouf
orb
ein
gth
ereev
ery

t
imeIn
eedy
ou,wh
eth
eri
tist
ota
lkabou
tth
efu
tur
e,t
ohe
lpwh
enIg
etin
to

ar
ese
archru
t,o
rju
stt
ogr
abc
offe
eandc
atchup
. Th
anky
ouf
orsh
apin
gmy
r
ese
archph
ilo
soph
y,f
orsh
arin
gyou
rre
sea
rchid
easw
ithm
e,andf
orh
elp
ingm
e

d
eve
lop m
yown
. On
eda
ywew
il
lfin
isha
llo
fth
eit
emsonou
rre
sea
rcht
o-d
o
l
istandth
enw
ewi
lltu
rna
roundand m
akem
ore
! Th
anky
ouf
orh
ost
ingm
eso

m
anyt
ime
satP
enn
. Th
eset
rip
swe
rea
lwa
yswh
ereId
id m
ybe
stw
ork(
and

a
teth
ebe
stf
ood
!)
. W
ork
ingw
ithy
oui
sso mu
chfunandIams
oth
ank
fulf
or

y
ourm
ent
orsh
ipandf
riend
ship
.

Th
anky
out
oDann
yRe
ichf
ori
gni
tin
gmyp
ass
ionf
orim
agin
gre
sea
rchand

c
ont
inu
ingt
odos
ofo
rth
ela
stfiv
eye
ars
. W
ork
ingw
ithy
oui
sex
tra
ord
ina
ry

andev
eryt
imeIg
ototh
eNIHt
ovi
sity
ourg
roupIl
eav
enew
lyin
spi
red
.It

i
sap
riv
il
eget
owo
rkw
ithy
ouandIth
anky
ouf
ory
ouram
azin
gco
llabo
rat
ion

and m
ent
orsh
ip

Th
anky
out
oth
ewond
erfu
lgr
oupo
ffr
iend
sth
atI m
adewh
il
eatH
opk
ins
.

Y
ouh
aveb
eenac
ont
inu
ouss
our
ceo
ffun
,suppo
rt,anden
cou
rag
emen
t. A

sp
eci
alth
anky
out
oth
efr
iend
sIa
lsoh
adth
epl
easu
ret
owo
rkw
ithdu
rin
gmy

PhD
:Mandy M
eji
a,G
ina
-Ma
riaP
omann
,andJ
ean
-Ph
il
ipp
eFo
rtin
. M
andy
,

th
anky
ouf
orb
ein
gmyc
onf
eren
cech
ica
,fo
rtu
rnin
gmein
toac
offe
esn
ob,and

f
orth
elon
g,sw
eat
ywa
lksin
tos
choo
lla
stsumm
er. Th
anky
ouf
ory
ouram
azin
g
f
riend
shipandf
ora
lwa
ysb
ein
gsosuppo
rtiv
eandpo
sit
ive
.Gin
a,m
eet
ingy
ou

m
adeth
iswh
oleg
radu
ates
choo
lth
ingw
orthth
etr
oub
le
. Th
anky
ouf
orm
akin
g

r
ese
archr
idi
cul
ous
lyfun(
andI m
eanr
idi
cul
ous
lyfun
..
.ev
enwh
eni
tpr
obab
ly

sh
ouldn
oth
aveb
een
).J
ean
-Ph
il
ipp
e,th
anky
ouf
orb
ein
gac
odin
gan
ima
lwi
th

v
i
m
e.Y
ou,w
ood
enh
and
,andth
eboo
sre
allyund
ers
tandwh
oIam
.Iti
sar
are
th
ingt
ofindinth
isl
ife
,esp
eci
allyf
orp
eop
lea
sst
ran
gea
sth
efiv
eofu
s. Th
ank

y
ouf
ory
ourf
riend
shipandf
orsh
arin
gyou
rtim
einB
alt
imo
rew
ith m
e.Iw
il
l

m
issy
ou.
Av
erysp
eci
alth
anky
out
omyf
riendandc
oll
eagu
eJohn Mu
sch
el
li
,wh
oI

h
avew
ork
edc
los
elyw
ithonev
ery
thin
g.Il
ook
edf
orw
ardt
ocom
ingin
tos
choo
l
ev
eryd
ays
oth
atIc
ouldh
angou
t,e
atm
agi
cbe
ans
,andd
ore
sea
rchw
ithy
ou.

Th
anky
ouf
ora
lwa
ysb
ein
gth
eret
ota
lkabou
tth
e“l
itt
led
eta
il
s”th
atend

upb
ein
gth
emo
stimpo
rtan
tpa
rtso
fth
ewo
rk. Th
anky
ouf
orn
otk
il
lin
gme

wh
il
ewew
erew
ork
ingonth
eENARtu
tor
ial(
Ikn
owIa
lmo
stk
il
ledy
ou.
..
).

Th
anky
ouf
ort
el
lin
gmet
oshu
tupwh
enIw
aswh
inin
gandc
all
ingm
etoc
ome

in
tos
choo
landw
orkonth
eda
ysIw
ant
edt
odoan
yth
ingbu
t.Y
ouh
elp
ed m
e

th
rou
ghth
eha
rde
standu
gli
estp
art
softh
ePhDandf
orth
isIw
il
lalw
aysb
e

th
ank
ful
.Iw
il
lmi
ssy
outh
emo
sto
fal
lth
eth
ing
satH
opk
ins
.

M
ostimpo
rtan
tly
,th
anky
out
omyf
ami
lyf
orth
eirun
cond
it
ion
all
oveand

suppo
rt. Ad
am,Ikn
owy
oua
ren
otanoffi
cia
lpa
rto
fmyf
ami
ly
,bu
tIh
ave

c
ons
ide
redy
ouab
roth
erf
ors
omet
imen
ow.M
om,D
ad,K
el
ly
,andAd
amth
is

th
esi
sisd
edi
cat
edt
oyou
. Th
anky
ouf
orund
ers
tand
ingh
owimpo
rtan
tth
isi
s

t
omeanda
llo
fth
eth
ing
sth
atIh
adt
ogiv
eupt
omak
eth
ispo
ssib
le
. Ad
am,

th
anky
ouf
ors
ti
lll
ovin
gmea
fte
rTHATt
ript
oBa
lt
imo
re. Th
anky
oua
llf
or

d
ropp
ingev
ery
thin
gea
cht
imeth
atIn
eed
edy
ou.Ic
ouldn
oth
aved
oneth
is
w
ith
outan
yofy
ou.Y
oua
reth
efou
rre
ason
sfo
rmysu
cce
ssandIl
ovey
ou.

v
ii
T
ableo
f Con
ten
ts

T
ableo
f Con
ten
ts v
i

L
isto
fTab
les x

L
isto
fFigu
res x
ii

1 In
troduc
tion 1

2 Atu
tor
ialfo
r mu
lti
-sequencec
lin
ica
lst
ruc
tura
lbra
in MR
I 5

2
.1 In
trodu
cti
on............................. 5

2
.1.
1 Wh
ata
reth
eseim
age
s? .................. 1
0

2
.1.
2 H
owc
anw
ehand
lesMR
I?................. 1
1
2
.1.
3 Wh
ata
res
omem
ajo
rpi
tfa
ll
swh
ens
tar
tin
gwo
rkin
gon

sMR
I?............................ 1
3

2
.2 Op
ens
cien
tifi
cpr
obl
emsa
sso
cia
ted w
ithsMR
Iofth
edi
sea
sed

b
rain................................. 1
5

2
.3 D
atas
tru
ctu
reandin
tui
tiv
ede
scr
ipt
iono
fas
soc
iat
edp
rob
lem
s. 1
8
2
.4 A
cqu
is
it
ionandr
econ
stru
cti
on................... 2
0

2
.5 P
re-p
roc
ess
ing............................ 2
1

v
ii
i
 2
.5.
1 Inh
omo
gen
eit
yco
rre
cti
on.................. 2
3
2
.5.
1.1 C
onc
ept
s ..................... 2
4

2
.5.
1.2 P
rac
tic
alapp
roa
che
s,s
oftw
are
,andapp
li
cat
ion

t
oda
ta ...................... 2
6
2
.5.
2 Sku
lls
tripp
ing ....................... 2
6

2
.5.
2.1 C
onc
ept
s ..................... 2
7
2
.5.
2.2 P
rac
tic
alapp
roa
che
s,s
oftw
are
,andapp
li
cat
ion

t
oda
ta ...................... 2
8

2
.5.
3 In
terpo
lat
ion ........................ 2
8

2
.5.
3.1 C
onc
ept
s ..................... 2
9

2
.5.
3.2 P
rac
tic
alapp
roa
che
s,s
oftw
are
,andapp
li
cat
ion

t
oda
ta ...................... 3
0

2
.5.
4 Sp
ati
alR
egi
str
ati
on..................... 3
0

2
.5.
4.1 C
onc
ept
s ..................... 3
1

2
.5.
4.2 P
rac
tic
alapp
roa
che
s,s
oftw
are
,andapp
li
cat
ion

t
oda
ta ...................... 3
6

2
.5.
5 In
ten
sit
yno
rma
li
zat
ion................... 4
1

2
.5.
5.1 C
onc
ept
s ..................... 4
2

2
.5.
5.2 P
rac
tic
alapp
roa
che
s,s
oftw
are
,andapp
li
cat
ion

t
oda
ta ...................... 4
3

2
.6 An
aly
sis............................... 4
6
2
.6.
1 L
esi
ons
egm
ent
ati
on .................... 4
6

2
.6.
2 L
esi
on m
app
ing....................... 4
9

2
.6.
3 L
ong
itud
ina
landc
ros
sse
cti
ona
lin
ten
sit
yan
aly
sis.... 5
1

2
.7 C
onc
lus
ion
s............................. 5
4

ix
3 OAS
ISi
s Au
toma
ted S
tat
ist
ica
lIn
ferencefo
r Segmen
tat
ion
,
w
ithapp
lica
tion
sto mu
ltip
lesc
lero
sisle
sionsegmen
tat
ionin

MR
I 55

3
.1 In
trodu
cti
on............................. 5
5
3
.2 M
ate
ria
lsand m
eth
ods....................... 5
9

3
.2.
1 S
tudypopu
lat
ion...................... 6
0

3
.2.
2 Exp
erim
ent
alm
eth
ods................... 6
1

3
.2.
3 Im
agep
rep
roc
ess
ing .................... 6
2

3
.2.
4 S
tat
ist
ica
lmod
el
ingandsp
ati
alsm
ooth
ing........ 6
2

3
.2.
5 B
raint
issu
ema
sk...................... 6
3

3
.2.
6 In
ten
sit
yno
rma
li
zat
ion................... 6
3

3
.2.
7 Sm
ooth
edv
olum
es..................... 6
5

3
.2.
8 OAS
ISi
sAu
tom
atedS
tat
ist
ica
lIn
fer
enc
efo
rSe
gmen
tat
ion6
7

3
.2.
9 OAS
IS m
ode
lrefin
emen
t.................. 7
0

3
.2.
10P
rob
abi
li
tym
apandb
ina
rys
egm
ent
ati
on ........ 7
1

3
.2.
11V
al
ida
tionw
ithg
olds
tand
ard
:va
lid
ati
ons
et1...... 7
2

3
.2.
12V
al
ida
tionw
ithexp
ertr
ank
ing
s:v
al
ida
tions
et1andv
al-

id
ati
ons
et2......................... 7
4

3
.3 Exp
erim
ent
alr
esu
lts........................ 7
7

3
.3.
1 V
al
ida
tions
et1
:tr
ain
ingw
ithg
olds
tand
ard....... 7
7

3
.3.
2 V
al
ida
tions
et1
:neu
ror
adi
olo
gis
tra
tin
gre
sul
ts ..... 7
9
3
.3.
3 V
al
ida
tions
et2
:neu
ror
adi
olo
gis
tra
tin
gre
sul
ts ..... 8
0

3
.3.
4 V
al
ida
tions
et2
:ra
tera
gre
emen
twi
thn
eur
orad
iol
ogi
st,
n
eur
olo
gis
t,andr
adi
olo
gis
t................. 8
1
3
.4 D
iscu
ssi
on.............................. 8
5

x
4 Acompa
risono
fsupe
rvi
sed mach
inelea
rninga
lgo
rithm
sand
fea
turev
ecto
rsfo
r MSle
sionsegmen
tat
ion u
sing mu
ltimoda
l

s
truc
tura
l MR
I 92

4
.1 In
trodu
cti
on............................. 9
2
4
.2 Exp
erim
ent
alm
eth
ods....................... 9
5

4
.2.
1 S
tudypopu
lat
ionandexp
erim
ent
alm
eth
ods....... 9
5

4
.2.
2 Im
agep
rep
roc
ess
ing .................... 9
5

4
.3 S
tat
ist
ica
lme
thod
s......................... 9
6

4
.3.
1 Sup
erv
isedc
las
sifi
cat
iona
lgo
rithm
s............ 9
7

4
.3.
2 F
eatu
reex
tra
cti
onfun
cti
onsandv
ect
ors......... 1
01

4
.3.
2.1 Unn
orm
ali
zed................... 1
01

4
.3.
2.2 N
orm
ali
zed.................... 1
01

4
.3.
2.3 V
oxe
lse
lec
tion.................. 1
02

4
.3.
2.4 Sm
ooth
ed..................... 1
04

4
.3.
2.5 M
omen
ts ..................... 1
04

4
.3.
2.6 Sm
ooth
edand m
omen
ts............. 1
05

4
.3.
3 T
rain
ingandv
al
ida
tions
tud
iesw
ith m
anu
all
esi
ons
eg-

m
ent
ati
ons.......................... 1
05

4
.3.
4 M
easu
reso
fou
tcom
eanda
gre
emen
t ........... 1
08

4
.4 R
esu
lts................................ 1
08

4
.4.
1 C
las
sifi
cat
ionp
erf
orm
anc
e................. 1
08
4
.4.
2 A
lgo
rithma
gre
emen
t.................... 1
12

4
.4.
3 C
ompu
tat
ion
alt
ime .................... 1
15
4
.4.
4 D
own
samp
lin
gth
etr
ain
ings
et:c
las
sifi
cat
ionp
erf
orm
anc
e
andc
ompu
tat
ion
alt
ime .................. 1
17

x
i
 4
.4.
5 Sup
erl
earn
erc
oeffi
cien
ts.................. 1
18
4
.4.
6 In
terp
ret
abi
li
ty....................... 1
20

4
.5 D
iscu
ssi
on.............................. 1
22

5 Re
lat
ing mu
lti
-sequencelong
itud
ina
lin
ten
sityp
rofi
lesandc
lin
-
ica
lcov
aria
tesininc
iden
t mu
ltip
lesc
lero
sisle
sion
s 128

5
.1 In
trodu
cti
on............................. 1
28
5
.2 M
ate
ria
land m
eth
ods ....................... 1
31

5
.2.
1 Im
agea
cqu
is
it
ionandp
rep
roc
ess
ing............ 1
31

5
.2.
2 P
ati
entd
emo
graph
ics.................... 1
32

5
.2.
3 L
esi
onp
rofi
les........................ 1
33

5
.2.
4 P
rin
cip
alc
ompon
entan
aly
sisandr
egr
ess
ion
s....... 1
36

5
.2.
4.1 B
iom
ark
er..................... 1
37

5
.2.
4.2 Exp
ertv
al
ida
tiono
fbi
oma
rke
r ......... 1
38

5
.2.
4.3 R
egr
ess
ion m
ode
l................. 1
39

5
.2.
5 F
unc
tion
-on
-sc
ala
rre
gre
ssi
ons............... 1
42

5
.3 R
esu
lts................................ 1
43

5
.3.
1 P
rin
cip
alc
ompon
entan
aly
sisandr
egr
ess
ion....... 1
43
5
.3.
1.1 B
iom
ark
er..................... 1
43

5
.3.
1.2 Exp
ertv
al
ida
tiono
fbi
oma
rke
r ......... 1
44

5
.3.
1.3 R
egr
ess
ion m
ode
l................. 1
52

5
.3.
2 F
unc
tion
-on
-sc
ala
rre
gre
ssi
on................ 1
54

5
.4 D
iscu
ssi
on.............................. 1
55

Append
ice
s 160

x
ii
A Append
ixto “OAS
ISi
s Au
toma
ted S
tat
ist
ica
lIn
ferencefo
r
Segmen
tat
ion
,wi
thapp
lica
tion
sto mu
ltip
lesc
lero
sisle
sionseg
-

men
tat
ionin MR
I 161

A
.1 OAS
ISc
oeffi
cien
ts ......................... 1
61
A
.2 R
epe
atedsub
jec
tsf
orv
al
ida
tions
tudy1............. 1
66

B Append
ixto“Acompa
risono
fsupe
rvi
sed mach
inelea
rninga
l-
go
rithm
sandfea
turev
ecto
rsfo
r MSle
sionsegmen
tat
ionu
sing

mu
ltimoda
lst
ruc
tura
l MR
I” 167

B
.1 C
las
sifi
cat
iona
lgo
rithm
s...................... 1
67

B
.1.
1 L
ogi
sti
cre
gre
ssi
on ..................... 1
68

B
.1.
2 L
ine
ard
isc
rim
inan
tan
aly
sis................ 1
68

B
.1.
3 Qu
adr
ati
cdi
scr
imin
antan
aly
sis.............. 1
69

B
.1.
4 G
aus
sian m
ixtu
rem
ode
l.................. 1
69

B
.1.
5 Suppo
rtv
ect
orm
ach
inew
ithl
ine
ark
ern
el........ 1
69

B
.1.
6 R
and
omf
ore
st ....................... 1
70

B
.1.
7 k
-ne
are
stn
eighbo
rs..................... 1
70

B
.1.
8 N
eur
aln
etw
ork....................... 1
70

B
.1.
9 Sup
erl
earn
er........................ 1
71

C Append
ixto “Re
lat
ing mu
lti
-sequencelong
itud
ina
lin
ten
sity

p
rofi
lesandc
lin
ica
lcov
aria
tesininc
iden
t mu
ltip
lesc
lero
sisle
-

s
ion
s” 172
C
.1L
ong
itud
ina
lpr
ofil
epip
elin
e.................... 1
72

C
.1.
1 Id
ent
ify
ingv
oxe
lsw
ithn
ewl
esi
onf
orm
ati
on ...... 1
73

C
.1.
2 In
ten
sit
yno
rma
li
zat
ion .................. 1
74

x
ii
i
 C
.1.
3 T
empo
rala
lignm
ent .................... 1
76
C
.1.
4 T
empo
ralin
terpo
lat
ion................... 1
76

C
.2 P
aram
etr
icboo
tst
rapp
ingp
roc
edu
re................ 1
77

C
.3 Exp
ertv
al
ida
tion.......................... 1
78
C
.4 P
rin
cip
alc
ompon
entan
aly
sisandr
egr
ess
ion........... 1
79

C
.5 F
unc
tion
-on
-sc
ala
rre
gre
ssi
on.................... 1
86

x
iv
L
isto
fTab
les

3
.1 R
ang
esf
orv
al
ida
tions
et2s
cann
ingp
aram
ete
rs......... 6
2

3
.2 Qu
ant
ita
tiv
eva
lid
ati
onr
esu
ltsf
orv
al
ida
tions
et1........ 7
9

3
.3 V
olum
eoff
als
epo
sit
ive
sfo
rva
lid
ati
ons
et1........... 7
9

3
.4 Qu
ali
tat
ivev
al
ida
tionr
esu
ltsf
orv
al
ida
tions
et1......... 8
0

3
.5 Qu
ali
tat
ivev
al
ida
tionr
esu
ltsf
orv
al
ida
tions
et2......... 8
3

4
.1 Sup
erv
isedc
las
sifi
cat
iona
lgo
rithm
sinR............. 9
9

4
.2 F
eatu
rev
ect
ors........................... 1
00

4
.3 Th
etr
ain
ingandv
al
ida
tions
ets.................. 1
07

5
.1 κc
oeffi
cien
tsf
orth
era
tin
gso
fth
ele
sions
egm
ent
ati
onandth
e

b
iom
ark
er............................... 1
51

A
.1 C
oeffi
cien
tsf
romth
efir
stfi
t.................... 1
64
A
.2 C
oeffi
cien
tsf
romth
ese
condfi
t .................. 1
65

A
.3 P
ref
err
ed m
eth
odf
orth
e5r
epe
atedsub
jec
ts........... 1
66

C
.1 C
oeffi
cien
tsf
rom mu
lt
iva
ria
tePCAr
egr
ess
ion m
ode
l ...... 1
84
C
.2 C
oeffi
cien
tsf
romun
iva
ria
tePCAr
egr
ess
ion m
ode
l........ 1
85

xv
L
isto
fFigu
res

2
.1 Mu
lt
i-
sequ
enc
e MR
Ida
taf
oron
esub
jec
t............. 8

2
.2 Dyn
ami
ccon
tra
stenh
anc
ing(DCE
)vo
lum
e ........... 9

2
.3 Inh
omo
gen
eit
yco
rre
cti
ono
fvo
lum
e................ 2
4

2
.4 Sku
lls
tripp
ingu
sin
gBET..................... 2
8

2
.5 S
tep
sofr
egi
str
ati
on:at
oyex
amp
le................ 3
8

2
.6 N
onl
ine
arr
egi
str
ati
ont
oat
emp
lat
e................ 4
0

2
.7 In
ten
sit
yno
rma
li
zat
ion m
eth
ods.................. 4
4

2
.8 Mu
lt
ipl
esc
ler
osi
sle
sions
egm
ent
ati
on............... 4
7
2
.9 Mu
lt
ipl
esc
ler
osi
sle
sionh
ist
ogr
ams................ 5
1

2
.10L
ong
itud
ina
lin
ten
sit
iesw
ith
in mu
lt
ipl
esc
ler
osi
sle
sion
s..... 5
2

3
.1 Ex
amp
leo
fth
e MR
Ida
ta ..................... 6
4

3
.2 Sm
ooth
ed MR
Ivo
lum
es ...................... 6
6

3
.3 Tw
ost
agesm
ooth
ingo
f MR
Ivo
lum
es............... 7
2

3
.4 P
art
ialROCcu
rvef
orv
al
ida
tions
et1 .............. 7
8

3
.5 B
oxp
loto
fse
gmen
tat
ionr
atin
gs.................. 8
1

3
.6 C
ereb
elluml
esi
on.......................... 8
9

4
.1 S
cat
terp
lot
softh
eT1
-w,T
2-wandFLA
IRv
oxe
lin
ten
sit
ies.. 1
02

xv
i
4
.2 Ex
amp
leo
fth
e MR
Ida
ta ..................... 1
03
4
.3 Th
epa
rti
alROCcu
rve
sfo
rth
ecl
ass
ific
ati
ona
lgo
rithm
s .... 1
09

4
.4 Th
esc
aledp
art
ialAUCf
ore
acha
lgo
rithm............ 1
11

4
.5 D
ices
imi
lar
ityc
oeffi
cien
tsf
ora
lla
lgo
rithm
s........... 1
14
4
.6 T
imet
ofitand m
akep
red
ict
ion
sfr
ome
acha
lgo
rithm...... 1
16

4
.7 D
own
samp
lin
gofth
etr
ain
ings
et................. 1
19
4
.8 Sup
erl
earn
erc
oeffi
cien
ts...................... 1
21

5
.1 L
ong
itud
ina
l MR
Istud
ies ..................... 1
34

5
.2 L
ong
itud
ina
l MR
Istud
iesw
ith
inl
esi
ons ............. 1
47

5
.3 Mu
lt
i-
sequ
enc
ele
sionp
rofi
les ................... 1
48

5
.4 M
eanp
rofi
leandfi
rstPC ..................... 1
49

5
.5 D
ist
ribu
tion
softh
era
tin
gsf
orth
etw
ora
ter
s .......... 1
50

5
.6 C
oeffi
cien
tsf
romth
ePCAR
egr
ess
ion m
ode
l........... 1
52

5
.7 FLA
IRc
oeffi
cien
tfun
cti
onsf
romth
efun
cti
on-
on-
sca
larr
egr
ess
ion1
55

C
.1 SuBL
IMEandOAS
ISs
egm
ent
ati
ons............... 1
75

C
.2 P
ass
ed................................ 1
80

C
.3 P
ass
edw
ith m
ino
rer
ror
s...................... 1
81

C
.4S
omer
ede
emin
gfe
atu
res...................... 1
82

C
.5 F
ai
led m
ise
rab
ly........................... 1
83

C
.6 T
2co
effic
ien
tfun
cti
onsf
romth
efun
cti
on-
on-
sca
larr
egr
ess
ion . 1
87
C
.7 PDc
oeffi
cien
tfun
cti
onsf
romth
efun
cti
on-
on-
sca
larr
egr
ess
ion. 1
88

C
.8 T
1co
effic
ien
tfun
cti
onsf
romth
efun
cti
on-
on-
sca
larr
egr
ess
ion . 1
89

xv
ii
Chap
ter1

In
troduc
tion

Mu
lt
ipl
esc
ler
osi
s(MS
)isaninfl
amm
ato
ryd
ise
aseo
fth
ebr
ainandsp
ina
lco
rd

ch
ara
cte
riz
edb
ydem
yel
ina
tin
gle
sion
s.S
tru
ctu
ralm
agn
eti
cre
son
anc
eim
ag-

in
g(sMR
I)i
sa m
edi
calim
agin
gte
chn
iqu
eth
ati
ssen
sit
ivet
oth
esel
esi
ons[
1].
Qu
ant
it
ivean
aly
seso
f MR
I,su
cha
sth
enumb
erandv
olum
eof MSl
esi
ons
,ar
e

e
ssen
tia
lfo
rdi
agn
osin
gth
edi
sea
seand m
oni
tor
ingi
tsp
rog
res
sion[
2,3
].Inad
-

d
it
ion
,th
efo
rma
tiono
fth
esel
esi
ons
,ac
omp
lexp
roc
essin
volv
inginfl
amm
ati
on,

t
issu
edam
age
,andr
epa
ir
,isa
lsoimpo
rtan
tfo
rdi
agn
osin
gand m
oni
tor
ingth
e

d
ise
ase[
4]. Wh
il
esMR
Iiss
ens
it
ivet
ole
siona
ctiv
ity
,th
erei
ssu
rpr
is
ing
lypoo
r

a
sso
cia
tionb
etw
eenc
lin
ica
lfind
ing
sandth
erad
iol
ogi
calex
ten
tofin
volv
emen
t

on MR
Ius
ingt
rad
it
ion
alv
olum
etr
icm
easu
res
. Th
isph
enom
enoni
sre
fer
redt
o

a
sth
ecl
ini
co-
rad
iol
ogi
calp
arad
ox[
5].
Th
ewo
rkinth
isth
esi
sisaneff
ortt
obr
idg
eth
isc
lin
ico
-rad
iol
ogi
calp
arad
ox

andl
inkth
elon
gitud
ina
lfind
ing
sons
tru
ctu
ral MR
Iinp
ati
ent
swi
th MSt
o

d
ise
ase
-mod
ify
ingt
rea
tmen
tando
the
rcl
ini
calin
form
ati
on. Ch
apt
er2o
fth
e

th
esi
sisanin
trodu
cti
ont
osMR
Ida
ta. Ch
apt
er3and4o
fth
eth
esi
sde
al

1
w
ith MSl
esi
ons
egm
ent
ati
onu
sin
g mu
lt
i-
sequ
enc
est
ruc
tur
al MR
I.Ch
apt
er5
i
sacu
lmin
ati
ono
fth
isw
ork
. Th
ele
sions
egm
ent
ati
ont
echn
iqu
eexp
lor
edin

Ch
apt
er3and4i
sex
tend
edt
obu
ildap
ipe
lin
etoex
tra
ctl
ong
itud
ina
lin
ten
sit
y

in
form
ati
on,o
rle
sionp
rofi
les
,fr
oml
esi
onsin mu
lt
i-
sequ
enc
esMR
I. A PCA
r
egr
ess
ion m
ode
listh
enin
trodu
cedt
ore
lat
eth
elon
gitud
ina
lle
sionp
rofi
lest
o

d
ise
ase
-mod
ify
ingt
rea
tmen
tando
the
rcl
ini
calin
form
ati
oninana
ttemp
tto
l
inkth
ein
form
ati
onf
romsMR
Itoc
lin
ica
lin
form
ati
on. Inadd
res
sin
gth
ese

c
lin
ica
lis
sue
,th
isth
esi
sal
soc
ont
ain
sanumb
ero
fbi
ost
ati
sti
calc
ont
ribu
tion
s:

th
ede
signandan
aly
siso
fexp
ertr
ate
rtr
ial
s,d
atar
edu
cti
ont
echn
iqu
esf
orh
igh

d
imen
sion
alandl
ong
itud
ina
lda
tath
rou
ghp
rin
cip
alc
ompon
entan
aly
sis(PCA
)

r
egr
ess
ion m
ode
ls
,andth
ecomp
ari
sono
fsup
erv
isedl
earn
inga
lgo
rithm
s.

Ch
apt
er2o
fth
isth
esi
sisanin
trodu
cti
ont
osMR
Ida
ta,andin
clud
esd
e-

t
ail
edin
stru
cti
onsandc
odef
orth
epr
epr
oce
ssin
gandan
aly
siso
fsMR
Ida
ta.

W
ith m
yadv
iso
rDr
.Cip
rianC
rain
ice
anu
,co
-adv
iso
rDr
. Ru
sse
llSh
inoh
ara
,

and D
r. An
iEl
oyan
,th
isch
apt
erh
asb
eend
eve
lop
edin
toabookch
apt
erin

th
eHandbooko
fMod
ernS
tat
ist
ica
lMe
thod
s:N
eur
oim
agin
gDa
ta An
aly
sis
,

en
tit
led“A T
uto
ria
lfo
r Mu
lt
i-s
equ
enc
eCl
ini
calS
tru
ctu
ralB
rain MR
I”[
6].

A
spa
rto
fsMR
Ian
aly
sisedu
cat
ion
,Ia
lsoc
o-d
eve
lop
edandt
augh
ttu
tor
i-

a
lsonth
etop
ica
tth
eSt
ati
sti
csand App
li
ed M
ath
ema
tic
alS
cien
ceIn
sti
tut
e

(SAMS
I)andth
eEa
ste
rnN
orthAm
eri
canR
egi
on(ENAR
)me
etin
g.M
orer
e-

c
ent
lyIc
o-d
eve
lop
edaC
our
ser
acou
rsew
ithD
r.C
rain
ice
anuandf
el
lowPhD
s
tud
entJ
ohn Mu
sch
el
lions
tru
ctu
ral MR
Ian
aly
sisandp
rep
roc
ess
ingu
sin
gth
e

s
tat
ist
ica
lso
ftw
areR
,th
atw
il
lber
ele
aseds
oon
.

Th
ema
jor
ityo
fmyw
orkf
orth
isth
esi
sha
sbe
end
edi
cat
edt
o MSl
esi
ons

s
egm
ent
ati
onu
sin
g mu
lt
i-
sequ
enc
esMR
I,wh
ichi
sco
ver
edinCh
apt
ers3and

2
4
. Wh
il
eman
yme
thod
sfo
rle
sions
egm
ent
ati
onex
istinth
eli
ter
atu
re,th
ese
m
eth
odsa
reo
ftend
ifficu
ltt
orep
rodu
ceandd
ono
tha
vepub
li
clya
vai
lab
les
oft
-

w
areimp
lem
ent
ati
ons
. Ch
apt
er3in
trodu
ces OAS
ISi
s Au
tom
atedS
tat
ist
ica
l

In
fer
enc
efo
rSe
gmen
tat
ion(OAS
IS)
,afu
llyau
tom
ated
,cr
oss
-se
cti
ona
lle
sion
s
egm
ent
ati
ona
lgo
rithm[
7]. OAS
ISu
sesal
ogi
sti
cre
gre
ssi
on m
ode
ltoc
rea
te

p
rob
abi
li
tym
apso
fle
sionp
res
enc
efo
r mu
lt
i-
sequ
enc
e MR
Istud
ies
. Inth
is
ch
apt
er,Ip
res
entth
e OAS
IS m
eth
odandp
erf
ormex
ten
siv
eva
lid
ati
ono
fth
e

m
eth
od,sh
owin
gin
cre
asedp
erf
orm
anc
eofOAS
ISo
verth
epr
evi
ouss
tat
eofth
e

a
rtl
esi
ons
egm
ent
ati
on m
eth
od. Th
eva
lid
ati
ono
fth
eOAS
IS m
eth
odin
clud
es

qu
ali
tat
ivev
al
ida
tion
,us
ingexp
ertr
ate
rtr
ial
swi
than
eur
olo
gis
t,n
eur
orad
i-

o
log
ist
,andr
adi
olo
gis
t. Th
e OAS
ISl
esi
ons
egm
ent
ati
ona
lgo
rithmi
sav
ai
lab
le

f
orpub
li
cus
eandi
scu
rren
tlyimp
lem
ent
eda
san Rp
ack
age(h
ttp
s:/
/cr
an.
r-

p
roj
ect
.or
g/w
eb/p
ack
age
s/o
asi
s/ind
ex.h
tml
). Ch
apt
er4c
omp
are
sth
elo
gis
tic

r
egr
ess
ionm
ode
lfr
omth
eOAS
ISa
lgo
rithma
gain
stanumb
ero
fsup
erv
isedm
a-

ch
inel
earn
inga
lgo
rithm
s[8
].H
ereIf
oundth
atth
elo
gis
ticr
egr
ess
ionm
ode
lha
s

p
erf
orm
anc
easw
el
lorb
ett
erth
anth
emo
rec
omp
lex m
ach
inel
earn
ingm
ode
ls

andth
isw
orki
llu
str
ate
sth
eimpo
rtan
ceo
fmod
elin
terp
ret
ati
onandp
ars
imon
y.

Ch
apt
er5d
esc
rib
esth
ecu
lmin
ati
ono
fth
isth
esi
swo
rk,ana
ttemp
ttob
rid
ge

th
ecl
ini
co-
rad
iol
ogi
calp
arad
ox.U
sin
gana
lgo
rithmIp
rev
iou
slyd
eve
lop
edf
or

s
egm
ent
ingn
ewanden
lar
gin
g MSl
esi
ons[
9],a
lon
gwi
thth
eOAS
ISa
lgo
rithm
,

Id
eve
lop
edap
ipe
lin
efo
rex
tra
ctin
gandn
orm
ali
zin
gle
sionp
rofi
les
,th
elon
-
g
itud
ina
lvo
xel
-lev
elin
ten
sit
iesonth
e mu
lt
i-
sequ
enc
esMR
Iwi
thin MSl
esi
ons
.

U
sin
gPCAt
oredu
ceth
edim
ens
iono
fth
ele
sionp
rofi
les
,Id
isc
ove
redth
atth
e

s
cor
eonth
efir
stPCi
sav
oxe
l-
lev
elb
iom
ark
ero
fle
sionr
epa
ir
. Th
ema
rke
r

3
i
sva
lid
atedb
ytw
ocl
ini
cian
sinanexp
ertr
ate
rtr
ial
. Th
ere
lat
ion
shipb
e-
tw
eenth
isb
iom
ark
erandth
ecl
ini
calm
easu
reso
fin
ter
esti
smod
eledu
sin
ga

PCAr
egr
ess
ion m
ode
l,andas
tat
ist
ica
llys
ign
ific
antr
ela
tion
shipb
etw
eenth
e

b
iom
ark
erandth
eus
eofd
ise
ase
-mod
ify
ingt
rea
tmen
t,s
ter
oid
s,andd
ist
anc
eto
th
ebound
aryo
fal
esi
onw
asf
ound[
10]
.

4
Chap
ter2

Atu
tor
ialfo
r mu
lti
-sequence
c
lin
ica
lst
ruc
tura
lbra
in MR
I

2
.1 In
troduc
tion

H
ighr
eso
lut
ions
tru
ctu
ralm
agn
eti
cre
son
anc
eim
agin
g(sMR
I)i
sus
edex
ten
-

s
ive
lyinc
lin
ica
lpr
act
ice
,asi
tpr
ovid
esd
eta
il
edan
atom
ica
lin
form
ati
ono
fth
e

l
ivin
gor
gan
ism
,iss
ens
it
ivet
oman
ypa
tho
log
ies
,anda
ssi
stsinth
edi
agn
osi
s
o
fdi
sea
se[
11]
. App
li
cat
ion
sofsMR
Ico
vere
ssen
tia
llyev
eryp
arto
fth
ehum
an

bodyf
romt
oest
obr
ainandaw
idev
ari
etyo
fdi
sea
sesf
roms
trok
e,c
anc
er,and

mu
lt
ipl
esc
ler
osi
s(MS
)toin
tern
alb
leed
ingandt
ornl
igam
ent
s.S
inc
eth
ein
tro
-

du
cti
ono
f MR
Iinth
e19
80s
,th
ela
cko
fsid
eeff
ect
s,th
econ
tinu
ous
lyimp
rov
ing
r
eso
lut
iono
fim
age
s,andth
ewid
eav
ai
lab
il
ityo
f MR
Isc
ann
ersh
avem
adesMR
I

in
stan
tlyr
eco
gni
zab
leinth
epopu
larl
ite
ratu
re[
12]
.Ind
eed
,wh
enon
eisa
sked

t
oha
vean MR
Iinac
lin
ica
lcon
tex
titi
salm
ostc
ert
ain
lyansMR
Iori
tsc
los
e

r
ela
tiv
e,th
edyn
ami
ccon
tra
stenh
anc
ing MR
I(DCE
-MR
I).Th
eseim
age
sar
e

5
fund
amen
tal
lyd
iffe
ren
tfr
omfun
cti
ona
l MR
I(fMR
I)ins
ize
,comp
lex
ity
,me
a-
su
rem
entt
arg
et,t
ypeo
fme
asu
rem
ent
,andin
tend
edu
se. Wh
il
efMR
Iaim
s

t
ostudyb
raina
ctiv
ity
,sMR
Irev
eal
san
atom
ica
lin
form
ati
on. Th
isd
ist
inc
tion

i
simpo
rtan
tasth
esc
ien
tifi
cpr
obl
emsands
tat
ist
ica
lte
chn
iqu
esf
orfMR
Iand
sMR
Ian
aly
sisd
iffe
rgr
eat
ly[
13]
,ye
tcon
fus
ionb
etw
eenth
etw
ocon
tinu
est
o

ex
istinth
eli
ter
atu
reandam
ongr
evi
ewe
rs. D
esp
iteth
een
orm
ousp
rac
tic
al
impo
rtan
ceo
fsMR
I,f
ews
tat
ist
ic
ian
sandb
ios
tat
ist
ic
ian
sha
vem
ader
ese
arch

c
ont
ribu
tion
sinth
isfi
eld
. Th
ism
ayb
edu
etoth
esub
tlea
spe
ctso
fsMR
I,th
e

r
ela
tiv
elyfl
atl
earn
ingcu
rve
,andth
ela
cko
fcon
tac
tbe
twe
ens
tat
ist
ic
ian
sand

b
ios
tat
ist
ic
ian
sandth
esc
ien
tis
tsw
ork
inginc
lin
ica
lneu
roim
agin
g. Ou
rgo
al

i
sredu
ceth
epr
iceo
fen
try
,ac
cel
era
tel
earn
ing
,andp
rov
ideth
ein
form
ati
on

r
equ
iredt
opr
ogr
essf
romn
ovi
cet
oin
it
iat
edsMR
Ire
sea
rch
er.

Th
isch
apt
eri
sde
sign
edt
opr
ovid
eatu
tor
ialf
orsMR
Ire
sea
rch
,in
trodu
ce

s
omem
ajo
run
solv
eds
cien
tifi
cpr
obl
emsinb
rainim
agin
gofp
ati
ent
swi
thn
eu-

r
olo
gic
ald
ise
ase
,andd
esc
rib
eth
eimpo
rtan
tte
chn
ica
lpr
obl
emsa
sso
cia
tedw
ith

d
ataan
aly
sis
.Im
agea
cqu
is
it
ionandp
re-p
roc
ess
ing
,esp
eci
allya
sitr
ela
test
o

p
re-p
roc
ess
ingp
ipe
lin
es,w
il
lal
sob
edi
scu
ssed
.Inou
rexp
eri
enc
e,i
tha
sbe
en

impo
ssib
let
osep
era
teth
eim
agep
re-p
roc
ess
ingp
ipe
lin
efr
oml
ate
ran
aly
sis
.

Th
epap
eri
sac
comp
ani
edb
ysMR
Ifo
rtw
osub
jec
tsw
ith mu
lt
ipl
esc
ler
osi
s

a
ttw
ovi
sit
sto
geth
erw
ithth
eas
soc
iat
ed Rc
odeth
atc
anb
eus
edt
oop
en,

v
isu
ali
ze,andc
ondu
ctsm
alls
tat
ist
ica
lan
aly
ses
. Th
eses
tud
iesh
aveb
eenp
re-
p
roc
ess
edu
sin
gth
epr
e-p
roc
ess
ings
tep
sou
tl
inedinth
isch
apt
er.

AnsMR
Istudyt
ypi
cal
lyc
ons
ist
ssev
era
ldiff
eren
tsMR
Isequ
enc
es,m
ost

c
omm
onlyth
eT1
-we
igh
ted(T
1),T
2-w
eigh
ted(T
2),F
luidA
ttenu
atedIn
ver
sion

R
eco
very(FLA
IR)
,andP
rot
onD
ens
ity(PD
).O
the
rsequ
enc
esa
rec
ont
inu
ous
ly

6
b
ein
gre
sea
rch
edand m
ayb
ecom
est
and
ardinfu
tur
esMR
Istud
ies
.Mo
reo
ver
,
th
etyp
eofm
agn
et(
1.5T
,3T
,or7T
),th
ebr
ando
f MR
Isc
ann
er,andth
ech
oic
e

o
fsc
ann
ingp
aram
ete
rsm
ayindu
cem
ajo
rdiff
eren
cesb
etw
eenim
age
s,ev
eni
f

th
eya
reo
fth
esam
esequ
enc
e. W
ere
fert
oth
esMR
Ico
ll
ect
iono
ftw
oorm
ore
s
equ
enc
esa
s mu
lt
i-
sequ
enc
esMR
I. W
ewi
lld
ist
ingu
ish mu
lt
i-
sequ
enc
esMR
I

f
rom mu
lt
i-m
oda
li
tyim
agin
g, wh
ichr
efe
rst
oth
ecomb
ina
tiono
fatl
eas
ttw
o
d
iffe
ren
ttyp
eso
fim
agin
g,f
orex
amp
lesMR
IandC
ompu
tedT
omo
graph
y(CT
),

o
rCTandP
osi
tronEm
itt
edT
omo
graph
y(PET
).

F
romad
atap
ersp
ect
ive
,ev
erys
equ
enc
eisath
reed
imen
sion
ala
rra
y,w
ith

e
achen
tryr
epr
esen
tin
gav
oxe
l,o
rth
reed
imen
sion
alp
ixe
l. Th
esi
zeo
fth
e

v
oxe
lsd
epend
sonth
eacqu
is
it
ionp
aram
ete
rsandp
rov
ide
sth
ere
solu
tiono
fth
e

im
age
.Fi
gur
e2.
1di
spl
aysd
ataf
romas
tand
ardsMR
Isequ
enc
epr
oto
colf
or

th
rees
li
cessh
owninth
eth
reer
ows
. Th
evo
xels
izef
orth
eseim
age
sha
sbe
en

in
terpo
lat
edt
o1×1×1 mm(
int
erpo
lat
iono
fsMR
Iisd
iscu
ssedind
eta
ilin

S
ect
ion2
.5.
3).S
li
cesa
red
isp
lay
ed,m
ovin
gfr
omth
ein
fer
iort
oth
esup
eri
oro
f

th
ebr
ainanda
rel
abe
ledA
,B,andC
,re
spe
ctiv
ely
.Ea
chc
olumnc
orr
espond
s

t
oad
iffe
ren
tsequ
enc
e–th
eFLA
IR(A
1,B
1,C
1),T
2(A
2,B
2,C
2),T
1(A
3,

B
3,C
3),andPD(A
4,B
4,C
4). Anin
tui
tiv
ewa
ytoth
inkabou
tth
ediff
eren
t

s
equ
enc
esi
sth
atth
eya
res
li
cesth
rou
ghth
ebr
ains
eenth
rou
ghd
iffe
ren
tfil
ter
s.

M
akin
gsu
chp
lot
sin R[
14]i
sre
lat
ive
lye
asyu
sin
gth
eoro.niftiRp
ack
age[
15]

p
ack
age
.Af
ters
ett
ingth
ewo
rkin
gdi
rec
toryt
oth
elo
cat
iono
fth
ecomp
res
sed

FLA
IRv
olum
e,th
efo
llow
ingl
ine
sofc
odew
il
llo
adth
evo
lum
eandp
loton
e

ax
ials
li
ceo
fth
eFLA
IRim
age
:
library(oro.nifti)

flair<-readNIfTI(’FLAIRnorm.nii.gz’,reorient=TRUE)

7
F
i gure2.1
: Mu l
ti-
sequence MRId a
taf o
ronesub je
ct. Threeaxia
lsl
icesar
e
sh ownone achrow( let
tersA,B , Cindi
cat
ead iff
erentsl
icegoingfr
omth e
infer
ior(A)t osuper
i o
r(C )o
fth ebrain
)indic
atingFLA IR(A 1
,B 1,C1),T2
(A 2,B2,C 2
),T 1(A 3,B 3
,C 3)
,andPD(A 4,B 4,C 4
). Asm a
ll MSlesi
onis
v
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sl
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r MSl e
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.

8
 image(flair[,,50])
Ap
loto
fth
esa
git
tal
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ron
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ialv
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romth
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ice
s[1
11,
132
,10
2]

(
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git
als
li
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oron
als
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ce,ax
ials
li
ce]
)canb
eob
tain
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sin
gth
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and

orthographic:
orthographic(flair,xyz=c(111,132,102))

Wh
il
eRp
ack
age
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ych
ang
e,imp
rov
e,o
rbe
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eob
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ete
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ela
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elye
asyt
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o

w
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omp
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les
. Th
isi
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i
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at

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)wh
ata
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it
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tar
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ear
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gth
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est
ion
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172 169 169 169 167

192 187 187 183 172

200 201 192 192 187

192 204 202 200 198

157 172 187 194 196

131 140 154 165 168

120 126 129 130 132

A B
F
igur
e2 .2
: A. Dynam
iccont
ras
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ium
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)
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omth i
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9
2
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th
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ime

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en

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ed

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E
achv
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ain
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ath
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e

l
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ralqu
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es,wh
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omp
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and
ard

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. Thu
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e

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e

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ctin
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d
atain
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sss
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in
ten
sit
yno
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4.

2
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lesMR
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Animpo
rtan
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ost

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ent
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oad
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ry m
oreth
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esMR
Istudyi
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ais
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tor
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and
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r

c
ondu
ctin
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aly
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ered
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ces
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eoraf
ewim
age
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ime
.
W
ere
comm
endt
ost
ored
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sin
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old
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ctu
reo
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e:

1
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MATLABR ,Python[
18]
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i
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1
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2
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taresome ma
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Th
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aly
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s

ons
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H
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irs
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],

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t
ioninS
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.5.
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rman
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o
fdiff
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,iti
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e

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andth
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erei
san
eedf
orv
al
ida
tionandr
epl
ica
tion w
orka
swe
lla
sund
ers
tand
ing

hum
anqu
ali
tat
ivea
sse
ssm
ento
fim
age
s. Th
isi
san
oth
erex
cel
len
toppo
rtun
ity

f
ors
tat
ist
ic
ian
sandb
ios
tat
ist
ic
ian
stob
ecom
ein
volv
edinim
agin
g. Af
our
th

m
ajo
rpi
tfa
lli
stoa
ssum
eth
atp
rob
lem
sinn
eur
oim
agin
gha
veb
eens
olv
ed. Th
e

r
ang
e,c
omp
lex
ity
,andd
ive
rsi
tyo
fun
solv
edp
rob
lem
sisa
ston
ish
ing
.Ind
eed
,
r
egi
str
ati
on,in
ten
sit
yno
rma
li
zat
ion
,lon
gitud
ina
lco
-re
gis
tra
tion
,sp
ati
alinh
o-

m
ogen
eit
y,s
egm
ent
ati
on,popu
lat
ionl
eve
lan
aly
sesa
rea
llw
ideop
enp
rob
lem
s.

F
if
th,qu
ant
ify
inga
sso
cia
tion
sbe
twe
enim
agin
gandh
eal
thi
sah
ardp
rob
lem

th
atn
eed
stob
ewe
llund
ers
toodandadd
res
sed
.Ind
eed
,br
ainch
ara
cte
ris
tic
s

1
4
a
reex
trem
elyh
ete
rog
enou
sac
ros
sind
ividu
als
,wh
il
elon
gitud
ina
lch
ang
est
end
t
obe mu
chsm
all
er.F
orex
amp
le
,inas
tudyo
ffr
act
ion
alan
iso
trop
y,a m
easu
re

d
eriv
edf
romd
iffu
sionw
eigh
tedim
agin
g,o
fth
eco
rpu
sca
llo
sum[
21]th
elon
gitu
-

d
ina
lva
riab
il
ityo
ver4
-5y
ear
son
lya
ccoun
tedf
or2t
o3%o
fth
eto
talob
serv
ed
v
ari
abi
li
ty. Th
isr
ais
esimpo
rtan
tpr
obl
emsf
orb
ios
tat
ist
ic
ian
sands
tat
ist
ic
ian
s

in m
anyn
eur
oim
agin
gstud
ieswh
ereth
esi
gna
l,i
fitex
ist
s,s
itsund
erap
il
eof
n
ois
e.

2
.2 Opensc
ien
tifi
cprob
lem
sas
soc
iated w
ith

sMR
Iofthed
isea
sedb
rain

G
iventh
ediv
ers
ityo
fdi
sea
sesanda
sso
cia
teds
cien
tifi
cqu
est
ion
s,i
tcanb
edi
f-

fi
cul
ttoid
ent
ifyimpo
rtan
tsc
ien
tifi
cpr
obl
ems
.Itm
ayb
esimp
let
oid
ent
ify

s
egm
ent
ati
ono
fwh
item
att
erp
ath
olo
gya
sag
ene
ralp
rob
lem(
seeS
ect
ion2
.6.
1
f
orad
iscu
ssi
ono
fle
sions
egm
ent
ati
onin MS
),th
oughw
ear
eaw
areth
atth
ere

a
refund
amen
tald
iffe
ren
cesb
etw
eenid
ent
ify
ingaff
ect
edt
issu
esin MS
,st
rok
e,

c
anc
er,t
raum
ati
cbr
ainin
jury(TB
I),o
rAl
zhe
ime
rDi
sea
se(AD
.) Wh
il
ere
cog
-

n
iz
ingth
esed
ifficu
lt
ies
,wea
ttemp
ttop
rov
ideano
verv
iewth
ati
sin
form
ativ
e.

Bu
tdu
etoth
esc
opeo
fth
epr
obl
ems
,wec
ann
otb
eexh
aus
tiv
e.
F
romac
lin
ica
lpe
rsp
ect
ive
,th
ein
ter
esti
sof
teninsub
jec
t-sp
ecifi
cda
ta.

A
tth
isl
eve
ltyp
ica
lsc
ien
tifi
cqu
est
ion
sar
ere
lat
edt
oex
ist
enc
e,l
oca
tion
,and

s
eve
rit
yofb
rainabn
orm
ali
tie
sth
atm
ayb
ecl
ini
cal
lyr
elev
ant
. An
oth
ers
eto
f
p
rob
lem
sisr
ela
tedt
oqu
ant
ify
ingth
evo
lum
eof wh
item
att
er,c
ereb
rosp
ina
l

flu
id(CSF
),g
raym
att
er,andb
rain
. Th
esep
rob
lem
sfa
llund
erth
eumb
rel
lao
f

1
5
b
raint
issu
ese
gmen
tat
ion
. M
oresub
tlep
rob
lem
scana
lsob
eadd
res
sed
,su
ch
a
slo
cal
izedabn
orm
ali
tie
s. Ex
amp
leso
fth
esea
reb
leed
ing
,gr
aym
att
erth
in-

n
ing
,orqu
ant
ify
ingunu
sua
lwh
item
att
erin
ten
sit
ydi
str
ibu
tion
s(r
efe
rredt
oas

“d
irt
ywh
item
att
er”
).F
orsMR
Istud
iesaqu
ireda
t mu
lt
ipl
evi
sit
s,b
iol
ogi
cal
ch
ang
esb
etw
eenth
etw
ovi
sit
sma
ybeo
fin
ter
est
. Anex
amp
lei
swh
eth
erb
rain

abn
orm
ali
tie
sha
ved
isapp
ear
edo
rha
vew
ors
ened
,andwh
eth
erth
erea
requ
an-
t
ita
tiv
ech
ang
esint
issu
evo
lum
eorqu
ali
tyb
etw
eenth
etw
ovi
sit
s. Ap
erv
asiv
e

t
echn
ica
lpr
obl
emi
showt
oal
ignim
age
softh
esam
esub
jec
t,h
owt
ovi
sua
li
ze

th
ediff
eren
cesb
etw
eenim
age
swh
enin
ten
sit
iesch
ang
esc
alef
romon
evi
sitt
o

th
enex
t,andh
owt
oel
imin
ateth
esc
ann
er/v
is
it
-sp
ecifi
cinh
omo
gen
eit
ies
.In

S
ect
ion2
.5.
1wew
il
ldi
scu
ssh
owt
oadd
res
sth
esp
ati
alinh
omo
gen
eit
yco
rre
c-

t
ion
,inS
ect
ion2
.5.
4wew
il
lpr
esen
tme
thod
sfo
rre
gis
tra
tion(
ali
gnin
gdiff
eren
t

b
rain
stoat
emp
lat
e)andc
o-r
egi
str
ati
on(
ali
gnin
gth
esMR
Isequ
enc
esf
orth
e

s
amesub
jec
t’sb
rainf
roms
eve
ralv
is
its
).A
fte
rapp
lyin
gin
ten
sit
yno
rma
li
zat
ion

a
sde
scr
ibedinS
ect
ion2
.5.
5,on
ecand
iffe
ren
ceth
ere
spe
ctiv
esequ
enc
esf
orth
e

s
amesub
jec
t. P
rob
ablyth
emo
std
isappo
int
ingp
arto
fth
isex
erc
iseonr
eal

d
atai
sth
att
ypi
cal
lyth
ediff
eren
cei
sno
tze
roandr
eve
alsth
eimp
erf
ect
ion
sof

th
ere
gis
tra
tionandn
orm
ali
zat
ionp
roc
edu
res
. Th
emo
sts
eri
ousp
rob
lemi
sth
e

f
actth
ated
gesandbound
ari
esd
ono
tal
ignp
erf
ect
lyands
omeob
viou
sdiff
er-

en
cesm
ays
imp
lyc
omef
romth
efa
ctth
atth
ema
gne
tics
ign
alw
ass
tron
gerin

ap
art
icu
larv
is
itth
ana
tth
eoth
erv
is
it
. Bu
t,wh
ereth
erei
sdi
sappo
intm
ent
,
th
erei
soppo
rtun
ity
.

Wh
enon
eism
ovin
gfr
omth
esub
jec
ttoth
epopu
lat
ionl
eve
l,an
ews
eto
f

s
cien
tifi
cpr
obl
ema
ris
es.Ind
eed
,atth
epopu
lat
ionl
eve
lon
ecou
ldb
ein
ter
est
ed

inm
app
ingth
elo
cat
iono
fle
sion
sonat
emp
lat
ebr
ainands
tudy
ingwh
eth
erth
e

1
6
l
oca
li
zat
iono
fth
esel
esi
onsi
sas
soc
iat
ed w
ithd
ise
ases
eve
rit
yorp
rog
res
sion
.
Ex
amp
leso
fsu
chp
rob
lem
sin
clud
esm
app
ingth
elo
cat
iono
f MSl
esi
onso
rof

th
est
rok
ecl
ota
fte
radm
iss
iont
oth
eIn
ten
siv
eCa
reUn
it(
ICU
.)An
oth
erp
rob
-

l
emi
stoqu
ant
ifyd
iffe
ren
cesandch
ang
esinb
raint
issu
esandth
eira
sso
cia
tion
w
ithh
eal
thou
tcom
es.F
orex
amp
le
,howi
sth
esi
zeandsh
apeo
fth
even
tri
cle
s

inth
ebr
aino
fap
ati
entin
fec
tedw
ithH
IVr
ela
tedt
oth
edu
rat
iono
fth
edi
s-
e
aseo
rwi
thth
etyp
eoft
rea
tmen
torw
ithth
etim
efr
omt
rea
tmen
tin
it
iat
ion
.

An
oth
erex
amp
lei
stos
tudyth
eas
soc
iat
ionb
etw
eenwh
item
att
erl
osso
rgr
ay

m
att
erth
inn
ingandp
rog
res
siont
oAD
.Hi
ghqu
ali
tysMR
Ida
taf
orth
ist
ype

o
fpr
obl
emi
spub
li
clya
vai
lab
leth
rou
ghth
eAl
zhe
ime
r’sD
ise
aseN
eur
oim
agin
g

In
it
iat
ive(ADN
I)(h
ttp
://
adn
i.
lon
i.u
sc.
edu
/). An
oth
ers
eto
fpr
obl
emsi
sto

s
tudyth
epopu
lat
ionl
eve
ltempo
ralev
olu
tiono
fle
sion
sorn
orm
ali
zedv
oxe
lin
-

t
ens
ityinl
esi
onsandth
eira
sso
cia
tionw
ithh
eal
thp
roc
ess
esand
/ort
rea
tmen
t.

F
orex
amp
le
,inas
trok
etr
ialon
ema
ybein
ter
est
edinwh
eth
erth
ebr
ainc
loti
s

e
lim
ina
teda
fte
rsu
rge
ry,h
owf
astth
ecl
oti
sel
imin
atedandwh
eth
erf
ast
ero
r

s
low
ere
lim
ina
tioni
sbe
tte
rfo
rth
epa
tien
t.Inan MSs
tudy
,on
ema
ybein
ter
-

e
stedinan
aly
zin
gre
tro
spe
ctiv
elywh
eth
erwh
item
att
erabn
orm
ali
tie
scou
ldb
e

u
sedt
opr
edi
ctwh
enandwh
erean
ewl
esi
onw
il
loc
cur
. Th
ela
sts
eto
fpr
obl
ems

i
stos
tudyth
est
ruc
tur
eofth
eda
taa
cro
ssth
epopu
lat
ione
ith
eru
sin
gun
su-

p
erv
isedt
echn
iqu
es,su
cha
spr
inc
ipa
lcompon
entan
aly
sis(PCA
)orc
lus
ter
ing
,

o
rsup
erv
isedt
echn
iqu
es,l
iker
egr
ess
ion
.Fo
rex
amp
le
,on
ecou
ldb
ein
ter
est
ed
inan
aly
zin
gth
epr
inc
ipa
ldi
rec
tion
sofv
ari
ati
oninth
ebr
ain m
orph
olo
gyand

i
tsa
sso
cia
tionw
ithh
eal
thou
tcom
es,c
lus
ter
ingo
fsub
jec
tsa
cco
rdin
gtoth
eir

im
agein
ten
sit
ieso
rbr
ain m
orph
olo
gy,o
rid
ent
ify
ingl
oca
tion
sinth
ebr
ainth
at

m
ayb
est
ron
glya
sso
cia
tedw
ithc
ogn
it
ived
ecl
ine
sre
lat
edt
oac
cel
era
teda
gin
g.

1
7
2
.3 Da
tas
truc
tureandin
tui
tiv
ede
scr
ipt
iono
f

a
ssoc
iatedp
rob
lem
s.

I
tisu
sefu
ltod
esc
rib
eth
eda
tas
tru
ctu
reandd
iscu
sssMR
Ifr
oman
ota
tion

p
ersp
ect
ive
. W
eden
oteb
yYijm(
vi )th
jm ein
ten
sit
yofth
emth
,m =1,
...
,M,
s
equ
enc
eofth
esMR
Ida
taa
tth
ejths
tudyv
is
it
,j=1,
...
,J,o
i fth
eithsub
jec
t,

i=1,
...
,I,a
tth
evo
xelv
i .F
jm o
rth
eda
taa
ccomp
any
ingth
isch
apt
erI=J=

,andM =4r
2 esu
lt
inginat
ota
lof1
6im
age
s.F
orth
osec
ase
swh
enth
erei
son
ly

on
esMR
Ipe
rsub
jec
t(e
.g.c
ros
s-s
ect
ion
alim
agin
gstud
ies
)th
eind
exjc
ould

b
eom
itt
ed.A
sth
eind
exe
si,j
,andkinv
ijkind
ica
te,im
age
sar
etyp
ica
llyn
ot

r
egi
ste
red
,inth
esen
seth
atv
oxe
lsd
ono
tha
veth
esam
ein
terp
ret
ati
onb
etw
een
th
esam
esMR
Isequ
enc
es,v
is
its
,orsub
jec
ts. At
ran
sfo
rma
tiono
fim
age
sth
at

en
sur
esth
atth
evo
xeld
epend
son
lyonth
esub
jec
t,th
ati
svjm=v
i iisc
all
edc
o-

r
egi
str
ati
on. At
ran
sfo
rma
tiono
fth
eim
aget
oat
emp
lat
e,X(
v),wh
ereth
evo
xel

d
oesn
otd
ependonth
esub
jec
tisc
all
edr
egi
str
ati
ont
oat
emp
lat
eors
imp
ly

r
egi
str
ati
on. Wh
il
eco
-re
gis
tra
tioni
sle
ssc
ont
rov
ers
ialandcu
rren
tso
ftw
are

s
eem
stoh
and
lei
twe
ll
,re
gis
tra
tiont
oat
emp
lat
era
ise
s mu
lt
ipl
epr
obl
ems
,

e
spe
cia
llyinb
rain
saff
ect
edb
ydi
sea
se. W
ewi
lld
iscu
ssr
egi
str
ati
onandc
o-

r
egi
str
ati
oninS
ect
ion2
.5.
4

Am
ajo
rpr
obl
emin
ima
gin
gisth
atim
age
sma
yha
vesp
ati
alinh
omo
gen
eit
ies
.
M
orep
rec
ise
ly
,th
ism
ean
sth
atth
ein
ten
sit
yofth
eim
ageinv
ari
oust
issu
es(
e.g
.

f
at,wh
item
att
er)v
ari
esb
yth
elo
cat
ioninth
ebr
ain
. Th
isc
anb
equ
iteob
viou
s

wh
en,f
orex
amp
le
,th
ein
fer
iorp
arto
fth
ebr
aini
sbr
igh
terth
anth
esup
eri
or.

Th
isc
anl
eadt
ose
riou
spr
obl
ems
,asg
raym
att
erinth
ein
fer
iorp
arto
fth
e

b
rain m
aya
ctu
allyb
e“wh
ite
r”th
anth
e wh
item
att
erinth
esup
eri
orp
art
.

1
8
Sp
ati
alinh
omo
gen
eit
iesv
aryins
eve
rit
y,andc
ano
ftenb
eve
rysub
tle
. Su
ch
sub
tled
ist
ort
ion
swou
ldb
edi
sca
rdedb
yahum
anob
serv
er,bu
tma
ycr
eat
ese
-

r
iou
spr
obl
ems wh
enon
etr
iest
oan
aly
zed
ata
.Fo
rex
amp
le
,th
eyh
aveb
een

sh
ownt
oha
veal
arg
ene
gat
iveeff
ecton MSl
esi
ons
egm
ent
ati
on[
7].F
roma
n
ota
tion
alp
ersp
ect
ive
,anim
agew
ithsp
ati
alinh
omo
gen
eit
iesw
il
lha
veth
elo
-

c
alin
ten
sit
ydi
str
ibu
tion
sinth
esam
eti
ssu
eva
rya
cro
ssl
oca
tion
sinth
ebr
ain
.
Th
epr
obl
emo
finh
omo
gen
eit
yco
rre
cti
ond
epend
sonth
edefin
it
iono
f“t
issu
e”

andr
equ
ire
sdi
str
ibu
tion m
atch
inga
cro
ssv
ari
oust
issu
etyp
esandb
rainl
oca
-

t
ion
s. Th
isi
sat
oughp
rob
lemw
ithimp
erf
ect
,bu
tre
ason
abl
eso
lut
ion
s. Th
is

i
sdi
scu
ssedind
eta
il
sinS
ect
ion2
.5.
1. Aqu
ickw
ayt
odi
agn
osesp
ati
alinh
omo
-

g
ene
it
iesi
stov
isu
allyid
ent
ifywh
item
att
er,f
at,g
raym
att
er,andbon
ere
gion
s

f
romv
ari
ousp
art
softh
ebr
ainandp
lotth
ehi
sto
gram
sofin
ten
sit
iesf
ore
ach

su
chr
egi
ons
epa
rat
ely
. Al
esseff
ect
ive
,bu
tfa
ste
ral
tern
ativ
eist
ocomp
areth
e

h
ist
ogr
amso
fax
ial
,sa
git
tal
,andc
oron
ald
ist
ribu
tion
s.O
fcou
rse
,ti
ssu
etyp
e

p
ropo
rti
onssh
ouldv
aryb
ysl
ice
,bu
tre
ason
abl
eapp
rox
ima
tion
scanb
eob
-

t
ain
ed. An
oth
era
lte
rna
tiv
eist
ous
eandv
isu
ali
zeana
ggr
ess
ivesm
ooth
erth
at

w
ouldh
ideb
iol
ogi
calin
form
ati
on,bu
twou
ldh
igh
ligh
tunu
sua
lsp
ati
alp
att
ern
s

o
fim
agein
ten
sit
y.

Wh
enev
eron
eisin
ter
est
edinan
aly
zin
gmo
reth
anon
esequ
enc
e,i
tisu
sefu
l

f
orth
eun
itsinwh
ichYijm(
vi )i
jm sexp
res
sedt
oha
veth
esam
ein
terp
ret
ati
on

andb
eonth
esam
esc
ale
. A
swem
ent
ion
ede
arl
ier
,th
isi
sno
tth
eca
sein

sMR
I,wh
ichc
anr
ais
efund
amen
talqu
est
ion
sre
lat
edt
opopu
lat
ionl
eve
leff
ect
s.

Ind
eed
,ifd
ataa
ren
otonth
esam
esc
aleev
ent
akin
gth
ediff
eren
cesb
etw
een
tw
oim
age
sdo
esn
otm
akes
ens
e. At
ran
sfo
rma
tiono
fim
agein
ten
sit
iesf
rom
th
erawim
aget
oanin
terp
ret
abl
esc
alei
sca
ll
edim
agein
ten
sit
yno
rma
li
zat
ion
.

1
9
Th
issh
ouldn
otb
emi
stak
enf
orim
ager
egi
str
ati
on,wh
ichi
sal
soo
ftenr
efe
rred
t
oinp
rac
tic
eas“
ima
gen
orm
ali
zat
ion
”.InS
ect
ion2
.5.
5wew
il
ldi
scu
ssth
e

s
tat
ist
ica
lpr
inc
ipl
eso
fim
agen
orm
ali
zat
ionandw
ewi
lld
iscu
ssv
ari
ousw
ayso
f

c
ondu
ctin
gim
agein
ten
sit
yno
rma
li
zat
ion
.

2
.4 Acqu
isi
tionandre
con
struc
tion

Th
econ
tra
sto
fanSMR
Ivo
lum
eisth
ere
lat
ived
iffe
ren
ceo
fsi
gna
lin
ten
sit
ies

w
ith
inth
evo
lum
e. Wh
enan MR
Isc
ani
sacqu
ired
,ch
ang
ingth
esc
ann
ingp
a-

r
ame
ter
sch
ang
esth
econ
tra
sto
fth
evo
lum
etop
rodu
ceth
ediff
eren
tsequ
enc
es,
su
cha
sFLA
IR,T
1,T
2,andPD
.Th
esc
ann
ingp
aram
ete
rsth
atc
ont
ribu
tet
o

th
econ
tra
sto
fanim
agea
reth
eflipan
gle(FA
),th
erep
eti
tiont
ime(TR
),th
e

in
ver
siont
ime(T
I),andth
eech
otim
e(TE
).A m
ored
eta
il
edd
esc
rip
tiono
f

im
ages
cann
ingp
aram
ete
rsc
anb
efoundin[
22]
. Sm
allch
ang
esinth
esc
an-

n
ingp
aram
ete
rsc
anr
esu
ltind
iffe
ren
tcon
tra
st.F
orex
amp
le
,tw
ovo
lum
esm
ay

bo
thb
ea“FLA
IR”v
olum
e,bu
tifa
cqu
iredw
ithd
iffe
ren
tsc
ann
ingp
aram
ete
rs

c
anh
aved
iffe
ren
tim
agec
ont
ras
ts. MR
Iph
ysi
cis
tar
econ
tinu
ally w
ork
ingt
o

d
eve
lopn
ewim
agin
gte
chn
iqu
esinth
efo
rmo
fdiff
eren
tcomb
ina
tion
softh
ese
p
aram
ete
rst
opr
odu
ceh
igh
erqu
ali
tyv
olum
es.I
tisth
ere
for
ede
sir
abl
e,bu
t

qu
ited
ifficu
lt
,tod
eve
lopa
lgo
rithm
sth
ata
rer
obu
stt
och
ang
esinth
esc
ann
ing

p
aram
ete
r.V
ari
abi
li
tyinth
econ
tra
stsc
ana
lsoa
ris
efr
omth
est
ren
gtho
fth
e

m
agn
etu
sedf
orim
agin
g. Th
ema
gne
tst
ren
gthi
sme
asu
reint
esl
as. Cu
rren
tly
,

c
omm
onfi
elds
tren
gth
sfo
rsMR
Iar
e1.
5T,3T
,and7T[
22]
.Sl
iceth
ickn
essand

th
ein
-pl
aner
eso
lut
iono
fth
eor
igin
alv
olum
esi
sal
soimpo
rtan
t,a
sth
evo
lum
es

2
0
m
ayb
ein
terpo
lat
eddu
rin
gim
agep
re-p
roc
ess
ing
.In
form
ati
onabou
tth
esc
an-
n
ingp
aram
ete
rs,s
li
ceth
ickn
ess
,andfi
elds
tren
gtho
fth
ema
gne
tcano
ftenb
e

f
oundinth
ehe
ade
rofth
esMR
Ivo
lum
e.

Du
rin
gacqu
is
it
ion
s,im
agin
gar
ti
fac
tsc
ana
ris
edu
etoth
eim
agin
gha
rdw
are
o
rfr
omth
esub
jec
t.I
tisw
el
les
tab
li
shedth
atth
ein
trodu
cti
ono
far
ti
fac
tsa
s-

s
oci
atedw
ithp
ati
entm
oti
onandth
eva
riab
il
itya
sso
cia
tedw
iths
cann
ersc
an
s
ign
ific
ant
lyd
egr
adeth
eac
cur
acyo
fre
sul
tsf
romfu
rth
eran
aly
sis[
23]. Th
ere
-

f
orev
olum
esf
romth
esc
ann
ert
ypi
cal
lyund
erg
oei
the
ra m
anu
alo
rau
tom
ati
c

qu
ali
tyc
ont
rolt
oas
sur
eth
atv
olum
esw
itha
rti
fac
tsa
rer
emo
vedb
efo
rean
aly
-

s
is
.[2
3]and[
24]bo
thp
ropo
seau
tom
ated m
eth
odsf
ora
sse
ssin
gth
equ
ali
tyo
f

anim
age
.

2
.5 P
re-p
roce
ssing

A
fte
rth
esMR
Ida
tai
sacqu
iredandr
econ
stru
cted
,da
taa
rep
re-p
roc
ess
edf
or

an
aly
sis
.Iti
sof
tenh
ardt
odefin
eex
act
ly wh
at“p
re-p
roc
ess
ing
”me
ans
,as

i
twi
llv
aryb
ystudy
,sc
ien
tis
t,o
rev
enan
aly
sis
. Ind
eed
,pr
e-p
roc
ess
ingand

im
agean
aly
sisa
rec
los
elyl
ink
ed,w
ithp
re-p
roc
ess
ingo
ftenh
avin
gad
ram
ati
c

imp
actonth
ean
aly
ticr
esu
lts
. Thu
s,i
tisimpo
rtan
tfo
rth
ebi
ost
ati
sti
cian
sand

s
tat
ist
ic
ian
swo
rkin
gwi
thsMR
Ida
tat
oha
vekn
owl
edg
eofth
epr
e-p
roc
ess
ing

s
tep
sandth
eirpo
ten
tia
limp
act
sonth
edown
str
eaman
aly
ses
.Fo
rth
epu
r-
po
seo
fth
isp
ape
r,w
ediv
ideim
agep
re-p
roc
ess
ingin
tof
ourm
ains
tep
s:1
)

inh
omo
gen
eit
yco
rre
cti
on;2
)sp
ati
alin
terpo
lat
ion
;3)sku
lls
tripp
ing
;4)sp
ati
al

r
egi
str
ati
on;and5
)in
ten
sit
yno
rma
li
zat
ion
. Ad
eta
il
edd
esc
rip
tiono
fea
chs
tep

w
iths
oftw
areandd
ataapp
li
cat
ion
sisp
rov
idedinth
iss
ect
ion
. Th
eses
tep
sar
e

2
1
t
ypi
cal
lyex
ecu
tedinth
iso
rde
rinanim
agep
re-p
roc
ess
ingp
ipe
lin
eandd
epend
onv
ari
ousch
oic
esandop
tim
ali
tyc
rit
eri
a. Ap
ipe
lin
eisach
oic
eofap
art
icu
lar

s
eto
fim
agep
re-p
roc
ess
ings
tep
sth
atc
anb
eapp
li
edt
oman
yim
age
s. Wh
il
e

w
esimp
li
fyh
eref
orund
ers
tand
ing
,anadd
it
ion
alc
omp
li
cat
ioni
sth
atth
eor
-
d
er,s
tep
s,anda
lgo
rithmf
ore
achs
tepa
ren
ota
gre
eduponinth
ecommun
ity
.

P
arto
fth
ere
asonf
orth
eplu
ral
ityo
fpip
elin
esi
sth
ati
tisd
ifficu
ltt
oqu
ant
ify
th
ediff
eren
ceinqu
ali
tyb
etw
eenp
re-p
roc
ess
ingp
ipe
lin
es.D
eve
lop
ingimp
rov
ed

a
lgo
rithm
sfo
rim
agep
re-p
roc
ess
ingand m
eth
odsf
orqu
ant
ify
ingth
equ
ali
tyo
f

p
ipe
lin
esi
sana
reafi
ll
edw
ithoppo
rtun
it
ies
.

Th
erea
rem
anyt
ool
sfo
rcr
eat
ingim
agep
re-p
roc
ess
ingp
ipe
lin
es. Th
ech
oic
e

o
ftoo
lssh
ouldb
eba
seduponth
etoo
lsa
vai
lab
il
ity
,re
sul
tsqu
ali
ty,andc
ompu
-

t
ati
ona
lfe
asib
il
ityf
orl
arg
eco
ll
ect
ion
sofim
age
s. Wh
il
ewed
obe
li
eveth
atth
ere

i
snoun
ive
rsa
llyb
estp
ipe
lin
e,an
on-
exh
aus
tiv
eli
sto
fpopu
larsMR
Ipip
elin
es

in
clud
eth
eLON
IPip
elin
ePr
oce
ssin
gEn
vir
onm
ent[
25]
,th
eFMR
IBS
oftw
are

L
ibr
ary(FSL
)[2
6],andJ
avaIm
ageS
cien
ceT
oolk
it(J
IST
)[2
7]imp
lem
ent
edin

M
edi
calIm
ageP
roc
ess
ingAn
aly
sisandV
isu
ali
zat
ion(M
IPAV
)[2
8]. Anex
cit
-

in
gnewt
oolf
orRu
ser
sisANTsR:AdvancedNormalizationToolswithR

(h
ttp
://
stn
ava
.gi
thub
.io
/ANT
sR/
ind
ex.h
tml
),ap
re-p
roc
ess
ingp
ipe
lin
eth
atc
an

b
erunth
rou
ghR.Im
agep
ipe
lin
eso
ftenf
ailonasub
seto
fim
age
s,wh
ich
,le
ft

un
cor
rec
ted
,cans
eri
ous
lyimp
actd
own
str
eaman
aly
ses
. Th
ere
for
e,an
oth
er

qu
ali
tyc
ont
rols
tep mu
stb
epe
rfo
rmed
, wh
icho
ftenc
ons
ist
sofaqu
ali
tat
ive

v
isu
alin
spe
cti
ono
fth
epr
epr
oce
ssedim
age
s.

2
2
2
.5.1 Inhomogene
ityco
rrec
tion

MR
Iin
ten
sit
yinh
omo
gen
eit
yisth
esl
owv
ari
ati
ono
fin
ten
sit
iesw
ith
inat
is
-
su
ecl
assinanim
age
.Inth
eli
ter
atu
rein
ten
sit
yinh
omo
gen
eit
yisa
lsor
efe
rred

t
oasin
ten
sit
ynonun
ifo
rmi
ty,sh
adin
g,th
ebi
asfi
eldo
rth
ega
infi
eld
.Sp
ati
al

inh
omo
gen
eit
ycanb
ecau
sedb
yth
e MR
Isc
ann
ero
rbyth
epr
ope
rti
eso
fth
e
ob
jec
tth
ati
sbe
ingim
aged
. Th
ela
tte
rcau
sei
sha
rdt
ocon
tro
landa
ccoun
tfo
r,

bu
tisr
ela
tiv
elysm
allinl
ow m
agn
eti
cfie
ldin
ten
sit
ysc
ann
ers
.Inh
omo
gen
eit
y

m
ayr
ais
ean
aly
tic
alch
all
eng
es,b
ecau
seb
asi
cas
sump
tion
sofv
ari
ousm
ode
ls

andt
echn
iqu
esm
ayb
evi
ola
ted
. Ac
ons
equ
enc
ecanb
eth
atm
eth
odsd
eve
lop
ed
f
orim
age
swi
thn
o,sm
all
,orkn
owninh
omo
gen
eit
yfie
ldp
att
ern
sma
yfa
ilin

h
ete
rog
ene
ousim
agin
gstud
ies wh
ereinh
omo
gen
eit
yfie
ldsc
anb
equ
itel
arg
e

o
rha
veun
exp
ect
edd
ist
ribu
tion
s.F
orex
amp
le
,man
yse
gmen
tat
iona
lgo
rithm
s

u
seim
agein
ten
sit
yth
resh
old
ingonon
eorm
oreim
age
sth
ata
rekn
ownt
odi
s-

c
rim
ina
tew
el
lbe
twe
ensp
ecifi
cti
ssu
ecl
ass
es.H
owev
er,i
fth
esam
eti
ssu
eha
s
d
iffe
ren
tin
ten
sit
ydi
str
ibu
tion
satd
iffe
ren
tlo
cat
ion
sinth
ebr
ainth
ens
egm
en-

t
ati
ona
lgo
rithm
scanb
ese
riou
slyaff
ect
ed.F
orex
amp
le
,Fi
gur
e2.
3Ad
isp
lay
s

aT
1vo
lum
efr
oma7Ts
cann
er,wh
il
eFi
gur
e2.
3Bd
isp
lay
sth
ees
tim
atedin
-

h
omo
gen
eit
yfie
ld,ind
ica
tin
ghi
ghe
rin
ten
sit
iesinth
ele
ft-bo
ttomc
orn
er. Thu
s,
g
raym
att
erinth
isa
reah
ash
igh
erin
ten
sit
iesth
anwh
item
att
era
rea
sino
the
r

a
rea
softh
ebr
ain(
gra
yma
tte
rlook
s“wh
ite
r”th
anwh
item
att
er.
) Wh
il
ere
s-

o
lut
ionandb
iol
ogi
cald
eta
il
sar
esh
arp
erinh
igh
erin
ten
sit
ysc
ann
ers
,sp
ati
al

inh
omo
gen
eit
yiskn
ownt
oin
cre
asew
ithth
efie
lds
tren
gtho
fth
ema
gne
t.

2
3
 A B

F
i gu
re2.3: A. Ax
ialsl
icefroma T 1-w ei
ghtedvo
lum eob
tainedfroma7T
scanne
r. Volumesfromscannerswithah ighermagne
ticfie
lds tr
engtho
ften
conta
in morein
tens
ityinhom o
geni
tya rt
ifac
ts,ass
eeninthisim a
ge.B. The
inhom o
geni
tyfieldforth
issl
iceasm od
eledbytheN 4ITKalgo
rithm.

2
.5.1
.1 Concep
ts

Th
einh
omo
gen
eit
yfie
ldo
fanim
agei
scomm
onlym
ode
ledmu
lt
ipl
ica
tiv
ely
.Fo
r

av
oxlv,th
e eob
serv
edin
ten
sit
yinanim
ageYm(
v), wh
ere
,fo
rsimp
li
cit
y,w
e

h
aved
ropp
edth
esub
jec
tandv
is
itind
exu
sedinS
ect
ion2
.3. C
onc
eptu
ally
,

th
eob
serv
edim
agei
smod
eleda
sYm(
v)=α(
v)Xm(
v)+e
v,wh
ereXm(
v)i
sth
e

t
ruev
oxe
lin
ten
sit
y,α(
v)i
sth
e mu
lt
ipl
ica
tiv
einh
omo
gen
eit
yfie
ld,ande
visan

add
it
ivee
rro
ras
sum
edt
ofo
llowaG
aus
siand
ist
ribu
tion
. Th
eadd
it
ivee
rro
ris
o
fteni
gno
redandd
ataa
rem
ode
ledadd
it
ive
lyonth
elo
g-in
ten
sit
ysc
ale
:

l
og{
Ym(
v)}=l
og{
Xm(
v)}+
log{α(
v)}
. (
2.1
)

2
4
 [
29]and[
30]p
rov
idec
omp
reh
ens
iver
evi
ewso
fme
thod
stoc
orr
ectf
orim
-
a
geinh
omo
gen
eit
ies
. Th
einh
omo
gen
eit
yfie
ldc
anb
eco
rre
ctedf
orp
rosp
ect
ive
ly

th
rou
ghph
ant
oms
can
s,th
eus
eofmu
lt
ipl
eco
il
s,o
rsp
eci
als
equ
enc
es. W
efo
cus

onr
etr
osp
ect
ivem
eth
odst
oes
tim
ateth
efie
ldf
romth
eth
eda
ta,a
sth
esea
re
m
ostr
elev
antt
oth
est
ati
sti
cian
.Cl
ear
ly
,th
ede
con
volu
tion m
ode
l2.
1requ
ire
s

s
tron
gas
sump
tion
stoen
sur
eid
ent
ifiab
il
ity
. Wh
il
eea
ch m
eth
odu
sedf
ore
sti
-
m
ati
onm
ake
ssl
igh
tlyd
iffe
ren
tte
chn
ica
las
sump
tion
s,in
tut
it
ive
lyth
eya
llm
ake

a
ssump
tion
sabou
tth
ede
gre
eofv
ari
ati
oninth
elo
g{Xm(
v)}andl
og{α(
v)}p
ro-

c
ess
es.T
ypi
cal
ly
,th
ougho
ftenn
otexp
li
cit
,on
eas
sum
esth
atl
og{α(
v)}v
ari
es

sp
ati
ally mu
chs
low
erth
anl
og{
Xm(
v)}. Und
erth
isa
ssump
tion
,ana
ggr
ess
ive

sm
ooth
er(
e.g
.3Dk
ern
elsm
ooth
erw
ithal
arg
ewind
ow)o
fth
eim
agec
ouldb
e
v
iew
eda
sane
stim
ato
rofl
og{α(
v)}. Th
ema
jor
ityo
finh
omo
gen
eit
yco
rre
cti
on

m
eth
odsc
anb
egr
oup
eda
s(1
)fil
ter
ing
,(2
)su
rfa
cefi
ttin
g,and(
3)s
tat
ist
ica
l

m
ode
ls
.Infi
lte
rin
gme
thod
s,th
einh
omo
gen
eit
yfie
ldi
sas
sum
edt
obeo
flow
sp
ati
alf
requ
encyandth
esi
gna
lofth
ean
atom
ica
lst
ruc
tur
esinth
eim
ageo
f

h
ighf
requ
ency
. Th
einh
omo
gen
eit
yfie
ldc
anth
enb
erem
ovedu
sin
gal
owp
ass

fi
lte
r. Su
rfa
cefi
ttin
gme
thod
sus
eat
issu
ese
gmen
tat
ionfi
rst
, wh
ichi
sth
en

f
oll
owedb
ysm
ooth
ingw
ith
int
issu
ecl
ass
es.S
tat
ist
ica
lmod
elsa
ssum
eth
atth
e
inh
omo
gen
eit
yfie
ldf
oll
owsap
art
icu
larr
and
omp
roc
essd
ist
ribu
tion
. W
ewi
ll

t
akeex
cep
tiont
oth
isn
omen
cla
tur
e,a
sal
lth
eseapp
roa
che
sar
eba
sedons
ta-

t
ist
ica
lmod
els
.How
eve
r,w
epr
ovid
eth
eac
cep
tedc
ate
gor
iza
tiont
ohe
lpw
ith

c
ommun
ica
tion
.

Wh
enth
etru
einh
omo
gen
eit
yfie
ldi
sno
tav
ai
lab
le
,cr
ite
riau
sedt
oas
ses
sth
e

p
erf
orm
anc
eofinh
omo
gen
eit
yco
rre
cti
on m
eth
odsin
clud
e:1
)va
rian
ceo
verth
e

en
tir
eim
ageo
rse
gmen
tedpo
rti
onso
fth
eim
age
;2)c
oeffi
cien
tofv
ari
ati
ono
ver

2
5
th
eim
age
;3)j
oin
tco
effic
ien
tofv
ari
ati
onb
etw
eentw
oti
ssu
ecl
ass
es. Wh
enth
e
t
rueinh
omo
gen
eit
yfie
ldi
sav
ai
lab
le
,th
eme
ansqu
aree
rro
rbe
twe
enth
ede
riv
ed

andt
rueinh
omo
gen
eit
yfie
ldi
sca
lcu
lat
ed.O
the
rimpo
rtan
tcon
sid
era
tion
sfo
r

a
sse
ssin
gth
esem
eth
odsa
res
tab
il
ity
,compu
terr
equ
irem
ent
s,and CPUt
ime
[
29]
.

2
.5.1
.2 P
rac
tica
lapp
roache
s,so
ftwa
re,andapp
lica
tiontoda
ta

Th
emo
stc
omm
onlyu
sed m
eth
odf
orinh
omo
gen
eit
yco
rre
cti
oni
sas
tat
ist
ica
l

m
ode
l,th
enonp
aram
etr
icn
onun
ifo
rmin
ten
sit
yno
rma
li
zat
ion(N
3)c
orr
ect
ion

[
19]
. Th
eme
thoda
ssum
esth
atf(
v) =l
og{
α(v)
}andu(
v) =l
og{
Xm(
v)}a
re

tw
oind
epend
entr
and
omv
ari
abl
esw
ithd
ist
ribu
ti sF andU,r
on esp
ect
ive
ly
.

Th
edi
str
ibu
tiono
fth
esum
softh
esetw
orand
omv
ari
abl
esi
sth
econ
volu
tion

o
fFandU. N
3se
arch
esf
orth
einh
omo
gen
eit
yfie
ldt
omax
imi
zeth
efr
equ
ency

c
ont
ento
fth
eim
agein
ten
sit
ydi
str
ibu
tionandc
ons
tra
insth
einh
omo
gen
eit
y
fi
eldt
obem
ode
leda
saG
aus
siand
ist
ribu
tionw
ithsm
allv
ari
anc
e.C
odef
orth
is

m
eth
odi
spub
li
clya
vai
lab
leandh
asb
eenimp
lem
ent
edin m
ostp
re-p
roc
ess
ing

p
ipe
lin
es.M
orer
ecen
tly
,animp
rov
emen
tandex
ten
siono
fth
eN3m
eth
odh
as

b
eenp
ropo
sed
,th
eN4
ITK[
20]
.Cod
efo
rth
ism
eth
odi
spub
li
clya
vai
lab
leand

th
eme
thodh
asa
lre
adyb
eenimp
lem
ent
edin m
anyp
ipe
lin
es. F
igu
re2
.3B

sh
owsth
einh
omo
gen
ityfi
elda
smod
eledb
yth
eN4ITKa
lgo
rithm[
20]
.

2
6
2
.5.2 Sku
lls
tripp
ing

Sku
lls
tripp
ingi
sth
epr
oce
sso
fex
tra
ctin
gth
ebr
ainf
romanim
ageb
yrem
ovin
g
th
eba
ckg
roundanda
llo
the
rti
ssu
e. M
oresp
ecifi
cal
ly
,th
epr
obl
emi
stoe
sti
-

m
ate Sijm(
vi )∈{0
jm ,1}
,th
eind
ica
torv
ari
abl
eofb
raint
issu
ebe
ingc
ont
ain
ed

inv
oxlv
e jmf
i romth
eim
age
sofe
achsub
jec
tate
achv
is
it
,Yijm(
vi )
jm. Th
isp
ro-
c
ess
,wh
ich m
ayb
econ
sid
eredas
egm
ent
ati
ont
ask(
seea
lsoS
ect
ion2
.6.
1),i
s

n
ece
ssa
ryf
orth
eid
ent
ific
ati
ono
fti
ssu
etob
estud
ied
.Er
ror
sinsku
lls
tripp
ing

c
anp
rodu
cebo
thfi
cti
tiou
seff
ect
sandr
edu
cepow
eri
fkeyr
egi
onso
fth
ebr
ain

a
ree
rron
eou
slyr
emo
ved
.

2
.5.2
.1 Concep
ts

Wh
il
edo
zen
soft
echn
iqu
esh
aveb
eenp
ropo
sedf
orth
ist
asko
verth
epa
sttw
o

d
ecad
es,th
emo
stc
omm
on m
eth
odr
ema
insth
ebr
ainex
tra
cti
ont
ool(BET
)

[
31]
. BETi
sas
imp
let
echn
iqu
eth
ata
imst
oit
era
tiv
elyfi
ta m
esha
roundth
e
su
rfa
ceo
fth
ebr
ain
,andh
asb
eensh
ownt
oha
vesup
eri
orp
erf
orm
anc
etoc
om-

p
etin
gme
thod
s,a
lth
oughi
tha
sdo
cum
ent
edl
imi
tat
ion
sin
clud
ingap
rop
ens
ity

t
oin
clud
eex
tra
cer
ebr
alt
issu
einth
ebr
ain m
ask[
32,3
3]. Wh
il
esev
era
lhyb
rid

m
eth
ods[
34,3
5]h
aveb
eenp
ropo
sedb
yin
teg
rat
ingg
ene
rat
iveandc
las
si
fyin
g
t
echn
iqu
est
opr
odu
cem
eth
odsth
ata
rer
obu
stt
odiff
eren
cesb
etw
eens
cann
ers

andp
rot
oco
ls
,nos
olu
tionh
ass
ati
sfa
cto
ri
lys
olv
edth
epr
obl
em. Thu
s,m
ost

im
agean
aly
sisg
roup
sst
il
lre
sor
ttom
anu
alc
orr
ect
iona
fte
rau
tom
ati
csku
ll

s
tripp
ing
. R
ecen
tly
, mu
lt
i-a
tla
slab
elfu
siont
echn
iqu
es[
36,3
7]h
avesh
own

g
rea
tpr
omi
sef
orsku
ll
-st
ripp
ing[
38,3
9];th
esem
eth
odsu
sed
efo
rmab
ler
egi
s-

t
rat
iont
ocomp
areth
esub
jec
tund
ers
tudyw
ithal
ibr
aryo
foth
erim
age
sfo
r

2
7
wh
ichm
anu
alsku
ll
-st
ripp
ingim
age
s(c
all
eda
tla
ses
)anda
ver
age(
orfu
se)th
ese
m
anu
all
abe
lsa
cro
ssa
tla
ses
.Pa
tch
-ba
sedt
echn
iqu
es[
40]h
avea
lsosh
owng
rea
t

p
rom
isew
iths
ign
ific
ant
lyl
owe
rcompu
tat
ion
albu
rden
. A
snew m
eth
odsa
re

d
eve
lop
ed,m
anyau
tho
rssubm
itr
esu
ltsf
ora
ctiv
ecomp
ari
sont
oav
al
ida
tion
r
esou
rce
,andc
omp
ari
son
sar
epub
li
clya
vai
lab
le[
41]
.

2
.5.2
.2 P
rac
tica
lapp
roache
s,so
ftwa
re,andapp
lica
tiontoda
ta

A
sBET[
31]i
ssoc
omm
onlyu
sed
,wed
emon
str
atei
tsapp
li
cat
iona
sane
asy
-to
-

u
seandc
ompu
tat
ion
allyp
rac
tic
alapp
roa
ch. BETw
asfi
rstimp
lem
ent
edinFSL

[
42]
,bu
tnowi
sav
ai
lab
leino
the
rim
agep
roc
ess
ingp
ack
age
sin
clud
ingM
IPAV

andJ
IST[
43]
.Us
ingM
IPAV
,sku
ll
-st
ripp
ingc
anb
each
iev
edu
sin
gBETona

T
1-w
eigh
tedim
ageinl
essth
ana m
inu
teonas
tand
ardp
ers
ona
lcompu
terand

anex
amp
leo
fth
ere
sul
tsi
ssh
owninF
igu
re2
.4.

2
.5.3 In
terpo
lat
ion

In
terpo
lat
iont
ran
sfo
rmsad
isc
ret
ear
rayo
fnumb
ersin
toac
ont
inu
ousim
age
.

A
swes
awinF
igu
re2
.2,sMR
Iar
ear
ray
sofin
ten
sit
yva
lue
sth
ath
aveb
een
s
amp
ledonag
rid
. Wh
enp
erf
orm
ingop
era
tion
ssu
cha
sim
ager
egi
str
ati
on,

m
agn
ific
ati
on,im
ager
esl
ic
ingandr
esamp
lin
g,andsu
rfa
cer
end
erin
giti
sde
-

s
irab
let
oha
veac
ont
inu
ousim
ageandt
okn
owth
eapp
rox
ima
tev
alu
eso
fth
e

im
agea
tpo
int
soth
erth
anth
oseonth
eor
igin
alg
rid
.

2
8
 A B

Fi
gure2.4
: Anaxi
alsl
iceo ff
roma3TT 1
-wei
ght
edimagingofap at
ientwith
MSb e
for
e(A,showing Yijm(
vi )
jm)anda
fte
r(B,show
ingYijm(
vi )
jmSijm(
vijm)
)
skul
lstr
ipp
ingus
in gBET .

2
.5.3
.1 Concep
ts

Anex
ten
siv
erev
iewandc
omp
ari
sono
fin
terpo
lat
ion m
eth
odsin m
edi
calim
-

a
gean
aly
sisc
anb
efoundin[
44]and[
45]
. Th
emo
stc
omm
onin
terpo
lat
ion

m
eth
odsinsMR
Ian
aly
sisa
ret
run
cat
edandw
ind
oweds
inc
,ne
are
stn
eighbo
rs,

l
ine
ar,qu
adr
ati
c,cub
icb
-sp
lin
es,cub
ic
,La
gran
ge,andG
aus
sianin
terpo
lat
ion
.

C
ons
ide
rth
evo
xel v=(xv,y
v,z
v) w
ithc
oord
ina
tes(
xv,y
v,z
v)tha
twe
ren
ot

n
ece
ssa
ri
lyam
ongth
ecoo
rdin
ate
swh
ered
ataw
eres
amp
led
. Th
enth
eim
age

c
anb
ein
terpo
lat
eda
tva
s

Ym(
v)=Ym(
xv,y
v,z
v)= Ym(
p,r
,s)
h(xv−p
,yv−r
,zv−s
)
p
,r,
s

2
9
wh
ereth
efun
cti
onh(
·,·
,·
)isth
ein
terpo
lat
ionk
ern
elandth
esumm
ati
oni
sdon
e
o
vera
llp
,r,swh
ered
ataa
reob
serv
ed.T
opr
ovid
esom
ein
tui
tionw
ede
scr
ibe

th
ein
terpo
lat
ionk
ern
elsf
or“
onen
ear
estn
eighbo
r”,“
lin
ear
”and“w
ind
owed
s
inc
”.F
oron
ene
are
stn
eighbo
rth
ein
terpo
lat
ionk
ern
eli
s:



 1 0≤|x|≤0.5
h(
x)=

0 e lsewh
ere

F
orl
ine
arin
terpo
lat
ionth
ein
terpo
lat
ionk
ern
eli
s:



 1−|x| 0≤|x|≤0.5
h(
x)=

 0 e
lsewh
ere

Th
esin
cfun
cti
oni
ssin
c(x) =sin
(πx)
πx
.I
f Nd
eno
testh
enumb
ero
fsuppo
rtin
g

po
int
sus
edf
orin
terpo
lat
ionth
enth
ewind
oweds
incin
terpo
lat
ionk
ern
eli
s


 s
in(πx)
πx
0≤|x|≤N
2
h(
x)=

 0 e
lsewh
ere

2
.5.3
.2 P
rac
tica
lapp
roache
s,so
ftwa
re,andapp
lica
tiontoda
ta

InsMR
Ipr
e-p
roc
ess
ing
,in
terpo
lat
ioni
slink
edc
los
elyw
ithsp
ati
alr
egi
str
ati
on.

A
sanim
agei
ssp
ati
allya
lign
edt
oan
oth
erim
ageo
rat
emp
lat
e,th
eim
age

b
ein
gre
gis
ter
ed mu
stb
ein
terpo
lat
edt
ode
term
ineth
eva
lue
softh
ere
gis
ter
ed

im
ageinth
enewc
oord
ina
tesp
ace
.In
terpo
lat
ionm
eth
odsa
ret
ypi
cal
lyatun
ing
p
aram
ete
rfo
rre
gis
tra
tionanda
reimpo
rtan
tasth
eyc
animp
actth
ecl
ari
ty

o
fth
eim
agea
fte
rre
gis
tra
tion
. W
ind
oweds
inch
asb
eensh
ownt
opr
odu
ce
g
oodr
esu
ltsina
cco
rdan
cew
ithth
enumb
ero
fsuppo
rtin
gpo
int
sus
edinth
e

3
0
in
terpo
lat
ion
,bu
tcanb
ecom
equ
itec
ompu
tat
ion
allyin
ten
siv
easth
enumb
er
o
fsuppo
rtin
gpo
int
sin
cre
ase
s[4
4].

2
.5.4 Spa
tia
l Reg
ist
rat
ion

R
egi
str
ati
oni
sth
epr
oce
sso
fde
term
inin
gth
esp
ati
ala
lignm
entandc
orr
espon
-

d
enc
ebe
twe
enim
age
s.C
ons
ide
rth
eca
sewh
enon
eisin
ter
est
edinr
egi
ste
rin
g
im
ageY(
p,r
,s)t
oY(
p,r
,s)
,wh
erep=1,
...
,P,r=1,
...
,R,ands=1,
...
,S
a
reth
eind
exe
softh
eth
reed
imen
sion
ala
rra
ys. Th
edim
ens
iono
fbo
tha
rra
ys

a
reP×R×S;wh
enth
ear
ray
sha
ved
iffe
ren
tdim
ens
ion
sin
terpo
lat
ion
,asd
e-

s
crib
edinS
ect
ion2
.5.
3,c
anb
eapp
li
ed.I
fweid
ent
ifyav
oxe
lwi
thi
tsa
rra
y

ind
exv=(p
,r,s
)th
enth
epr
odu
cto
fre
gis
tra
tioni
sab
ije
ctiv
etr
ans
form
ati
on

m
ap, v→ T(
v),f
romon
eim
ager
efe
ren
cesy
stemt
oan
oth
er. Th
ere
gis
ter
ed

im
ageinth
ere
fer
enc
esy
stemo
fY(
·,·
,·
)isth
enY{T(
p,r
,s)
}wh
ere
asr
esu
ltso
r

im
age
scanb
eob
tain
edinth
e“n
ativ
esp
ace
”byu
sin
gth
eba
ckt
ran
sfo
rma
tion

v→ T−1(
v).I
tisimpo
rtan
tton
oteth
atr
egi
str
ati
oni
sat
ran
sfo
rma
tiono
f

sp
aceandd
oesn
otaff
ectim
agein
ten
sit
ies
;how
eve
r,im
agein
ten
sit
iesc
anb
e

u
sedt
ofindop
tim
alt
ran
sfo
rma
tion
sinasp
ecifi
ccl
asso
ftr
ans
form
ati
ons
.In
th
iss
ect
ion w
efo
cusonin
tra
-sub
jec
tre
gis
tra
tion
,al
sor
efe
rredt
oassp
ati
al
n
orm
ali
zat
ion
.In
ter
-sub
jec
tre
gis
tra
tionandr
egi
str
ati
ont
oag
roupt
emp
lat
e

im
agea
red
iscu
ssedinth
eAn
aly
siss
ect
ion
.[4
6]p
rov
ide
sad
eta
il
edsumm
ary

o
fre
gis
tra
tion m
eth
odsandw
eus
eth
eno
tat
ionin
trodu
cedinth
ist
extinth
e
f
oll
owin
gde
scr
ipt
ion
.

3
1
2
.5.4
.1 Concep
ts

Th
erei
saninfin
itenumb
ero
ftr
ans
form
ati
onsv→ T(
v)andth
eyr
ang
efr
om
u
sel
esst
ous
efu
l.F
orex
amp
le
,giv
entw
oim
age
sexp
res
sedonth
esam
e3Dg
rid

on
ecanp
erf
ect
lyt
ran
sfo
rme
achind
ividu
alpo
intf
romth
efir
stim
aget
oea
ch

ind
ividu
alpo
intinth
ese
condim
age
. Su
chat
ran
sfo
rma
tion m
ayo
rma
yno
t
r
esp
ects
omeo
rde
randi
sch
ara
cte
riz
edb
yth
ede
gre
eofsm
oothn
ess(numb
er

o
fde
gre
eso
ffr
eed
om)
. Ar
and
oma
ssi
gnm
ento
find
exe
swou
ldh
aveP×R×S!

d
egr
eeso
ffr
eed
om,w
ithm
ostt
ran
sfo
rma
tion
sbe
ingu
sel
essandun
inf
orm
ativ
e.
H
erew
ewi
lld
esc
rib
eaf
ewu
sefu
ltr
ans
form
ati
ons
,in
clud
ingr
igidandaffin
eand

w
ewi
llp
rov
ideth
ene
ces
saryt
ool
sfo
rnon
-l
ine
arandd
iffe
omo
rficapp
roa
che
s.

R
igidr
egi
str
ati
oni
sth
esimp
les
ttyp
eofr
egi
str
ati
onandc
ons
ist
sofat
ran
s-

l
ati
onandr
ota
tion
. Thu
s,3Dr
igidr
egi
str
ati
onsh
aves
ix-d
egr
eeso
ffr
eed
om,

3a
sso
cia
tedw
ithth
etr
ans
lat
ionv
ect
or,t=(t
x,t
y,t
z)
,inth
ex,yandzd
ire
c-

t
ion
sand3a
sso
cia
tedw
ithth
ero
tat
ionp
aram
ete
rsθ=(α
,β,γ)
.Fo
rav
oxe
l

v=(i
,j,k
)th
eri
gidt
ran
sfo
rma
tionc
anb
ewr
itt
ena
s:

Trigid(
v)=R
v+t

wh
ere
 
 co
sβcosγ cosαsinγ+s
inαsinβc o
sγ sinαsinγ−cosαs
inβc osγ
 
R= 
 −co
sβsinγ c
osαcosγ−sinαsinβsinγ s
inαcosγ+co
sα sinβsinγ.

 
s
inβ −sinαco
sβ co
sαcosβ

Anaffin
ere
gis
tra
tionh
asth
esam
efo
rma
sth
eri
gidand
iso
fth
etyp
eTaffine(
v)=

A
v+t
,wi
thth
ediff
eren
ceth
atth
ema
trixAi
sno
tcon
str
ain
edt
obear
ota
tion

3
2
m
atr
ix. Thu
s,th
eto
talnumb
ero
fde
gre
eso
ffr
eed
omo
f3Daffin
etr
ans
form
ati
on
i
s12w
ith9d
egr
eeso
ffr
eed
omc
orr
espond
ingt
oth
e9en
tri
eso
fth
ema
trixA

and3c
orr
espond
ingt
oth
etr
ans
lat
ionv
ect
ort
.
Ch
oos
ingth
ere
gis
tra
tionc
las
s(e
.g.r
igido
raffin
e)i
sac
ruc
ials
tep
,th
ough

on
est
il
lne
edst
oes
tim
ateth
epa
ram
ete
rso
fre
gis
tra
tioninth
eindu
cedsp
ace
s.

Th
isi
sdon
eth
rou
ghou
tth
emin
imi
zat
iono
fau
ti
li
tyfun
cti
on. Th
erea
reth
ree
m
ain w
ayso
fcon
stru
ctin
gau
ti
li
tyfun
cti
onsu
sin
g:1
)landm
ark
s;2
)su
rfa
ce

fi
ttin
g;and3
)vo
xel
-s
imi
lar
itym
etr
ics
.Inl
andm
arkb
asedr
egi
str
ati
on,fidu
cia
l

m
ark
erso
rlandm
arkpo
intid
ent
ifiedb
yhandinth
eim
age
sar
eus
eda
spo
int
s

o
fre
fer
enc
e. Afidu
cia
lma
rke
risanob
jec
tth
ati
spl
acedinth
efie
ldo
fvi
ewin

anim
age
. Th
esel
andm
ark
srep
lac
eth
eor
igin
alf
ram
eofr
efe
ren
ceandt
ran
sfo
r-

m
ati
onsa
reapp
li
edt
oredu
ceap
art
icu
lard
ist
anc
ebe
twe
enth
em,wh
ichc
ould

in
clud
emin
imi
zin
gth
ege
ome
tri
cdi
stan
ceo
rac
omb
ina
tionb
etw
eenth
ege
o-

m
etr
icd
ist
anc
eandth
ein
ten
sit
iesinth
eim
age
.Ei
the
rth
eRoo
tMe
anSqu
are

(RMS
)Er
roro
rFidu
cia
lRe
gis
tra
tionE
rro
r(FRE
)canb
eop
tim
izedt
ose
lec
t
th
ere
gis
tra
tionp
aram
ete
rs. Th
eer
roro
fth
ere
gis
tra
tionc
anb
eas
ses
sedb
yre
-

po
rtin
gth
eTa
rge
tRe
gis
tra
tionE
rro
r(TRE
)fo
rth
enon
-landm
arka
rea
sinth
e

im
age
.Landm
arkb
asedr
egi
str
ati
onr
equ
ire
sth
eid
ent
ific
ati
ono
flandm
ark
s,

wh
ichc
anb
etim
econ
sum
ingand m
ayb
epr
onet
oob
serv
ere
rro
r. Th
ere
for
e,

find
ingl
andm
ark
sau
tom
ati
cal
lyandr
el
iab
lyi
sana
ctiv
ear
eao
fre
sea
rch
. An
ex
cel
len
tcomp
reh
ens
ived
esc
rip
tiono
fsh
apean
aly
sisandl
andm
ark
-ba
sedr
eg-

i
str
ati
onc
anb
efoundin[
47]
.

Su
rfa
ceb
asedr
egi
str
ati
ont
ake
sin
toa
ccoun
tth
ediff
eren
tge
ome
tri
cst
ruc
-
tu
reso
fth
ebr
aint
oimp
rov
eth
ein
tra
-sub
jec
tva
riab
il
ityo
fbr
ainsh
ape
saf
-

t
err
egi
str
ati
on.S
eve
ralm
eth
odsex
istf
orsu
rfa
ceb
asedr
egi
str
ati
onin
clud
ing

3
3
m
eth
odsa
vai
lab
leinth
ewid
elyu
seds
oftw
areF
reeSu
rfe
r(h
ttp
://
sur
fer
.nm
r.m
gh.h
arv
ard
.edu
).
Insu
rfa
cer
egi
str
ati
on,th
eid
eai
stoth
inko
fth
eceb
era
lco
rtexa
sasu
rfa
ce

wh
ichi
str
ans
form
edin
toth
enewsp
aces
oth
atth
egy
riandsu
lc
ionth
eco
rtex

a
rem
atch
ed.
V
oxe
l-
sim
ila
rit
yba
sedr
egi
str
ati
on m
eth
odsa
repopu
lar
,asth
eyd
ono
tre
-

qu
ireth
eid
ent
ific
ati
ono
flandm
ark
sors
egm
ent
ati
ono
fth
eim
age
.He
reth
e
r
egi
str
ati
onTi
sop
tim
izedb
yafun
cti
ono
fth
evo
xelv
alu
esinth
etw
oim
age
s.

F
orim
age
softh
esam
emod
ali
ty,th
esumo
fsh
aredd
iffe
ren
ce(SSD
)canb
e
u
sed
:

1
SSD= |
Y{T(
v)}−Y(
v)|
nv∈Ω

wh
ere Ωi
sth
eim
aged
oma
ino
fth
etw
oim
age
s, Y{T(
v)}i
sim
agea
fte
rth
e

t
ran
sfo
rma
tionTi
sapp
li
edandY(
v)i
sth
evo
xelin
ten
sit
yofth
eta
rge
tim
age
.

An
oth
erpopu
lars
imi
lar
ityfun
cti
oni
sco
rre
lat
ionc
oeffi
cien
t(CC
)be
twe
enth
e

in
ten
sit
yva
lue
sinth
etw
oim
age
sandi
sdefin
eda
s

¯
v∈Ω[
Y{T(
v)}−ȲT]
[Y(
v)−Y]
CC= ,
¯2
v∈Ω[
Y{T(
v)}−ȲT]
2·
v∈Ω[
Y(v)−Y]

¯
wh
ere ȲT = v∈Ω Y{
T(v)
}/nandY = v∈Ω Y(
v)/n
. F
orim
age
sth
ata
re

ob
tain
eda
sdiff
eren
tsequ
enc
eso
rev
end
iffe
ren
tmod
ali
tie
s,th
ein
ten
sit
ieso
f

th
eim
age
scand
iffe
rqu
ited
ram
ati
cal
ly
. Thu
s,j
oin
ten
trop
yiso
ftenu
sed

a
sana
lte
rna
tiv
eme
thod
sre
gis
tra
tionop
tim
iza
tion m
eth
od.F
orav
ect
oro
f

p
rob
abi
li
tie
sp=(p
1,.
..,p
K)th
een
trop
yH(
p)=− kp
klo
g(p
k).En
trop
ycan

b
eth
ough
tofa
sa m
easu
reo
fin
form
ati
onc
ont
ain
edinth
eim
age
. M
aximum

3
4
en
trop
y,l
og(
K),i
sob
tain
edwh
enp
1=.
..=p
K =1/K.M
inimumen
trop
y,0
,
i
sob
tain
edwh
enp
1=1andp
2=.
..=p
K =0
.Max
imumen
trop
yco
rre
spond
s

t
oap
erf
ect
lych
aot
icen
vir
onm
ent(
e.g
.rand
oma
ssi
gnm
ento
fsh
ade
sofg
ray
t
oanim
age
),wh
ere
asm
inimumen
trop
yco
rre
spond
stoap
erf
ect
lyo
rgan
ized

sy
stem(
e.g
.as
sign
ingth
esam
esh
adeo
fgr
ayt
oth
een
tir
eim
age
.)R
egi
str
ati
on

i
sof
tend
oneth
rou
gh m
inim
iz
ingj
oin
ten
trop
y,

H(
A,B)= p
AB(
a,b)
logp
AB(
a,b)
a b

T
wh
erep
AB(
a,b)i
sth
ejo
intp
rob
abi
li
tyo
fth
epa
iro
fim
agev
alu
esainim
ageA

andbinim
ageB b
ein
gob
serv
eda
tth
esam
evo
xel
.Asim
agein
ten
sit
iesc
an

b
ecomp
let
elyd
iffe
ren
tmin
imi
zin A
gH(,B)d
ire
ctlyd
oesn
ott
ypi
cal
ly w
ork

d
ire
ctly
.In
ste
ad,th
ehi
sto
gramo
fea
chim
agein
ten
sit
iesc
anb
epa
rti
tion
ed

in
toqu
ant
il
esandon
ecana
sse
ssth
atth
etw
oim
age
sha
veth
esam
ein
ten
sit
y

a
tvo
xelvi
fth
eim
agein
ten
sit
iesf
allw
ith
inth
esam
ein
ter
-qu
ant
il
ein
terv
alo
f

th
eim
age
-sp
ecifi
cin
ten
sit
ydi
str
ibu
tion
.Inas
cat
terp
loto
fim
agein
ten
sit
ies
,

a
tth
eco
rre
spond
ingv
oxe
ls A
,H(,B)i
sasymm
etr
icm
easu
reo
fhowf
arth
e

po
int
sar
efr
omth
eid
ent
ityl
ine
. Am
ajo
rpr
obl
eminth
isc
ont
exti
sth
atth
ere
a
rem
anyb
ack
ground(n
on-
tis
sue
)vo
xel
s,wh
ichc
ouldd
omin
ateth
eme
asu
re.

T
omi
tig
ateth
eeff
ecto
fth
eman
yba
ckg
roundv
oxe
ls
,jo
inten
trop
ycanb
e

r
epl
acedb
y mu
tua
lin
form
ati
on

I(
A,B)=H(
A)+H(
B)−H(
A,B)

Th
e mu
tua
lin
form
ati
oni
sa m
easu
reo
fth
e mu
tua
ldep
end
enc
eofth
etw
o

3
5
im
age
s.
Inp
rac
tic
eth
eeff
ecto
fth
esem
easu
resi
sof
tenn
otc
omp
let
elyund
ers
tood

and m
ino
ras
sump
tion
scanh
aves
eri
ouseff
ect
sonth
ere
sul
tso
fre
gis
tra
tion
.

N
ote
,fo
rex
amp
le
,th
atth
equ
ant
il
etr
ans
form
ati
onth
atw
eha
vein
trodu
ced
abo
vei
s,e
ssen
tia
lly
,ah
ist
ogr
amm
ath
cin
gapp
roa
chf
ors
ign
alin
ten
sit
ies
.Su
ch

app
roa
che
scanb
ese
riou
slyaff
ect
edi
fth
ere
lat
ivein
ten
sit
iesinim
age
sha
ve
d
iffe
ren
tdi
str
ibu
tion
s. F
orex
amp
le
,ab
rain w
ithl
arg
erv
ent
ric
lesw
il
lha
ve

al
arg
ernumb
ero
fvo
xel
sinth
ece
reb
ro-
spin
alflu
id(CSF
)th
anas
tand
ard

t
emp
lat
e.S
imi
lar
ly
,ab
rainw
ithal
arg
ele
sionw
ithsp
ecifi
cin
ten
sit
ypr
ope
rti
es

w
il
lha
veah
ist
ogr
amw
ithafund
amen
tal
lya
lte
redsh
ape
.Ign
orin
gth
eeff
ect
s

o
fpa
tho
logyandb
etw
een
-sub
jec
tva
riab
il
ityc
anh
avel
arg
eeff
ect
sonth
ere
sul
ts

o
fre
gis
tra
tionandi
son
eofth
edi
rty
,un
spok
eno
f,s
ecr
etso
fre
gis
tra
tion
.

2
.5.4
.2 P
rac
tica
lapp
roache
s,so
ftwa
re,andapp
lica
tiontoda
ta

W
enowd
iscu
ssandv
isu
ali
zes
omes
imp
leex
amp
lessh
owin
gth
epr
oce
sso
fre
g-

i
str
ati
on.R
egi
str
ati
onc
anb
eth
ough
tofa
sac
oll
ect
iono
fst
epsth
att
ran
sfo
rm

th
eim
agein
toth
etemp
lat
esp
ace
. R
eca
llth
atr
egi
str
ati
oni
sat
ran
sfo
rma
-

t
iononth
evo
xell
oca
tionandn
oto
fim
agein
ten
sit
ies
;im
agein
ten
sit
iesc
an

b
eus
edt
oop
tim
izeth
etr
ans
form
ati
onu
sin
g,f
orex
amp
le
,diff
eren
cesb
etw
een

th
etr
ans
form
edim
ageandat
emp
lat
e. Suppo
seth
atw
eob
serv
eas
imp
le2
-

d
imen
sion
al(
2D)im
aged
epi
ctedinF
igu
re2
.5(
topl
eftp
ane
l)th
atn
eed
sto
b
etr
ans
form
edt
oth
etemp
lat
esp
ace(
topr
igh
tpan
el)
.Inth
isex
amp
le
,th
e

t
emp
lat
eim
agei
sac
loc
kwi
ser
ota
tiono
fth
eob
serv
edim
ageb
yaπ/2d
egr
ee

an
gleandash
if
t.H
enc
e,w
ecanu
seth
efo
llow
ingr
ota
tion m
atr
ixt
otr
ans
form
th
eob
serv
edd
atain
toth
etemp
lat
esp
ace
.

3
6
  
cos(
π/2
) −s
in(π/2
)
R=  
s
in(
π/2
) co
s(π/2)

T
Thu
s,f
ore
achp
ixe
lwi
thc
oord
ina
tesx=(x1,x
2) weob
tainth
ecoo
rdin
ate
s
T
inth
enewsp
acey=(y
1,y
2) asy= Rx. Th
ere
sul
tin
gim
agei
ssh
ownin
th
ele
ftm
idd
lep
ane
lofF
igu
re2
.5. W
ithash
if
tinth
e Xc
oord
ina
tew
ema
y

c
omp
let
elyr
egi
ste
rth
eob
serv
edim
agein
toth
etemp
lat
esp
ace
. Th
esh
if
tcan

b
ein
corpo
rat
edinth
etr
ans
form
ati
ona
sfo
llow
s:

    
y1  c os(
π/2
) −s
in(π/2
) −1
01 x1 
    
 y =  s
in(
π/2
) co
s(π/2) 0  x 
 2   2 
    
1 0 0 1 1

Ac
omp
ari
sonb
etw
eenth
etop
-r
igh
tandt
op-m
idd
lep
ane
lsinF
igu
re2
.5ind
i-

c
ate
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atth
ere
sul
tin
gim
agei
sve
rys
imi
lart
oth
eim
ageinth
etemp
lat
esp
ace
;

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act
,be
cau
seth
isi
sat
oyex
amp
le
,th
eya
reid
ent
ica
l.
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igidt
ran
sfo
rma
tioni
sus
efu
linc
ase
swh
ens
eve
ralim
age
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ron
esub
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t

a
rea
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iredo
verar
ela
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elysh
ortp
eri
odo
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ectth
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s

t
obes
imi
larex
cep
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atth
esub
jec
tma
yha
vech
ang
edpo
sit
ion
sbe
twe
enth
e

im
agea
cqu
is
it
ion
s.I
fth
eacqu
iredim
ageh
asd
iffe
ren
tvo
xeld
imen
sion
sth
an
th
etemp
lat
eim
age
,wem
ayw
antt
ous
eanaffin
etr
ans
form
ati
on.Inas
econd

ex
amp
le
,th
eob
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edd
atai
ssimp
lyaπ/4d
egr
eer
ota
tiono
fth
etemp
lat
e

im
agewh
il
eth
epix
els
izei
sha
lfth
ato
fth
epix
els
izeo
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etemp
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eim
age
.
W
ema
yus
eth
efo
llow
ingt
ran
sfo
rma
tion m
atr
ixt
otr
ans
formth
eob
serv
ed

im
agein
toth
etemp
lat
esp
ace
.

3
7
     
y1 cos(
−π/4) −s
in(
−π/4) 0 x1 
  1  
 y =  s
in−
( π/4
) co
s(−π/4
) 0 x 
  2
2  2 
    
1 0 0 1 1

Th
eim
ageinF
igu
re2
.5i
sba
sedonr
ound
ingth
enon
int
ege
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rdin
ate
s. Thu
s,
a
sde
scr
ibedinS
ect
ion2
.5.
3,in
terpo
lat
iono
fth
ein
ten
sit
iesi
sne
ededt
oob
tain

th
ecomp
let
eim
age
.Asd
iscu
ssedabo
ve,on
ceth
eus
erch
oos
esth
epa
ram
ete
r-

i
zat
ion(
e.g
.ri
gid
,affin
e,e
tc.
)andth
eob
jec
tiv
efun
cti
ont
obem
inim
izedth
e

t
ran
sfo
rma
tion m
atr
ixc
anb
ees
tim
ated
.

S
eve
rals
oftw
are
sex
istt
oes
tim
ateth
etr
ans
form
ati
on m
atr
ixf
or3Dim
age

d
ata
,in
clud
ingth
e Adv
anc
ed N
orm
ali
zat
ionT
ool
s(ANTS
)de
scr
ibedb
y[4
8],

FMR
IBS
oftw
areL
ibr
ary(FSL
)(s
ee[
26]f
orag
ene
ralo
verv
iewo
fFSL
),M
edi
cal

Im
ageP
roc
ess
ingAn
aly
sisandV
isu
ali
zat
ion(M
IPAV
)(h
ttp
://m
ipa
v.c
it
.nih
.go
v)

andS
tat
ist
ica
lPa
ram
etr
icM
app
ing(SPM
)(h
ttp
://www
.fil
.ion
.uc
l.a
c.uk
/spm
/).

Th
etopl
eftim
ageinF
igu
re2
.6sh
owson
esl
iceo
fa3d
imen
sion
alT
1im
age
.

Suppo
seth
atd
ataf
rommu
lt
ipl
esub
jec
tsn
eedt
ober
egi
ste
redin
toth
etemp
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e

sp
acesh
owninth
etopr
igh
tpan
el
;th
isi
sth
eMon
tre
alN
eur
olo
gic
alIn
sti
tut
e
(MN
I)t
emp
lat
e. Th
efo
llow
ingc
odeinFSLc
anb
eus
edt
oob
tainth
eaffin
e

t
ran
sfo
rma
tion m
atr
ixf
romth
eim
agein
toth
etemp
lat
esp
ace
.

flirt-inBrain.nii.gz-refTemplate.nii.gz -outBrain_affine.nii.gz

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ereB
rain
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i.g
zcon
tain
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ii
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eim
age
.

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ere
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tin
gBr
ainaffin
e.n
ii
.gzw
il
lbeth
eim
aget
ran
sfo
rmedin
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lat
e

3
8
F
igu
re2
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tep
sofr
egi
str
ati
on:at
oyex
amp
le
.

3
9
sp
ace
,fin
ally
,th
eaffin
e.m
atw
il
lsh
owth
etr
ans
form
ati
on m
atr
ix.

    
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  −1
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F
igur
e2.6
: Appl
ica
tionoftwos
oftwa
remethods(th
efunc
tionfli
rtonbott
om
l
eftandANT saffineonbo t
tomrigh
t)t
or e
gis
terarea
lbrainimag
e(tople
ft)
t
oat emp
lat
e( t
oprigh
t).

4
0
 As
imi
lart
ran
sfo
rma
tionc
anb
eob
tain
edu
sin
gth
e ANT
sso
ftw
are
.How
-
ev
er,th
efun
cti
on ANTSp
rov
ide
sth
etr
ans
form
ati
on m
atr
ixa
sanou
tcom
e

andas
econdfun
cti
onh
ast
obeu
sedt
otr
ans
formth
eim
agein
toth
enewsp
ace

b
asedonth
ees
tim
ated m
atr
ixf
romANTS
.

ANTS3-mMI[Brain.nii.gz,Template.nii.gz,1,4]-oimg.nii.gz
-rGauss[3,0]-i0

WarpImageMultiTransform3Brain.nii.gzBrainWarp.nii.gz -R

Template.nii.gz -iimgAffine.txt

I
fth
ebr
ains
tru
ctu
resa
res
imi
larupt
oaffin
ediff
eren
cesth
enth
eme
th-

od
sde
scr
ibedabo
vew
il
llik
elyp
rodu
cer
eas
onab
ler
esu
lts
.How
eve
r,ins
ome
c
ase
son
ear
eao
fth
ebr
ain m
ayn
eedt
obet
ran
sfo
rmed m
oreth
ansu
rround
-

in
gti
ssu
eort
issu
efr
omad
iffe
ren
tpa
rto
fth
ebr
ain
. App
roa
che
sth
atg
o

b
eyondaffin
etr
ans
form
ati
onsa
ret
ypi
cal
lyr
efe
rredt
oasn
on-
lin
earandd
iffe
o-

m
orfi
capp
roa
che
s.H
erei
son
epa
ram
ete
riz
ati
oninANT
stoob
tainan
on-
lin
ear

t
ran
sfo
rma
tion
:

ANTS3-mCC[Brain.nii.gz,Template.nii.gz,1,8]-oimg.nii.gz

-rGauss[1,1]-i30*20*5-tSyN[0.25]

WarpImageMultiTransform3Brain.nii.gzBrainWarp.nii.gz -R
Template.nii.gz -iimgAffine.txtBrainInverseWarp.nii.gz

[
48]p
rov
ide
sano
verv
iewo
fhowon
ecanu
seANT
stoob
tainn
on-
lin
eart
ran
sfo
r-

m
ati
onso
fth
eim
age
sfr
omp
ati
ent
swi
thd
ise
ase
,byf
ocu
sin
gth
eop
tim
iza
tion

fun
cti
ont
oth
ear
eac
ont
ain
ingth
ehe
alth
yti
ssu
e.

4
1
2
.5.5 In
ten
sityno
rma
liza
tion

C
ondu
ctin
gan
ytyp
eofpopu
lat
ion
-lev
elan
aly
siso
rin
fer
enc
eond
atau
sua
lly
r
equ
ire
sth
atth
eun
itso
fme
asu
rem
enth
aveth
esam
eme
anin
gfo
rev
erysub
jec
t

andv
is
it
.Ind
eed
, wh
enun
itsa
red
iffe
ren
t,ev
enc
alcu
lat
ingas
imp
lea
ver
age

i
sno
tpo
ssib
le
. Th
isi
saw
el
l-kn
ownp
rob
leminsMR
Iim
agean
aly
sis
,asth
ese
m
oda
li
tie
sar
eme
asu
redina
rbi
tra
ryun
itsth
atd
ependon m
anyf
act
orsin
-

c
lud
ingth
esc
ann
er,p
rot
oco
l,and m
anu
alad
jus
tmen
tsm
adeb
yth
erad
iol
ogy

t
echn
ic
iana
cqu
ir
ingth
eim
age
s. Th
eimpo
rtan
ceo
fin
ten
sit
yno
rma
li
zat
ionh
as

b
eenemph
asi
zedb
ynum
erou
spub
li
cat
ion
sinth
eim
agin
gli
ter
atu
re[
49,5
0,5
1].
Th
eno
rma
li
zat
ionp
roc
esssh
ouldp
rodu
ceun
itsth
at:1
)ha
veac
omm
onin
ter
-

p
ret
ati
ona
tth
eti
ssu
e-t
ypel
eve
l;2
)ar
erep
li
cab
le
;3) p
res
erv
eth
eranko
f

in
ten
sit
ies
;4)h
aves
imi
lard
ist
ribu
tion
sfo
rth
esam
eti
ssu
eso
fin
ter
esta
cro
ss

andw
ith
inp
ati
ent
s;5
)ar
eno
tinflu
enc
edb
ybi
olo
gic
alabn
orm
ali
tyo
rpopu
la-

t
ionh
ete
rog
ene
ity
;6)a
rem
inim
allys
ens
it
ivet
ono
iseanda
rti
fac
ts;and7
)do
n
otr
esu
ltinth
elo
sso
fin
form
ati
one
ith
erdu
etop
ath
olo
gyo
roth
erph
enom
ena
.

Th
esep
rin
cip
les
,pr
opo
sedin[
52]andr
efe
rredt
oasth
est
ati
sti
calp
rin
cip
leso
f

im
agen
orm
ali
zat
ion(SP
IN)
,gu
ideth
ema
them
ati
calf
ormu
lat
iond
esc
rib
edin

th
enex
tse
cti
on.

2
.5.5
.1 Concep
ts

C
ons
ide
rth
eim
agein
ten
sit
yYij(
v)a
tea
chv
oxe
lvexp
res
sedina
rbi
tra
ryun
its

and m
easu
redf
orsub
jec
tia
tvi
sitj
.No
rma
li
zat
ioni
san
ytr
ans
form
ati
ono
f

th
etyp
eYij(
v)→ Nij{Yij(
v)}.I
tisu
sefu
ltoc
onc
eptu
ali
zeth
ehi
sto
gramo
f

in
ten
sit
iesYij(
v)a
sa m
ixtu
reo
fden
sit
ies

4
2
 K
hij(
x)= wijkf
i (
jk x)
, (
2.2
)
k=1

wh
eref
i (
jk x)a
reth
esub
jec
t/v
is
it
-sp
ecifi
cin
ten
sit
yden
sit
ieso
femp
tysp
aceand
kn
ownt
issu
es,su
cha
swh
item
att
er,g
raym
att
er,c
ereb
rosp
ina
lflu
id,bon
e,sk
in,

andl
esi
ons
. Th
ewe
igh
tswijk≥0sumt
o1andr
epr
esen
tth
ere
lat
ivew
eigh
tso
f
c
ompon
ent
sk=1,
...
,K. Th
isin
clud
esbo
thc
ase
swi
thandw
ith
outp
ath
olo
gy,
a
sth
ewe
igh
tfo
rle
sion
scanb
eal
low
edt
obe0
.Ca
refu
lin
spe
cti
ono
fSP
IN

4su
gge
ststh
ata
fte
rno
rma
li
zat
ionf
i (
jk ·
)sh
ouldb
easc
los
etoon
ean
oth
era
s

po
ssib
lef
ora
lliandjandf
oran
yfix
edk. Thu
s,an
atu
rals
tar
tin
gpo
intw
ould

b
etoc
ons
ide
rtr
ans
form
ati
onsth
atr
edu
ceth
edi
stan
ceb
etw
eenth
efi
jk(x)f
or

an
yfix
edk. T
oge
the
rwi
thSP
IN1
,th
issu
gge
ststh
eex
ist
enc
eofth
efo
llow
ing
N K
th
eor
eti
calm
ode
linn
orm
ali
zedsp
acef
ora
llim
age
s:g
ij(x)= k=1 wi
jkgk(
x),

wh
ereth
eden
sit
iesg
k(x)a
reind
epend
ento
fsub
jec
tsand
/orv
is
its
,th
ough

th
ewe
igh
tsa
ssi
gnedt
oth
esed
ens
it
iesd
ependonsub
jec
tandv
is
itand m
ay
b
eth
eme
asu
reo
fin
ter
estin m
edi
cals
tud
ies
. Th
efund
amen
tald
ifficu
ltyo
f
N
n
orm
ali
zat
ioni
stofindat
ran
sfo
rma
tionf
romhij(
x)t
ogj(
i x)th
atr
esp
ect
sth
e

o
rde
rin
gofd
ist
ribu
tion
sandth
eir mu
tua
ldi
stan
cesinth
eno
rma
li
zedsp
ace
.

2
.5.5
.2 P
rac
tica
lapp
roache
s,so
ftwa
re,andapp
lica
tiontoda
ta

Th
emo
stw
ide
lyu
sedim
agen
orm
ali
zat
iont
echn
iqu
esh
avec
ent
eredonh
is
-

t
ogr
am m
atch
ing[
49,5
3,5
0].F
irs
t,at
emp
lat
ehi
sto
grami
scon
stru
cted
,usu
-

a
llyb
yav
era
gin
gac
ros
sag
roupo
fsub
jec
tsinat
rain
ings
et. Th
en,an
onl
ine
ar

t
ran
sfo
rma
tionNij(
·)(
oft
enal
ine
arsp
lin
e)i
ses
tim
atedf
ore
achsub
jec
tate
ach

v
is
itt
omin
imi
zean
ydev
iat
ion
sbe
twe
enth
eno
rma
li
zedh
ist
ogr
amNij{Yij(
v)}

andth
etemp
lat
e.A
lth
oughh
ist
ogr
am m
atch
ingm
eth
odsp
rodu
cer
epl
icab
le

4
3
r
esu
lts
,th
eya
reb
asedona
ssump
tion
sth
ata
reo
ftenv
iol
ated
:1)th
eti
ssu
e-t
ype
d
ist
ribu
tioni
sth
esam
eac
ros
ssub
jec
tsandv
is
its
;2)th
eab
sen
ceo
fabn
orm
al

p
ath
olo
gy;and3
)th
eab
sen
ceo
fte
chn
ica
lar
ti
fac
ts.F
orex
amp
le
,Fi
gur
e2.
7

sh
owsh
owth
eas
sump
tiono
fcomm
ond
ist
ribu
tion
soft
issu
eth
rou
ghou
tth
e
h
eadc
anc
aus
emi
sma
tch
ingo
fgr
aym
att
er(GM
)toc
ereb
rosp
ina
lflu
id(CSF
);

n
oteh
owan
orm
al-
app
ear
ingp
arto
fth
ebr
ain(
rawd
atash
owninth
etopp
ane
l)
i
sindu
cedt
osh
owe
ros
iono
f GMb
yhi
sto
gramn
orm
ali
zat
ion(h
ist
ogr
amn
or-

m
ali
zedd
atash
owninth
ebo
ttoml
eftp
ane
l)
.

R
awIm
age R
awH
is
tog
ram
A B

Equ
al
izedH
is
tog
ram
D

H
is
tog
ram
-Equ
al
ized
Image
C

Wh
iteS
tr
ipeNo
rma
l
iza
tion
E

F
igu r
e2.7:Firstcolumn:r e
giono fintere
stfromp a
tientwith MC Ishownb efore
(A)anda f
ter(C )h is
togram m at
ching. R edsquareindicatesregionofg ray
ma
tt e
ronth eunn o rmal
izedim ageth atdisappear
sa ft
erh istog
ram m atching
.
Se
c ondc o
lumn:h istograms( shadeso fgrayindica
ted iff
e rentstudyvisits)of
theg ra
ym a
tterb efor
e(B )anda fter(D )his
togram m a
t chingand(E ) wh i
te
st
ripen ormal
izati
onf orsubje c
tsin ADN I.N o
teth elar
g ep ropor
tiono fgray
ma
tt e
rm ismatchedt obackground( zerointens
ity
)afterhistogram m at
chin g
.

4
4
 Ana
lte
rna
tiv
eme
thod[
54,5
5]th
ath
asb
eenp
ropo
sedi
stom
atchth
eun
-
d
erly
ingap
art
icu
larsubd
ist
ribu
tionc
ons
ist
ingo
far
efe
ren
cet
issu
easw
el
las

po
ssib
le
. W
eca
llth
ist
issu
e-sp
ecifi
chi
sto
gramn
orm
ali
zat
ion
.Iti
simpo
rtan
t

t
ono
teth
ata
lth
oughth
edi
str
ibu
tiono
fin
ten
sit
iesinth
ere
fer
enc
eti
ssu
ear
e
m
atch
ed,r
egi
onso
fno
rma
lti
ssu
ewi
thin
ten
sit
iesou
tsid
eth
eran
geo
fth
ere
f-

e
ren
cet
issu
ear
eno
tne
ces
sar
ilyc
omp
arab
le
;th
etru
eno
rma
li
zat
ionfun
cti
on
Nij(
·)i
sof
tenn
onl
ine
ar(du
etod
iffe
ren
cesinp
rot
oco
l,e
tc.
)andthu
sno
rma
l-

i
zin
gwi
thr
esp
ectt
o wh
item
att
erm
ayn
otr
esu
ltinn
orm
ali
zedg
raym
att
er

in
ten
sit
ies
.Ti
ssu
e-sp
ecifi
chi
sto
gramn
orm
ali
zat
iond
oes
,how
eve
r,m
ain
tainth
e

n
atu
ralv
ari
abi
li
tyino
the
rti
ssu
etyp
es,a
llow
ingf
orth
estudyo
fpa
tho
logy
.

A
ssum
efo
rth
emom
entth
atf
orev
erysub
jec
tandv
is
itw
eha
veana
rea

o
fre
fer
enc
eti
ssu
e(asub
-ma
sk,u
sua
llyo
fth
e wh
item
att
er)
. Th
en w
ecan

a
ccu
rat
elye
stim
atef
ij1(
x)(
sayk=1f
orwh
item
att
er)f
ore
ach iandjand
N
ob
tainan
orm
ali
zede
stim
ato
rth
ath
asm
eanz
eroandv
ari
anc
eon
e,f
ij1(
x)=

σij1f
i (
jk µij1+σij1x)
,wh
ereµij1 andσij1 a
reth
eme
anands
tand
ardd
evi
ati
on
N
o
ffi
j1(
x),r
esp
ect
ive
ly
. Ane
stim
ato
rofg
1(x)i
sth
eav
era
geo
ffi
j1(
x)andl
ine
ar

n
orm
ali
zat
ionw
ithr
esp
ectt
oth
ewh
ite
-ma
tte
rdi
str
ibu
tioni
s
K
N
hij(
x)= wijk[
σij1f
i (
jk µij1+σij1x)
]. (
2.3
)
k=1

A
llun
itsa
reexp
res
sedin mu
lt
ipl
eso
fst
and
ardd
evi
ati
ons
, σij1,o
fth
ewh
ite
-

m
att
erin
ten
sit
ies
,andz
eroi
sth
eav
era
gein
ten
sit
yof wh
item
att
er. Th
is

m
eth
odr
el
iesonth
eav
ai
lab
il
ityo
far
efe
ren
cet
issu
e(u
sua
lly wh
item
att
er)

m
askind
ica
tin
gar
egi
ono
fth
ebr
ainth
atsh
ouldb
ecomp
arab
lea
cro
sssub
-

j
ect
s. Th
isi
sof
tenun
ava
ilab
leb
efo
rein
ten
sit
yno
rma
li
zat
ion
,how
eve
r,and

4
5
[
52]p
ropo
sedandv
al
ida
tedafu
llyau
tom
ati
cme
thodth
ata
void
sth
is
.
C
ons
ide
ra T
1sMR
I, Yij(
v),f
orsub
jec
ti=1,
...
,n.[
52]u
sen
orm
al-

app
ear
ing wh
item
att
er(NAWM
)asar
efe
ren
cec
olo
r,s
inc
eiti
sth
ela
rge
st
and m
ostc
ont
igu
ousb
raint
issu
e.T
oid
ent
ifyth
edi
str
ibu
tiono
f NAWMin
-

t
ens
it
ies
,[5
2]u
seap
ena
li
zedsp
lin
esm
ooth
er[
56]t
oes
tim
ateth
emod
eofth
e

in
ten
sit
yhi
sto
gramin wh
item
att
er,µ∗
i
j1(
thel
arg
estn
on-b
ack
groundp
eak
).
T
oes
tim
ateth
eva
riab
il
ityw
ith
in NAWMonth
erawim
age
,th
eye
stim
ate
∗ −1
th
est
and
ardd
evi
ati
onσi
j1o
fin
ten
sit
iesin Ω
i,τ= {v:Hi
j[ µ∗
H(i1)−τ
j ]<
−1
Yij(
v)< Hi
j[ µ∗
H(i1)+τ
j ]
}, wh
ichi
sre
fer
redt
oasth
e wh
ites
trip
e(wh
ere
x
Hij(
x)= −∞ hij(
x)dx)
.He
reτi
saqu
ant
il
eto
ler
anc
einth
eor
igin
alsp
aceo
f

in
ten
sit
ies
. Th
ees
tim
ati fµ∗
ono i
j1a
∗
ndσi
j1w
asb
eenf
oundt
ober
ema
rkab
ly

r
obu
sta
cro
sss
eve
ralth
ous
andim
age
s(f
ailu
rer
ate<1%
).I
fth
efam
ilyo
fden
-

s
it
iesf
ij1(
v)c
anb
epa
ram
ete
riz
edb
ytw
opa
ram
ete
rsth µ∗
enµij1=ψ1(i
∗
1,σ
j i1)
j

µ∗
andσij1 = ψ2(ij
∗
1,σ
i1)(
j p
roo
ffo
llow
sfr
omth
eme
thodo
fmom
ent
s). Thu
s,

m
atch
ing µ∗
i
j1a
∗
ndσi
j1(
est
imab
led
ire
ctlyf
romth
ewh
ites
trip
ewi
thou
tpr
ior

s
egm
ent
ati
on)r
esu
ltsin m
atch
ingµij1 andσij1,andth
ist
issu
e-sp
ecifi
chi
s-

t
ogr
amn
orm
ali
zat
ion m
eth
odh
asb
eensh
ownt
ope
rfo
rmw
el
linl
arg
e mu
lt
i-

c
ent
ers
tud
ies
.

2
.6 Ana
lys
is

2
.6.1 Le
sionsegmen
tat
ion

S
egm
ent
ati
oni
sth
elab
elin
gofv
oxe
lsinanim
agea
cco
rdin
gtop
art
icu
larp
rop
-

e
rti
eso
fth
evo
xel(
e.g
.th
etyp
eoft
issu
eth
evo
xelc
ont
ain
s).Ex
amp
lesin
clud
e

4
6
s
egm
ent
ingandc
omp
arin
gth
ecin
gul
ategy
ruso
fsub
jec
tsw
iths
chi
zoph
ren
ia
andh
eal
thyc
ont
rol
s[5
7]ands
egm
ent
ingth
ehippo
campu
stoa
sse
ssv
olum
elo
ss

du
etoch
ron
ich
eavyd
rink
ing[
58]
. Ar
evi
ewo
fme
thod
sfo
rse
gmen
tat
iono
f

b
rainsMR
Icanb
efoundin[
59]and[
60]
.

Fi
gure2.
8: A. Anax
ials
lic
efromthe FLAIRvolumefromap a
tientwith
mul
tip
les
cle
ros
is
.B.M anu
alexp
erts
egmenta
tiono
fthele
sion
sfr
omth i
ssl
ice.

H
erew
ede
scr
ibeth
epr
obl
emo
fse
gmen
tat
iono
fbr
ainl
esi
onsin mu
lt
ipl
e

s
cle
ros
is(MS
)fr
omas
ing
lesMR
Istudy
. MSi
saninfl
amm
ato
ryd
ise
aseo
f

th
ebr
ainandsp
ina
lco
rdch
ara
cte
riz
edb
ydem
yel
ina
tin
gle
sion
sth
atc
anb
e

ob
serv
ed w
ithsMR
I[6
1].In MSqu
ant
ita
tiv
ean
aly
seso
fsMR
I,su
cha
sth
e

numb
erandv
olum
eofl
esi
onsinanim
age
,ar
ees
sen
tia
lfo
rdi
agn
osin
gth
edi
s-
e
aseandm
oni
tor
ingd
ise
asep
rog
res
sion
[2]
.Inp
rac
tic
e, MS
les
ion
sar
emanu
ally

s
egm
ent
edb
yexp
ert
sfr
omsMR
I.F
igu
re2
.8sh
owsanex
amp
leo
fa m
anu
al
s
egm
ent
ati
ono
fle
sionv
oxe
ls
.Asm
anu
alo
rsem
i-au
tom
ateds
egm
ent
ati
onso
f

im
age
sar
etim
econ
sum
ing
,co
stly
,andp
ron
etol
arg
ein
ter
-andin
tra
-ob
serv
er

v
ari
abi
li
ty[
62]
,dev
elopm
ento
fau
tom
ated m
eth
odso
fle
sions
egm
ent
ati
oni
s

4
7
ana
ctiv
efie
ldo
fre
sea
rch[
63]
.Rev
iew
sofcu
rren
tle
sions
egm
ent
ati
on m
eth
ods
c
anb
efoundin[
63]
,[6
4],and[
65]
.Le
sionTOAD
sisar
ead
ilya
vai
lab
les
oft
-

w
aref
orl
esi
ons
egm
ent
ati
onth
atrun
sinth
eJISTp
ipe
lin
een
vio
rnm
ent[
66]
.

Anex
cel
len
tre
sou
rcef
orl
esi
ons
egm
ent
ati
ond
atai
sth
e MSl
esi
ons
egm
ent
a-
t
ionch
all
eng
e20
08[
67]
. Th
isd
atab
asein
clud
esMR
Ivo
lum
esa
cqu
ireda
tth
e

Ch
ild
ren
’sH
osp
ita
lBo
stonandUn
ive
rsi
tyo
fNo
rthC
aro
liaa
lon
gwi
thexp
ert
m
anu
als
egm
ent
ati
ons
.

L
esi
onss
egm
ent
ati
oni
sac
las
sifi
cat
ionp
rob
lem
.Inth
eli
ter
atu
re,sup
er-

v
isedc
las
sifi
ersa
ret
rain
edonexp
ertm
anu
als
egm
ent
ati
onso
fle
sionv
oxe
lso
r

un
sup
erv
isedc
las
sifi
ersu
sec
lus
ter
ingm
eth
odst
oid
ent
ifyl
esi
onv
oxe
ls. Th
e

c
ova
ria
teso
rfe
atu
resinth
emod
ela
red
eriv
edf
romth
ediff
eren
tim
agin
gse
-

qu
enc
esYm. F
romth
eseim
age
san
atom
ica
lin
form
ati
ond
eriv
edf
roma
tla
ses

and
/orth
evo
xel
-lev
elin
ten
sit
yin
form
ati
onf
romanim
agin
gmod
ali
tyYm(
v)

c
anb
eus
edf
orc
las
sifi
cat
ion[
65]
. T
oil
lus
tra
teth
epr
obl
em,w
epr
ovid
ean
o
verv
iewo
fal
esi
ons
egm
ent
ati
onm
eth
odf
romth
eli
ter
atu
re[
7],a
siti
sal
ogi
s-

t
icr
egr
ess
ion m
ode
l,a m
ode
lth
ati
sfam
il
iart
ost
ati
sti
cianandb
ios
tat
ist
ican
s.

L
etLi(
v) =1i
fth
emanu
als
egm
ent
ati
ono
fvo
xelvi
sal
esi
onf
orsub
jec
ti

andl
etLi(
v)=0o
the
rwi
se.C
onc
aten
ateth
emanu
als
egm
ent
ati
onsf
rome
ach

v
oxe
lfo
ral
lsub
jec
tsin
toas
ing
lev
ect
orL.S
imi
lar
ly
,le
tY d
eno
teth
ede
sign

m
atr
ixo
ffe
atu
resd
eriv
edf
romth
ediff
eren
tim
agin
gmod
ali
tie
sfo
ral
lofth
e

v
oxe
lsandsub
jec
ts. W
ecanth
en m
ode
lth
epr
obab
il
ityth
atal
esi
onc
ont
ain
s

av
oxe
lwi
thth
elo
gis
ticr
egr
ess
ion m
ode
l:

l
ogi
t{P{L(
v)=1
}=Y(
v)β

4
8
R
ecen
tly
,ith
asb
eenf
oundth
atf
orl
esi
ons
egm
ent
ati
onth
epa
rti
cul
arc
las
sifi
-
c
ati
ona
lgo
rithmi
sle
ssimpo
rtan
tth
anth
edev
elopm
ento
fth
efe
atu
res[
8].In

sp
iteo
fth
is
,me
thod
scon
tinu
etob
ecl
ass
ifieda
cco
rdin
gtoth
eme
thodu
sedf
or

c
las
sifi
cat
ionandn
otb
yth
efe
atu
resp
ace
.Ind
eed
,th
ecl
ass
ific
ati
on m
eth
od
(
e.g
.rand
omf
orr
est
,svm
,orl
ogi
sti
cre
gre
ssi
on)off
ersb
asi
cal
lyn
oin
form
a-

t
iononwh
ata
ctu
allyimp
rov
esp
red
ict
ion
.Inas
emin
alp
ape
r[6
8],D
.J.H
and
n
ote
s“th
eex
trap
erf
orm
anc
etob
each
iev
edb
ymo
res
oph
ist
ica
tedc
las
sifi
ca-

t
ionru
les
,bey
ondth
ata
tta
inedb
ysimp
lem
eth
ods
,issm
all
”.I
tfo
llow
sth
ati
f

a
spe
ctso
fth
ecl
ass
ific
ati
onp
rob
lema
ren
ota
ccu
rat
elyd
esc
rib
ed(
e.g
.,i
fin
cor
-

r
ectd
ist
ribu
tion
sha
veb
eenu
sed
,in
cor
rec
tcl
assd
efin
it
ion
sha
veb
eenad
opt
ed,

in
app
rop
ria
tep
erf
orm
anc
ecomp
ari
sonc
rit
eri
aha
veb
eenapp
li
ed,e
tc.
),th
en

th
erepo
rtedadv
ant
ageo
fth
emo
res
oph
ist
ica
ted m
eth
odsm
ayb
ein
cor
rec
t.”

W
esub
scr
ibet
oth
isv
iew
,th
oughw
ede
scr
ibei
tmo
rep
las
tic
allya
s“th
erea
re

v
eryf
ewr
eas
onab
lew
ayso
fcu
ttin
gth
epo
tat
o.”H
ere
,th
epo
tat
ois
,ofc
our
se,

th
ecl
oudo
fpo
int
sinth
efe
atu
resp
ace
.

Am
ajo
rsou
rceo
fdiffi
cul
tyinau
tom
ateds
egm
ent
ati
ono
f MR
Iisdu
eto

v
ari
abl
eim
agin
gacqu
is
it
ionp
aram
ete
rs[
65,6
3]. M
osts
egm
ent
ati
on m
eth
ods

h
avetun
ingp
aram
ete
rsth
ata
read
jus
tedt
oap
art
icu
lard
atas
etand m
ayn
ot

g
ene
ral
izet
oan
ewd
atas
etw
ithd
iffe
ren
tacqu
is
it
ionp
aram
ete
rs.L
esi
ons
eg-

m
ent
ati
oni
sal
soc
los
elyin
ter
twin
edw
ithim
agep
re-p
roc
ess
ing
.Me
thod
sus
ing

an
atom
ica
lin
form
ati
onr
elyonp
rop
ern
onl
ine
arsp
ati
alr
egi
str
ati
ont
oat
em-
p
lat
eim
age
. Th
eus
eofim
agein
ten
sit
iesr
equ
ire
shi
ghqu
ali
tyinh
omo
gen
eit
y

c
orr
ect
ionandin
ten
sit
yno
rma
li
zat
ion–o
the
rwi
sepopu
lat
ionl
eve
lmod
el
ing

i
shop
ele
ss. Th
erea
reev
enl
esi
ons
egm
ent
ati
on m
eth
odsinth
eli
ter
atu
reth
at

i
ter
ateb
etw
eenl
esi
ons
egm
ent
ati
onandinh
omo
gen
eit
y[6
9].

4
9
2
.6.2 Le
sion mapp
ing

InS
ect
ion2
.5.
4wed
iscu
ssedsp
ati
alr
egi
str
ati
onm
eth
odsf
ors
tru
ctu
ralim
age
s.
Th
erea
retw
oma
ini
ssu
esinth
econ
tex
tofr
egi
str
ati
oninp
res
enc
eofl
esi
ons
:

1
)Itc
anb
eve
ryh
ardt
ofindth
ebe
stw
ayt
ore
gis
terim
age
sfo
rman
ysub
jec
ts

in
toth
esam
ebr
aini
fth
eirim
age
sar
edi
sto
rteddu
etod
ise
ase
;2)sh
ouldth
e
s
egm
ent
ati
ono
fle
sion
sbep
erf
orm
edb
efo
reo
raf
terr
egi
str
ati
on.I
fth
ele
sion
s

inth
ebr
ainh
aveb
eenh
and
-se
gmen
tedinth
ena
tiv
esp
ace
,orinth
eri
gid
ly

r
egi
ste
redsp
acewh
ichi
scomm
onin MSs
tud
ies
,th
enon
ecanu
seth
ele
sion

m
ask
stoex
tra
ctth
ear
easth
ata
rew
ith
inth
ele
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seth
ehe
alth
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ain
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orr
egi
str
ati
on.B
oth ANT
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li
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clud
ingth
e

l
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omth
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ene
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atin
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ans
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on m
atr
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or

in
stan
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cti
on

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ingl
esi
onm
ask
scanb
etr
ans
form
edin
toth
etemp
lat
esp
aceb
yapp
lyin
g

th
etr
ans
form
ati
on.

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5
0
A
fte
rre
gis
ter
inga
llth
ema
sk m
apsin
toth
etemp
lat
esp
acew
ecanp
lotas
o-
c
all
edl
esi
onh
ist
ogr
amwh
ichsh
owsth
epr
eve
len
ceo
fle
sion
sinc
ert
aina
rea
sof

th
ebr
aina
ssh
owninF
igu
re2
.9.

F
igu
re2.9
: Twos
li
cesfromahist
ogr
amofl
esi
onsc
ons
tru
ctedu
sin
gnon
-l
ine
ar
r
egi
str
ati
onofob
servedima
gesinANTs
.

2
.6.3 Long
itud
ina
landc
ros
ssec
tiona
lin
ten
sityana
lys
is

An
oth
erv
eryimpo
rtan
ttyp
eofan
aly
sisi
stod
ire
ctlyan
aly
zeth
ein
ten
sit
iesin

th
eim
agea
fte
rin
ten
sit
yno
rma
li
zat
ion
.Ind
eed
,af
terin
ten
sit
yno
rma
li
zat
ion
,

w
ecanc
omp
areandqu
ant
ifyth
ehi
sto
gram
sofin
ten
sit
iesw
ith
ine
achs
equ
enc
e

o
rcomb
ineda
cro
sss
equ
enc
es. Th
isc
ouldb
edon
eatth
ebr
ainl
eve
l, wh
ich
r
equ
ire
son
lyin
ten
sit
yno
rma
li
zat
ion
,ora
tth
eti
ssu
elev
el
, wh
ich w
oulda
lso

r
equ
ireas
egm
ent
ati
ona
lgo
rithm
.Fo
rex
amp
le
,atth
epopu
lat
ionl
eve
lon
ema
y

b
ein
ter
est
edinth
ein
ten
sit
ydi
str
ibu
tion
inwh
item
att
er. Th
isc
ouldb
edon
eby
ob
tain
ingth
ehi
sto
gramin
ten
sit
ies
,st
ack
ingth
emina m
atr
ixandc
ondu
ctin
g

aPCAo
roth
erd
imen
sion
ali
tyr
edu
cti
onapp
roa
ch. As
imi
laran
aly
sisc
ould

5
1
F
igu
re2.1
0:Voxe
lint
ens
it
iesf
orFLA IR(t
oppanel
s),T1(midd
lepane
ls)
,and
T
2(bot
tompanel
s)imag
esinale
sion(l
abe
ledl
esi
on1 4
)fo
ron esub
jec
to v
er8
y
ear
sat40vi
sit
s.

5
2
b
econdu
cteda
tth
ele
sionl
eve
lifon
eisin
ter
est
edinc
ros
s-s
ect
ion
ald
iffe
ren
ces
inl
esi
onin
ten
sit
ydi
str
ibu
tion
s. An
oth
erpo
ssib
il
ityi
stos
tudyth
eas
soc
iat
ion

b
etw
eenth
esed
ist
ribu
tion
sandh
eal
thou
tcom
es.

T
opr
ovid
eav
iewo
f wh
atc
ouldb
each
iev
ed,c
ons
ide
ras
tudyo
fna
tur
al
h
ist
oryo
f MSc
ondu
ctedb
yDan
ie
lRe
icha
tth
eNa
tion
alIn
sti
tut
eso
fHe
alth

(N
IH.
)Fi
gur
e2.
10d
isp
lay
sth
evo
xel
-sp
ecifi
cin
ten
sit
ieso
fth
e FLA
IR(
top
p
ane
ls)
,T1(m
idd
lep
ane
ls)
,andT
2(bo
ttomp
ane
ls)im
age
sinal
esi
on(
lab
eled

l
esi
on1
4)f
oron
esub
jec
tov
er8y
ear
sat4
0vi
sit
s. Th
ex-
axi
srep
res
ent
stim
ein

d
aysandth
ey-
axi
srep
res
ent
sim
agein
ten
sit
iesa
sst
and
ardd
evi
ati
onso
fwh
ite

m
att
erin
ten
sit
ies
;se
eSe
cti
on2
.5.
5fo
rmo
red
eta
il
s. Th
efir
stc
olumnd
isp
lay
s

th
eth
rees
equ
enc
esa
lon
ganax
ials
li
ce,w
ith MSl
esi
onsb
ein
gvi
sib
lea
round

th
even
tri
cle
s,e
spe
cia
llyinth
eFLA
IRand T
1im
age
s. Th
ese
condc
olumn

d
isp
lay
sth
eco
rre
spond
ingv
oxe
lin
ten
sit
ies
, wh
il
eth
eth
irdc
olumnd
isp
lay
s

th
evo
xelin
ten
sit
iesinth
econ
tra
lat
era
lpa
rto
fth
ebr
ainc
orr
espond
ingt
oth
e

l
esi
on. Th
econ
tra
lat
era
lar
eao
fth
ebr
aini
sus
edh
erea
scon
tro
l. Th
efou
rth

c
olumnp
rov
ide
sth
ediff
eren
ceinv
oxe
lin
ten
sit
iesb
etw
eene
achv
oxe
landi
ts

c
ont
ral
ate
ralc
orr
espond
entv
oxe
l.

Th
eor
ang
eve
rti
call
ineind
ica
testh
efir
stt
imewh
enl
esi
on1
4wa
sid
ent
ified

u
sin
gth
eSuBL
IMEa
lgo
rithm
,[5
5]ana
lgo
rithmd
esi
gnedt
ose
gmen
tnewand

en
lar
gin
g MSl
esi
on,th
oughth
ele
sionm
ayh
aveo
ccu
rrede
arl
ierth
anth
isv
is
it
.

Ind
eed
,be
for
eth
ele
sioni
sob
serv
edth
erei
sar
ounda1
.5y
earg
apb
etw
eenth
e

MR
Ivi
sit
s.V
is
itsa
reind
ica
teda
saru
gonth
ex-
axi
s;n
oti
ceth
atth
erea
re

f
ewv
is
itsinth
ebe
ginn
ingf
oll
owedb
yman
ymon
thlyv
is
itsa
fte
rle
sion1
4is

d
ete
cted
. Th
isi
sju
ston
eex
amp
leo
fth
eda
ta,ands
imi
larp
lot
scann
owb
e
ob
tain
edf
ora
lll
esi
ons
. Th
isr
ais
iesimpo
rtan
tsc
ien
tifi
cqu
est
ion
s,su
cha
s:1
)

5
3
h
owm
anyp
att
ern
sof
int
ens
it
iesa
reth
ereb
efo
reanda
fte
rth
ele
sion
isd
ete
cted
?
2
)ar
eth
eresub
tlech
ang
esinim
agein
ten
sit
iesb
efo
reth
ele
sioni
sde
tec
tedth
at

c
ouldp
red
ictth
ele
sionl
oca
li
zat
iono
rtim
ing
?3)a
rec
ert
ainwh
item
att
era
rea
s

w
ithsp
ecifi
cin
ten
sit
ypa
tte
rnsm
orep
ron
etol
esi
onf
orm
ati
on?

2
.7 Conc
lus
ion
s

W
ecou
ldh
avew
rit
tenabook
. W
epr
obab
lysh
ouldh
avew
rit
tenabook
.Af
-

t
erfin
ish
ingth
isch
apt
er,w
ere
ali
zeth
atw
eba
relys
cra
tch
edth
esu
rfa
ceo
f

on
eofth
emo
stex
cit
inga
rea
sofr
ese
archins
tat
ist
icsandb
ios
tat
ist
ics
.Fa
r
f
romb
ein
gexh
aus
tiv
e,th
isch
apt
erin
trodu
cesfund
amen
talan
aly
ticc
onc
ept
s

inn
eur
oim
agin
gth
ata
rep
ert
inen
tbo
tht
ohe
alth
ysub
jec
tsbu
t,e
spe
cia
lly
,to

th
osewh
osuff
erf
romb
raind
ise
ase
s. Wh
il
eth
enumb
ero
fbi
ost
ati
sti
can
sand

s
tat
ist
ic
ian
swh
owo
rkinth
isa
reai
sin
cred
iblysm
allg
iventh
eimpo
rtan
ceo
f

th
epr
obl
em,th
osewh
o“g
eth
ook
ed”b
ecom
epa
ssi
ona
teabou
tlook
inginth
e

m
ostqu
ant
ita
tiv
ewa
ypo
ssib
lein
toth
ebr
ainandd
eal
ingw
ithc
omp
lexan
aly
tic

p
rob
lem
s.F
arf
roms
end
ingth
eme
ssa
geth
atth
isa
reao
fre
sea
rchi
scl
osed
,ou
r

ownp
erc
ept
ioni
sth
atr
ese
archi
sju
stn
ows
tar
tin
g.Impo
rtan
tcon
cep
tsh
ave
a
lre
adyb
eenin
trodu
cedandp
rog
res
sha
sbe
ena
chi
eved
. H
owev
er,w
ith
out

kn
owin
g wh
ath
asa
lre
adyb
eena
chi
evedth
ere
sea
rchc
ommun
ityw
il
lsimp
ly

r
ein
ven
tth
ewh
eel
.

5
4
Chap
ter3

OAS
ISi
s Au
toma
tedS
tat
ist
ica
l
In
ferencefo
rSegmen
tat
ion
,wi
th
app
lica
tion
sto mu
ltip
lesc
lero
sis
le
sionsegmen
tat
ionin MR
I

3
.1 In
troduc
tion

Mu
lt
ipl
esc
ler
osi
s(MS
)isaninfl
amm
ato
ryd
ise
aseo
fth
ebr
ainandsp
ina
lco
rd

ch
ara
cte
riz
edb
ydem
yel
ina
tin
gle
sion
sth
ata
rem
oste
asi
lyid
ent
ified
,atl
eas
ton
m
agn
eti
cre
son
anc
eim
agin
g(MR
I)s
tud
ies
,inth
ewh
item
att
ero
fth
ebr
ain[
1].

Qu
ant
it
ivean
aly
seso
f MR
I,su
cha
sth
enumb
erandv
olum
eofl
esi
ons
,ar
ees
-

s
ent
ialf
orf
ord
iagn
osin
gth
edi
sea
seand m
oni
tor
ingi
tsp
rog
res
sion[
2,3
]. MR
I

m
easu
resa
rea
lsoac
omm
onp
rim
aryendpo
intinph
aseI
Iimmun
omodu
lat
ory

5
5
d
rugth
erap
ytr
ial
s[7
0].Inth
eset
ria
ls
,ei
the
rmanu
alo
rsem
i-au
tom
ateds
eg-
m
ent
ati
onsa
reu
sedt
ocompu
teth
eto
talnumb
ero
fle
sion
sandth
eto
tall
esi
on

v
olum
e[6
5]. M
anu
ald
el
ine
ati
oni
sch
all
eng
inga
sth
ree
-dim
ens
ion
alin
form
a-

t
ionf
roms
eve
ral MR
Imod
ali
tie
s mu
stb
ein
teg
rat
ed[
71]
. M
anu
ala
sse
ssm
ent
o
f MR
Iisa
lsop
ron
etol
arg
ein
ter
-andin
tra
-ob
serv
erv
ari
abi
li
ty[
62]
. Wh
il
e

s
emi
-au
tom
ated m
eth
odsh
aveb
eenf
oundt
ode
cre
asein
ter
-andin
tra
-ra
ter
v
ari
abi
li
ty,th
eys
ti
llr
equ
irem
anu
alr
ead
erinpu
tanda
ret
imec
onsum
ing[
63]
.

Th
ere
for
eas
ens
it
iveandsp
ecifi
cau
tom
ated m
eth
odt
ode
tec
tle
sion
sinth
e

b
raini
ses
sen
tia
lfo
rth
ean
aly
siso
fstud
iesw
ithah
ighnumb
erso
f MSp
ati
ent
s.

Ac
omp
reh
ens
iver
evi
ewo
fcu
rren
tlya
vai
lab
leau
tom
ated
,cr
oss
-se
cti
ona
l MS

l
esi
ons
egm
ent
ati
on m
eth
ods
,orm
eth
odsu
sedt
oid
ent
ifyl
esi
onsf
romas
ing
le

MR
Istudy
,isp
rov
idedin[
71]
. W
ediv
ideth
esem
eth
odsin
tof
ourc
ate
gor
ies
:

sup
erv
isedc
las
sifi
erw
ithana
tla
s,sup
erv
isedc
las
sifi
erw
ithn
oat
las
,un
sup
er-

v
isedc
las
sifi
erw
ithana
tla
s,andun
sup
erv
isedc
las
sifi
erw
ithn
oat
las
. W
efo
cus

onsup
erv
isedm
eth
odsw
ith
outa
tla
ses
,asth
eme
thodw
epr
opo
sei
sinth
isc
at-

e
gory
.Sup
erv
isedm
eth
odsw
ith
outa
tla
sest
rainonm
anu
allys
egm
ent
edim
age
s

ann
ota
tedb
yexp
ert
sandu
seim
agein
ten
sit
ieso
f MR
Itoc
las
si
fyl
esi
ons[
71]
.

Sup
erv
isedc
las
sifi
cat
iona
lgo
rithm
sar
eapp
li
edt
oth
evo
lum
es:a
rtifi
cia
lneu
ral

n
etw
ork
s[7
2],sp
ati
alc
lus
ter
ing[
73]
,k-n
ear
estn
eighbo
rs[
74,7
5,7
6],P
arz
en

w
ind
ow[
77]
,Pa
rzen w
ind
owand m
orph
olo
gic
alg
ray
sca
ler
econ
stru
cti
on[
78]
,

B
aye
s[7
9],Ad
aBoo
st[
80]
,simu
lat
edann
eal
ingand M
ark
ovr
and
omfi
eld
s[8
1],
andg
raphcu
ts[
82]
.Al
lofth
eaf
orem
ent
ion
ed m
eth
odsex
cep
t[7
6]u
se mu
lt
i-

m
oda
li
ty MR
Iin
form
ati
ont
ocl
ass
ifyl
esi
ons
. Th
emo
stw
ide
ly-u
sedf
eatu
re

a
cro
ssa
lls
egm
ent
ati
on m
eth
odsi
svo
xelin
ten
sit
y,wh
ichd
eriv
ess
tren
gthf
rom

a mu
lt
i-m
oda
li
tyapp
roa
ch[
71]
.

5
6
 Th
eme
thod w
epr
opo
seu
sesal
ogi
sti
cre
gre
ssi
on m
ode
ltoa
ssi
gnv
oxe
l-
l
eve
lpr
obab
il
it
ieso
fle
sionp
res
enc
eins
tru
ctu
ral MR
Iofp
ati
ent
swi
th MS
.

L
ogi
sti
cre
gre
ssi
on m
ode
lsh
aveb
eenu
sedf
ors
egm
ent
ati
ono
fbr
aint
issu
es

andp
ath
olo
gyin MR
I[8
3,8
4,8
5].F
orapp
li
cat
ion
sto MS
,lo
gis
ticr
egr
ess
ion
h
asb
eenu
sedf
ord
ete
cti
ono
fgad
olin
iumenh
anc
ingl
esi
ons[
86]
,pr
edi
cti
ono
f

g
ado
lin
iumenh
anc
ingl
esi
onsw
ith
outadm
ini
ste
rin
gcon
tra
sta
gen
ts[
87]
,and
f
ors
egm
ent
ati
ono
fnewanden
lar
gin
g MSl
esi
ons[
9].T
oou
rkn
owl
edg
elo
gis
tic

r
egr
ess
ionh
asn
otb
eenu
sedinc
ros
s-s
ect
ion
als
egm
ent
ati
ono
f MSl
esi
onsin

s
tru
ctu
ral MR
I.

On
ediffi
cul
tyinau
tom
ateds
egm
ent
ati
ono
f MR
Iisdu
etov
ari
abl
eim
agin
g

a
cqu
is
it
ionp
aram
ete
rs[
71]
.Al
lofth
ese
gmen
tat
ion m
eth
odsr
evi
ewedin[
71]

h
avetun
ingp
aram
ete
rsth
ata
read
jus
tedt
oap
art
icu
lard
atas
etand m
ayn
ot

g
ene
ral
izet
oan
ewd
atas
etw
ithd
iffe
ren
tacqu
is
it
ionp
aram
ete
rs. Th
esep
a-

r
ame
ter
sar
eno
tin
form
edb
yth
eda
taandth
ere
for
e mu
stb
etun
edemp
ir
ica
lly
,

o
ftenw
ithl
itt
let
onoin
terp
ret
abi
li
tyo
fth
epa
ram
ete
r. App
li
cat
iont
oan
ew

d
atas
etm
ayr
equ
ires
eve
rali
ter
ati
onso
fse
gmen
tat
ion
stoad
jus
tth
etun
ingp
a-

r
ame
ter
stov
alu
esth
atp
rodu
cea
ccep
tab
les
egm
ent
ati
ons
.Am
eth
odinwh
ich

th
etun
ingp
aram
ete
rsa
rein
form
edb
yth
eda
taandf
orwh
ichad
jus
tmen
tsa
re

in
tui
tiv
eands
imp
lew
ouldth
ere
for
ebev
alu
abl
e.

As
econdd
ifficu
ltyinin
ten
sit
y-b
aseds
egm
ent
ati
oni
sth
at MR
Ida
taa
re

a
cqu
iredina
rbi
tra
ryun
its
;un
itsc
anv
ary w
ide
lyb
etw
eenand w
ith
inim
ag-
in
gcen
ter
s. Th
esev
ari
ati
onsa
rea
ttr
ibu
tedt
osc
ann
erh
ardw
are
,in
ter
act
ion
s

b
etw
eenh
ardw
areandp
ati
ent
s,andv
ari
ati
onsina
cqu
is
it
ionp
aram
ete
rs[
62]
.

5
7
Th
ere
for
e,p
rop
erin
ten
sit
yno
rma
li
zat
ioni
ses
sen
tia
lind
eve
lop
ingag
ene
ral
iz-
ab
les
egm
ent
ati
on m
eth
od. M
anyo
fth
ese
gmen
tat
ion m
eth
odsu
sein
ten
sit
y-

n
orm
ali
zedv
olum
es[
65]
,bu
tth
esem
eth
odsd
ono
tdem
ons
tra
teth
egen
era
l-

i
zab
il
ityo
fth
eno
rma
li
zat
ionp
roc
edu
ret
och
ang
esinim
agin
gacqu
is
it
ionp
a-
r
ame
ter
sandim
agin
gcen
ter
s.In[
63]th
eau
tho
rsp
erf
orm
edaPubM
edand

G
oog
leS
cho
lars
ear
chf
or MSl
esi
ons
egm
ent
ati
onp
ape
rs. O
fth
e47p
ape
rs
th
atm
etth
eirs
ear
chc
rit
eri
a,on
ly1
3ofth
esep
ape
rsu
sed mu
lt
icen
terd
ataf
or

v
al
ida
tion
,andth
ela
rge
std
atab
aseu
sedf
orv
al
ida
tionc
ons
ist
edo
f41sub
jec
ts.

T
osh
owg
ene
ral
izab
il
ity
,me
thod
s mu
stb
eva
lid
atedon mu
lt
icen
terd
ataw
ith

m
anysub
jec
ts.

Ath
irdd
ifficu
ltyi
sin
ten
sit
yinh
omo
gen
eit
y,th
esl
owsp
ati
alin
ten
sit
yva
ria
-

t
ion
softh
esam
eti
ssu
ewi
thinan MR
Ivo
lum
e.Inh
omo
gen
eit
ycans
ign
ific
ant
ly

r
edu
ceth
eac
cur
acyo
fim
ages
egm
ent
ati
on[
29]
,andth
ere
for
esom
efo
rmo
f

sp
ati
aln
orm
ali
zat
ioni
sne
ces
saryf
ora
ccu
rat
ele
sions
egm
ent
ati
on.M
ostl
esi
on

s
egm
ent
ati
on m
eth
odsa
ssum
eth
atth
eseinh
omo
gen
eit
iesh
aveb
eenc
orr
ect
ed

du
rin
gim
agep
rep
roc
ess
ing
,bu
tweh
avef
ounds
tron
gsp
ati
alp
att
ern
swi
thin

t
issu
etyp
eev
ena
fte
rth
eN3inh
omo
gen
eit
yco
rre
cti
ona
lgo
rithm[
19]i
sapp
li
ed.

T
oadd
res
sth
eseandr
ela
tedp
rob
lem
s,w
epr
opo
se OAS
ISi
s Au
tom
ated

S
tat
ist
ica
lIn
fer
enc
efo
rSe
gmen
tat
ion(OAS
IS)
,afu
llyau
tom
ated
,gen
era
li
z-

ab
le
,andn
ove
lst
ati
sti
calm
eth
odf
orc
ros
s-s
ect
ion
al MSl
esi
ons
egm
ent
ati
on.

U
sin
gin
ten
sit
yin
form
ati
onf
rom mu
lt
ipl
emod
ali
tie
sof MR
I,al
ogi
sti
cre
gre
s-
s
ion m
ode
las
sign
svo
xel
-lev
elp
rob
abi
li
tie
sofl
esi
onp
res
enc
e.A
fte
rtr
ain
ingon

m
anu
als
egm
ent
ati
ons
,th
e OAS
IS m
ode
lpr
odu
cesin
terp
ret
abl
ere
sul
tsinth
e

f
ormo
fre
gre
ssi
onc
oeffi
cien
tsth
atc
anb
eapp
li
edt
oim
agin
gstud
iesqu
ick
ly

ande
asi
ly
. OAS
ISu
sesin
ten
sit
y-n
orm
ali
zedb
rain MR
Ivo
lum
es,en
abl
ingth
e

5
8
m
ode
ltog
ene
ral
izet
och
ang
esins
cann
eranda
cqu
is
it
ions
equ
enc
e. OAS
ISa
lso
ad
jus
tsf
orin
ten
sit
yinh
omo
gen
eit
iesth
atp
rep
roc
ess
ingb
iasfi
eldc
orr
ect
ion

p
roc
edu
resd
ono
trem
ove
,us
ingsm
ooth
edv
olum
es. Th
isa
llow
sfo
rmo
rea
ccu
-

r
ates
egm
ent
ati
ono
fbr
aina
rea
sth
ata
reh
igh
lyd
ist
ort
edb
yinh
omo
gen
eit
ies
,
su
cha
sth
ece
reb
ellum
. On
eofth
emo
stp
rac
tic
alp
rop
ert
ieso
f OAS
ISi
sth
at

th
eme
thodi
sfu
llyt
ran
spa
ren
t,e
asyt
oexp
lainandimp
lem
ent
,ands
imp
let
o
m
odi
fyf
orn
ewd
atas
ets
.

T
oil
lus
tra
teth
egen
era
li
zab
il
ityo
fOAS
ISt
och
ang
esinim
agin
gacqu
is
it
ion

p
aram
ete
rs,w
eev
alu
atedth
epe
rfo
rman
ceo
fth
eal
gor
ithmonat
ota
lof3
00 MR
I

s
tud
iesf
romtw
osep
ara
teim
agin
gcen
ter
swi
thv
ary
inga
cqu
is
it
ionp
aram
ete
rs.

Th
isi
sac
ruc
ialc
rit
eri
onf
ora
sse
ssin
gth
egen
era
li
zab
il
ityandu
ti
li
tyo
fth
e

m
eth
od.

3
.2 Ma
ter
ial
sand me
thod
s

Inth
iss
ect
ionw
ein
trodu
ce OAS
IS,a m
eth
odin
spi
redb
ySub
tra
cti
onB
ased

In
fer
enc
efo
rMod
el
ingandE
stim
ati
on(SuBL
IME
),anau
tom
ated m
eth
odf
or

th
elon
gitud
ina
lse
gmen
tat
iono
fin
cid
entanden
lar
gin
g MSl
esi
ons[
9].B
efo
re
th
eOAS
ISl
ogi
sti
cre
gre
ssi
onm
ode
lisfi
t,ab
raint
issu
ema
ski
scr
eat
ed,a
ll MR
I
v
olum
esa
rein
ten
sit
yno
rma
li
zed
,andsm
ooth
edv
olum
esa
rec
rea
tedt
ocap
tur
e

l
oca
lsp
ati
alin
form
ati
onandad
jus
tfo
rrem
ain
ingfi
eldinh
omo
gen
eit
ies
. Th
e

OAS
IS m
eth
odin
volv
estw
oit
era
tion
sofm
ode
lfit
tin
g:th
efir
stt
ope
rfo
rman
in
it
iall
esi
ons
egm
ent
ati
onandth
ese
condt
ous
eth
isin
it
iall
esi
ons
egm
ent
ati
on

t
orem
ovel
esi
ons
, wh
ichc
and
ist
ortth
esm
ooth
edv
olum
es. A
fte
rth
efin
al
m
ode
lisfi
t,th
ere
gre
ssi
onc
oeffi
cien
tsa
reapp
li
edt
opr
odu
ceth
reed
imen
sion
al

5
9
m
apso
fvo
xel
-lev
elp
rob
abi
li
tie
sofl
esi
onp
res
enc
e.
W
eev
alu
ateth
epe
rfo
rman
ceo
fOAS
ISon MR
Ivo
lum
eso
fth
ebr
aina
cqu
ired

w
ithv
ari
ousa
cqu
is
it
ionp
rot
oco
ls
. W
eus
eda
tas
etsf
romtw
odiff
eren
tim
agin
g

c
ent
ersf
orv
al
ida
tion
,wh
ichw
ere
fert
oasv
al
ida
tions
et1andv
al
ida
tions
et
2
.va
lid
ati
ons
et1h
asm
anu
all
esi
ons
egm
ent
ati
ons
. W
etr
ain
edth
e OAS
IS

m
eth
odonasub
seto
fth
estud
iesinth
isd
ata
set
,andt
est
edonth
erem
ain
ing
s
tud
ies
. Anexp
ertev
alu
atedth
ese
gmen
tat
ion
sfr
omv
al
ida
tions
et1
.va
lid
ati
on

s
et2i
sus
edt
odem
ons
tra
teg
ene
ral
izab
il
ityt
och
ang
esinim
agea
cqu
is
it
ion

p
aram
ete
rs. W
eapp
li
edth
eco
effic
ien
tsf
romth
emod
elt
rain
edonv
al
ida
tion

s
et1t
oth
estud
iesinv
al
ida
tions
et2
,andexp
ert
sev
alu
atedth
eOAS
ISl
esi
on

s
egm
ent
ati
ons
.

3
.2.1 S
tudypopu
lat
ion

v
al
ida
tions
et1c
ont
ain
sat
ota
lof1
31 MR
Istud
iesf
rom1
31sub
jec
ts.O
fth
ese

s
tud
ies
,98a
ref
romp
ati
ent
swi
th MSand3
3ar
ehe
alth
yvo
lun
tee
rsc
ans
.Of

th
e98p
ati
ent
swi
th MS
,th
emed
iana
gei
s44y
ear
s(IQR
:[3
3,5
4])
,72a
re

f
ema
le(
26m
ale
),andth
emed
ianEDSSi
s3.
5(IQR
:[2
,6]
). Th
emed
iana
geo
f

th
ehe
alth
yvo
lun
tee
rsi
s34(
IQR
:[2
8,4
2])and1
9ar
efem
ale(
14m
ale
).

v
al
ida
tions
et2c
ont
ain
sat
ota
lof1
69 MR
Istud
iesf
rom1
49sub
jec
ts.

Tw
ent
ysub
jec
tsinv
al
ida
tions
et2h
aveb
ase
lin
eandf
oll
ow-ups
can
s. Th
e
m
eant
imeb
etw
eenb
ase
lin
eandf
oll
ow-upf
orth
ese2
0sub
jec
tsi
s13
2da
ys

(
IQR
:[5
1,1
82]
). Th
esub
jec
tsinth
eva
lid
ati
ons
eta
rea m
ixtu
reo
fhe
alth
y

v
olun
tee
rsandp
ati
ent
s:1
10o
fth
epa
tien
tsh
ave MS
,38h
aveo
the
rneu
rol
ogi
cal

d
ise
ase
s,andon
eisah
eal
thyv
olun
tee
r. Th
emed
iana
geo
fth
e MSp
ati
ent
s

6
0
i
s42(
IQR
:[3
3,5
0])
;54a
ref
ema
le(
56m
ale
);6
8ha
ver
elap
sin
grem
itt
ing MS
,
3
1ha
vep
rim
aryp
rog
res
siv
e MS
,and1
1ha
ves
econd
aryp
rog
res
siv
e MS
.Th
e

m
edi
ana
geo
fth
epa
tien
tsw
itho
the
rneu
rol
ogi
cald
ise
ase
sis4
1ye
ars
,(IQR
:

[
35,5
1])and8a
ref
ema
le(
30m
ale
). Th
ehe
alth
yvo
lun
tee
risa2
8ye
aro
ld
f
ema
le
.

3
.2.2 Expe
rimen
tal me
thod
s

T
1-w
eigh
ted
,T2
-we
igh
ted
,flu
id-
att
enu
atedin
ver
sionr
eco
very(FLA
IR)and

p
rot
ond
ens
ity(PD
)vo
lum
esw
erea
cqu
iredf
ora
llsub
jec
tsa
tea
chs
tudy
,and
a
llim
agin
gpr
oto
col
swe
reapp
rov
edb
ylo
calin
sti
tut
ion
alr
evi
ewbo
ard
s.F
or

v
al
ida
tions
et1
,3DT
1-MPRAGEim
age
s(r
epe
tit
iont
ime(TR
)=1
0ms
;ech
o

t
ime(TE
) =6m
s;fl
ipan
gl )α=8◦;in
e(FA ver
siont
ime(T
I) =8
35m
s,r
eso
-

lu
tion =1
.1 mm× 1
.1 mm× 1
.1 mm
),2DT
2-w
eigh
tedp
re-
con
tra
stFLA
IR

im
age
s(TR =1
100
0ms
; TE =6
8ms
;TI =2
800m
s;in
-pl
aner
eso
lut
ion =
0
.83 mm× 0
.83 mm
;sl
iceth
ickn
ess =2
.2 mm
),T
2-w
eigh
tedandPDim
age
s

(TR=4
200m
s;TE=
12/
80m
s;r
eso
lut
ion=0
.83 mm×0
.83 mm×2
.2 mm
)

w
erea
cqu
iredona3t
esl
a MR
Isc
ann
er(Ph
il
ipsM
edi
calSy
stem
s,B
est
, Th
e
N
eth
erl
and
s).

F
orv
al
ida
tions
et2
,th
e3DT
2-w
eigh
tedpo
st-
con
tra
stFLA
IRw
asa
cqu
ired

u
sin
gav
ari
abl
eflipan
gles
equ
enc
e,th
e2DPDandT
2-w
eigh
tedv
olum
esu
s-

in
gadu
al-
ech
ofa
st-
spin
-ech
osequ
enc
e,andth
e3DT
1-w
eigh
tedv
olum
eus
ing

anin
ver
sion
-pr
epa
redf
astspo
il
edg
rad
ien
t-e
chos
equ
enc
e. Th
eses
tud
iesw
ere

a
cqu
iredonas
ing
le3t
esl
a MR
Isc
ann
er(S
ign
aEx
cit
eHDx
t; GEH
eal
thc
are
,
M
ilw
auk
ee,W
isc
ons
in)
.Tab
le3
.1c
ont
ain
sth
eran
gesf
orth
eva
lid
ati
ons
et2

6
1
s
cann
ingp
aram
ete
rs.

Tab
le3.
1:R ange
sforv
al
idat
ionset2s
cannin
gp ar
ame
ter
s
FA(deg
rees
) TR(m s
) TE(ms) TI(ms)
FLAIR 90 (480
0,8 8
02)(124.
3,151
.4)(1481
,2 20
0)
T2
-wei
ghted 90 531
7 (116
.2,124
.2) NA
PD 90 5317 (16.
0,23.
7) NA
T1
-wei
ghted (6
,13) (8
.7,9.1
) (3
.2,3
.6) (45
0,725)

3
.2.3 Imagep
rep
roce
ssing

B
efo
rebu
ild
ingou
rst
ati
sti
calm
ode
lfo
rth
ele
sions
egm
ent
ati
on,w
epr
epr
o-

c
ess
edth
eim
age
sfr
omv
al
ida
tions
et1andv
al
ida
tions
et2u
sin
gth
etoo
lsp
ro-

v
idedin M
edi
calIm
ageP
roc
ess
ing An
aly
sisand V
isu
ali
zat
ion(M
IPAV
)[2
8],
TOADS
-CRU
ISE(h
ttp
://www
.ni
trc
.or
g/p
roj
ect
s/t
oad
s-c
rui
se/
),andJ
avaIm
-

a
geS
cien
ceT
oolk
it(J
IST
)[2
7]s
oftw
arep
ack
age
s. W
efir
str
igid
lya
lign
edth
e

T
1-w
eigh
tedim
ageo
fea
chsub
jec
tin
toth
eMon
tre
alN
eur
olo
gic
alIn
sti
tut
e
3
(MN
I)s
tand
ardsp
ace(v
oxe
lre
solu
tion1mm). W
eth
enr
egi
ste
redth
eFLA
IR,

PD
,andT
2-w
eigh
tedim
age
sofe
achsub
jec
ttoth
eal
ign
edT
1-w
eigh
tedim
age
s.

W
eal
soapp
li
edth
eN3inh
omo
gen
eit
yco
rre
cti
ona
lgo
rithm[
19]t
oal
lim
age
s
andr
emo
vedex
tra
cer
ebr
alv
oxe
lsu
sin
gSPECTRE
,asku
ll
-st
ripp
ingp
roc
edu
re

[
88]
.

3
.2.4 S
tat
ist
ica
l mode
lingandspa
tia
lsmoo
thing

W
epe
rfo
rmeda
lls
tat
ist
ica
lmod
el
inginth
e Ren
vir
onm
ent(v
ers
ion2
.12
.0,

RF
ound
ati
onf
orS
tat
ist
ica
lCompu
tin
g,V
ienn
a, Au
str
ia)w
ithth
epa
cka
ges

An
aly
zeFMR
I[8
9],b
iglm[
90]
, ff[
91]
,and ROCR[
92]
. W
eus
edth
e FSL

6
2
t
oolf
slm
ath
s(h
ttp
://www
.fm
rib
.ox
.ac
.uk
/fs
l)f
orth
eth
reed
imen
sion
alsp
ati
al
sm
ooth
ingo
fth
evo
lum
es.

3
.2.5 B
raint
issue ma
sk

Th
efir
sts
tepin OAS
ISi
stoc
rea
tea m
asko
fth
ebr
ainth
atex
clud
esc
ere
-

b
rosp
ina
lflu
id(CSF
).CSFi
sex
clud
edb
ecau
sei
tdi
srup
tsth
ecap
tur
eofth
e
inh
omo
gen
eit
yfie
ldandd
ist
ort
sth
erep
res
ent
ati
ono
fth
elo
calc
ereb
ralf
eatu
res

wh
enc
rea
tin
gsm
ooth
edv
olum
es.T
omak
eth
ism
ask
,weu
sedth
eex
tra
cer
ebr
al

v
oxe
lrem
ova
lma
skd
esc
rib
edinth
eIm
ageP
rep
roc
ess
ingS
ect
ionandex
clud
ed

v
oxe
lsinth
ema
skth
atapp
earh
ypo
int
ens
einth
eFLA
IRv
olum
e.B
ecau
seCSF

i
shypo
int
ens
einth
eFLA
IR,w
eemp
ir
ica
llyf
oundth
atex
clud
ingv
oxe
lsf
all
ing
b
elowth
ebo
ttom1
5thp
erc
ent
il
eofFLA
IRin
ten
sit
ieso
verth
eex
tra
cer
ebr
al

v
oxe
lrem
ova
lma
skr
emo
vesCSFou
tsid
eofth
ebr
ainandinth
even
tri
cle
s. W
e

r
efe
rtoth
ism
aska
sth
ebr
aint
issu
ema
sk.F
igu
re3
.1Bsh
owsas
li
ceo
fth
e

b
raint
issu
ema
skf
orap
art
icu
larsub
jec
tfo
ril
lus
tra
tion
.

3
.2.6 In
ten
sityno
rma
liza
tion

W
eus
edin
ten
sit
iesf
romth
eFLA
IR,PD
,T2
-we
igh
ted
,andT
1-w
eigh
tedv
ol-

um
est
oid
ent
ifyth
epr
esen
ceo
f MSl
esi
ons
. W
eden
oteth
eob
serv
edin
ten
sit
y

o
fvo
xelv,f
orsub
jec
tib
y:

0
Mi(v)
, M=FLA
IR,PD
,T2
,T1

wh
ereM ind
ica
testh
eim
agin
gsequ
enc
e.

6
3
Figure3.1
:A .Axialsl
icefr omdiffer
entm odal
iti
esofin ten
sityn orma
liz
edb ra
in
MR Iofas in g
lesub jec
t:A 1. FLAIRim age
. A 2
. T 2-we
i ghtedimage. A 3.
PDim age
. A 4
. T 1
-w e
ightedim age
. B .B ra
intissuem asko fanaxi a
ls l
ice
ofth ebrain.C . Axialsl
i ceofsele
ctv oxe
lsfor OAS IS m odel
ing. D.M anua
l
lesionsegm enta
tiono fanax ials
lic
eo fthebrain.E.Ax ia
ls l
iceofbraint i
ssue
maskw i
thd ilat
edl es
ion m ask madeataf a
lseposit
iver ateo f1%r emoved.F .
Axialsl
iceo fthesm oothedp robab
il
itym ap withint ens
itys cal
e. G.B inary
segm en
tationo fth eprob abi
li
tym apf r
omth e OAS IS m od e
la tfa
lsepo si
tive
rateof.00 5overl
aidonth eFLA IRim age.

6
4
 MR
Ivo
lum
esa
rea
cqu
iredina
rbi
tra
ryun
its
. An
aly
zin
gim
age
sac
ros
ssub
-
j
ect
sandim
agin
gcen
ter
srequ
ire
sth
atim
age
sben
orm
ali
zeds
oth
atv
oxe
l

in
ten
sit
iesh
avec
omm
onin
terp
ret
ati
ons
.Fo
rno
rma
li
zat
ion
,wead
aptth
eno
r-

m
ali
zat
ion m
eth
odf
rom[
93]t
ono
rma
li
zat
ionw
ithr
esp
ectt
oth
ebr
aint
issu
e
m
ask
. Th
eno
rma
li
zedin
ten
sit
yofv
oxe
l v,f
orsub
jec
tii
sden
otedb
y:

0
N
Mi(v)−µ0i
,M
Mi (
v)= 0
σi,M

wh
ereµ0
,Ma
i
0
ndσi
,Ma
reth
eme
anands
tand
ardd
evi
ati
ono
fth
eob
serv
edv
oxe
l

in
ten
sit
iesinth
ebr
aint
issu
ema
sko
fsub
jec
ti,f
roms
equ
enc
eM. Th
eno
rma
l-

i
zedv
oxe
lin
ten
sit
iesa
res
tand
ards
cor
eso
fth
ebr
aint
issu
ema
sk.F
igu
re3
.1A

sh
owsas
li
ceo
fth
eno
rma
li
zedim
age
sfr
oma
llf
ourm
oda
li
tie
sfr
omas
ing
le
sub
jec
twi
th MS
:FLA
IR,T
2-w
eigh
ted
,PD
,andT
1-w
eigh
ted
.

3
.2.7 Smoo
thedvo
lume
s

T
oac
coun
tfo
rin
ten
sit
yinh
omo
gen
eit
iesth
atr
ema
ina
fte
rin
it
ialinh
omo
gen
eit
y

c
orr
ect
ion
,weu
seas
equ
enc
eof mu
lt
ire
solu
tionsm
ooth
edv
olum
es,ob
tain
ed
u
sin
gdiff
eren
tlev
elso
fsm
ooth
ing
. Th
esm
ooth
edv
olum
esa
rec
rea
tedb
yth
ree

d
imen
sion
alsm
ooth
ingo
fth
eno
rma
li
zedv
olum
efr
ome
ach m
oda
li
tyo
verth
e

b
raint
issu
ema
sk. AG
aus
siansm
ooth
erw
ithr
ela
tiv
elyl
arg
eke
rne
lwind
ow

s
izei
sus
edt
osm
ootho
verth
efe
atu
resinth
ebr
ainandc
aptu
reth
epa
tte
rno
f

th
erem
ain
inginh
omo
gen
eit
y.

F
orsub
jec
tiandim
agin
gmod
ali
tyM,l
etkb
eth
esi
zeo
fth
eke
rne
lwin
-

d
ow. Th
enth
ein
ten
sit
yinv
oxe
lvo
fth
esm
ooth
edv
olum
eofim
agin
gmod
ali
ty
N
M i
sexp
res
seda
sGMi (
v,k)
. Th
esm
ooth
edv
olum
esa
reu
sedinth
e OAS
IS

6
5
m
ode
ltoin
corpo
rat
esp
ati
alin
form
ati
onandt
oac
coun
tfo
rinh
omo
gen
eit
iesin
th
ebr
ainth
atp
ers
ista
fte
rN3c
orr
ect
ion
.Fo
rOAS
ISw
eus
esm
ooth
edv
olum
es

a
sco
var
iat
esw
ithk
ern
elw
ind
ows
ize
sof1
0and2
0vo
xel
s, wh
ichw
eref
ound

emp
ir
ica
llyonv
al
ida
tions
et1t
owo
rk w
el
l.F
igu
re3
.2sh
owsth
esm
ooth
ed
v
olum
esf
orbo
thk
ern
elw
ind
ows
ize
sof1
0and2
0fr
ome
achm
oda
li
ty. Th
eke
r-

n
elw
ind
ows
izeo
f20sm
ooth
sov
erth
ean
atom
ica
lfe
atu
resa
lmo
stc
omp
let
ely
,
wh
il
eth
eke
rne
lwind
ows
izeo
f10s
ti
llp
res
erv
ess
omeo
fth
esef
eatu
res
,su
ch

a
sth
ehyp
erin
tes
it
ieso
fth
egr
aym
att
erinth
eFLA
IR,T
2-w
eigh
ted
,andPD

v
olum
esandh
ypo
int
ens
it
ieso
fth
egr
aym
att
erinth
eT1
-we
igh
tedv
olum
e.

F
i gure3.2: Axialsl
icefromaas ing
lesub j
ectofthesm oothedvolum esf
roma l
l
modali
ties.R owon econta
insth esm oothedv o
lum eswithk e
rnelw indowsize
of1 0andr owtw oc ont
ainsthesm oothedv olumesw i
thk erne
lw ind owsiz
eo f
20.C olumnAc onta
instheFLA IRim a
g es
,Bc ontain
sth eT 2
-weightedim ag
es,
Cc ontainsth ePDim agesand Dc ontainstheT 1-we
i ght
edim ages. Tolink
N
thefi gu r
ew iththen otat
ionusedinth isp ape
r:A 1. GFLA IRi (v,10
);A 2.
N N N N
GFLA IRi( v,2 0
);B 1.GT2 i(v
,1 0
);B 2.GT2 i(v,20)
;C 1
.GPDi ( v,10)
;C 2.
N N N
GPDi (v
,2 0
);D 1.GT1 i (
v,10)
;D 2.G T 1i (
v,20)
;E .Sc a
leofintensi
tie
sin the
sm oothedv olum e
s.

6
6
3
.2.8 OAS
ISi
s Au
toma
tedS
tat
ist
ica
lIn
ferencefo
rSeg
-

men
tat
ion

Inth
iss
ect
ionw
ein
trodu
ceth
e OAS
IS m
ode
l. OAS
ISu
sesl
ogi
sti
cre
gre
ssi
on

t
omod
elth
epr
obab
il
ityth
atav
oxe
lisp
arto
fal
esi
on. W
ech
oos
elo
gis
tic
r
egr
ess
ionb
ecau
sei
tisex
trem
elys
imp
leande
asyt
oin
terp
ret
. W
emod
ell
esi
ons

a
tth
evo
xell
eve
lus
ingFLA
IR,PD
,T2
-we
igh
ted
,andT
1-w
eigh
tedin
ten
sit
ies

a
swe
lla
sth
ein
ten
sit
iesf
romth
esm
ooth
edv
olum
eso
fea
ch m
oda
li
tyw
ith

k
ern
elw
ind
ows
ize
sof1
0and2
0vo
xel
s. Th
emod
el mu
stb
etr
ain
edona

g
olds
tand
ard m
easu
reo
fle
sionp
res
enc
e.F
igu
re3
.1Di
sanex
amp
leo
fmanu
al

l
esi
ons
egm
ent
ati
on, wh
ichi
sanapp
rop
ria
teg
olds
tand
ard m
easu
ref
orth
e

OAS
IS m
ode
l. Th
ere
sul
tofou
rmod
eli
sac
oll
ect
iono
fco
effic
ien
tsth
atc
an

b
eus
edt
ocr
eat
eth
ree
-dim
ens
ion
alm
apso
fth
epr
obab
il
it
ieso
fle
sionp
res
enc
e.

OAS
ISob
tain
sth
ees
tim
atedl
ogi
tofth
epr
obab
il
ityo
fea
chv
oxe
lbe
ingp
arto
fa

l
esi
onb
ywe
igh
tin
gth
ese1
2im
age
s(th
efou
rim
agin
gmod
ali
tie
sandsm
ooth
ed

v
olum
esf
ore
ach m
oda
li
ty)w
ithth
eco
effic
ien
ts.

Th
efir
sts
tepo
fth
emod
el
ingp
roc
edu
rei
stos
ele
ctc
and
ida
tev
oxe
lst
o

m
inim
izef
als
epo
sit
ive
sandc
ompu
tat
iont
ime
.Le
sion
sapp
eara
shyp
erin
ten
-

s
it
iesinth
eFLA
IRv
olum
e. Th
ebr
aint
issu
ema
skw
asapp
li
edt
oth
eFLA
IR

v
olum
e,andth
e85
thp
erc
ent
il
eandabo
veo
fvo
xel
sinth
ebr
aint
issu
ema
sk

w
eres
ele
cteda
scand
ida
tev
oxe
lsf
orl
esi
onp
res
enc
e.Inv
al
ida
tions
et1
,th
ere
w
ereat
ota
lof1
,09
3,3
94l
esi
onv
oxe
ls(
avo
lum
eof1
,03cm3)
9 . Th
evo
xels
ele
c-

t
ionp
roc
edu
reex
clud
ed6
4,5
56(
6%)o
fth
esev
oxe
ls
,bu
tlow
eredth
ese
arch
abl
e

a
reat
o15%o
fth
eor
igin
als
ize
. Th
isp
roc
edu
rea
lsod
ecr
eas
esth
enumb
ero
f

po
ten
tia
lfa
lsepo
sit
ivev
oxe
ls
.Us
ingth
isth
resh
olda
lsos
ign
ific
ant
lyd
ecr
eas
es

6
7
th
enumb
ero
fvo
xel
sth
emod
el mu
stb
efiton
,al
low
ingf
ora mu
chf
ast
erfi
t.
F
igu
re3
.1Csh
owsas
li
ceo
fth
evo
xels
ele
cti
on m
askf
oras
ing
lesub
jec
t.

W
eth
enfi
tav
oxe
l-
lev
ell
ogi
sti
cre
gre
ssi
on m
ode
lov
erth
ecand
ida
tev
oxe
ls
.

Inth
eOAS
ISm
ode
l,th
epr
obab
il
ityth
atav
oxe
lisp
arto
fal
esi
oni
srep
res
ent
ed
a
sP{
Li(
v) =1
}, wh
ereLi
sar
and
omv
ari
abl
eden
otin
gvo
xel
-lev
ell
esi
on

p
res
enc
e.I
fth
erei
sal
esi
oninv
oxe
lvf
orsub
jec
ti,th
enLi(
v)=1
.Oth
erw
ise
,
Li(
v)=0
. Th
epr
obab
il
ityth
atav
oxe
lvc
ont
ain
sle
sionin
cid
enc
eism
ode
led

w
ithth
efo
llow
ingl
ogi
sti
cre
gre
ssi
on m
ode
l:

6
8
 l
ogi
t[
P{ v)=1
Li( }] = β0 +
N N N
β1FLA
IRi (
v) + β2GFLA
IRi (
v,1
0) + β3GFLA
IRi (
v,2
0) +
N N N
β4PDi (
v) + β5GPDi (
v,1
0) + β6GPDi (
v,2
0) +
N N N
β7T2
i(v) + β8GT2
i(v
,10
) + β9GT2
i(v
,20
) +
N N N
β10T1
i(v) + β11GT1
i(v
,10
) + β12GT1
i(v
,20
) [
1]
N N N N
+ β13FLA
IRi (
v)∗GFLA
IRi (
v,1
0) + β14FLA
IRi (
v)∗GFLA
IRi (
v,2
0)
N N N N
+ β15PDi (
v)∗GPDi (
v,1
0) + β16PDi (
v)∗GPDi (
v,2
0)

6
9
N N N N
+ β17T2
i(v)∗GT2
i(v
,10
) + β18T2
i(v)∗GT2
i(v
,20
)
N N N N
+ β19T1
i(v)∗GT1
i(v
,10
) + β20T1
i(v)∗GT1
i(v
,20
)
Th
eeff
ecto
fma
gne
ticfi
eldinh
omo
gen
eit
iesa
reth
ough
ttob
e mu
lt
ipl
ica
tiv
e,
s
oweu
seth
ein
ter
act
ion
sbe
twe
enth
eno
rma
li
zedv
olum
eandth
esm
ooth
ed

v
olum
einth
emod
el
.

3
.2.9 OAS
IS mode
lrefinemen
t

Th
ese
condi
ter
ati
ono
fth
eOAS
IS m
ode
lfit
tin
gisd
onet
oredu
ceth
einflu
enc
e
o
fle
sion
sinth
esm
ooth
edv
olum
es.F
irs
t,w
efitth
emod
elandu
seth
ees
tim
ated

c
oeffi
cien
tst
ocr
eat
emap
softh
ees
tim
atedp
rob
abi
li
tyo
fle
sionp
res
enc
eate
ach

v
oxe
l.T
oin
corpo
rat
esp
ati
alin
form
ati
ono
fth
ene
ighbo
rin
gvo
xel
sandr
edu
ce

n
ois
e,w
esm
oothth
ees
tim
atedp
rob
abi
li
tie
sfr
omth
emod
elu
sin
ga G
aus
sian

k
ern
elw
ithw
ind
ows
izeo
f3 mm
. Th
isk
ern
els
izew
asemp
ir
ica
llych
osenand

f
oundt
ope
rfo
rmw
el
l. Th
ere
sul
tin
gpr
obab
il
itym
apsw
ereth
enth
resh
old
ed

u
sin
gal
ibe
ralf
als
epo
sit
iver
ateo
f1%(
thr
esh
oldv
alu
eof0
.10
),wh
ichr
esu
lted

in m
ode
lba
sedh
ards
egm
ent
ati
onso
fle
sion
s. Th
esel
esi
onsm
ask
swe
reth
en

d
ila
tedb
y5v
oxe
lst
oen
sur
eth
atth
een
tir
ele
sionw
asc
aptu
redandr
emo
ved

f
romth
ebr
aint
issu
ema
sk.F
igu
re3
.1Esh
owsth
ebr
aint
issu
ema
skw
ithth
e

l
esi
onsr
emo
ved
.Newsm
ooth
edv
olum
esw
erec
rea
tedb
yapp
lyin
ga G
aus
sian
sm
ooth
erw
ithk
ern
elw
ind
ows
ize
sof1
0and2
0toth
eno
rma
li
zedim
agef
rom

e
achm
oda
li
tyo
verth
ebr
aint
issu
ema
skw
ithth
ele
sion
srem
oved
. W
einp
ain
ted

th
esm
ooth
edv
olum
est
ofil
lth
epl
ace
s wh
erel
esi
onsw
erer
emo
ved w
ithth
e

v
alu
esw
ewou
ldexp
ectinth
isa
reai
fitw
ereo
ccup
iedb
yno
rma
l,h
eal
thyt
issu
e.

Th
ein
ten
sit
yinv
oxe
lvo
fth
eno
rma
li
zedim
agea
fte
rth
ese
cond G
aus
sian

sm
ooth
erh
asb
eenapp
li
edi
slab
eleda
s,G2Mi
N
(
v,k)
.Fi
gur
e3.
3sh
owsanax
-

i
als
li
cef
orasub
jec
tofth
eFLA
IRv
olum
eandth
esm
ooth
edv
olum
efo
rth
is

7
0
im
agew
ithk
ern
elw
ind
ows
ize
sof1
0and2
0be
for
eanda
fte
rth
ele
sion
swe
re
N
r
emo
ved
.Tol
inkth
efigu
rew
ithth
eno
tat
ion
,Fi
gur
e3.
3Ash
owsFLA
IRi (
v),

F
igu
re3
.3Bsh
owsas
cal
eofin
ten
sit
iesinth
esm
ooth
edv
olum
es,F
igu
re3
.3C
1
N
sh
owsGFLA
IRi (
v,1
0),F
igu
re3
.3C
2sh
owsG2FLA N
IRi (
v,1
0),F
igu
re3
.3D
1
N
sh
owsGFLA
IRi (
v,2
0),andF
igu
re3
.3D
2sh
owsG2FLA N
IRi (
v,2
0). Th
ele
-

s
ion
sar
ecap
tur
edinth
efir
stsm
ooth
edv
olum
e,e
spe
cia
llyw
ithth
eke
rne
lsi
ze
o
f10
,bu
tar
eno
tcap
tur
edinth
ese
condsm
ooth
edv
olum
e. Th
emod
el[
1]w
as

r
efito
verth
esam
evo
xel
sus
ingth
ese
condsm
ooth
edv
olum
etoob
tainth
efin
al

c
oeffi
cien
tsth
ata
reu
sedt
ocr
eat
eth
efin
alp
rob
abi
li
tym
aps
.Ag
ain
,th
efin
al

e
stim
atedp
rob
abi
li
tie
sar
esm
ooth
edu
sin
gaG
aus
siank
ern
elw
ithw
ind
ows
ize

o
f3 mm
.Fi
gur
e3.
1Fsh
owsas
li
ceo
fth
epr
obab
il
itym
apf
orasub
jec
tand

as
cal
eofin
ten
sit
ies
.Redind
ica
tesa
rea
swi
thah
igh
erp
rob
abi
li
tyo
fbe
inga

l
esi
onandb
lueind
ica
tesa
rea
swi
thal
owe
rpr
obab
il
ityo
fbe
ingal
esi
on.

3
.2.10 P
robab
il
ity mapandb
ina
rysegmen
tat
ion

U
sin
gth
isfi
tted m
ode
ltog
ene
rat
eap
rob
abi
li
tym
apf
orth
een
tir
ebr
ainf
rom

as
eto
fnewim
age
stak
esabou
t30m
inu
tesf
ore
achs
tudyu
sin
gas
tand
ard

w
ork
sta
tion
. Th
eGau
ssi
ansm
ooth
ingi
sth
esl
owe
sts
tepo
fth
eal
gor
ithmand

t
ake
sapp
rox
ima
telyon
eminu
tef
ore
achv
olum
e. Th
esec
ompu
tat
ion
scanb
e

p
ara
ll
el
izedt
otak
esub
stan
tia
llyl
esst
ime
;th
een
tir
eal
gor
ithmc
anb
erunin

app
rox
ima
tely5 m
inu
tesw
ith8c
ore
s.T
omak
eap
rob
abi
li
tym
apf
oran
ew

s
tudy
,th
etw
ose
tso
fre
gre
ssi
onc
oeffi
cien
ts,ab
rainm
ask
,andth
eFLA
IR,PD
,

T
2-w
eigh
ted
,and T
1-w
eigh
tedv
olum
esa
rer
equ
ired
. U
sin
gpopu
lat
ion
-lev
el

7
1
Fi
gur
e3.3
: Axialsl
iceoftheFLAIRv olum eandthefirstandsecondsmoothed
vo
lumesc
reatedfromth eFLAIRim ageforas ing
lesubje
c t
.T ol
inkthefi gur
e
N
wi
ththenotat
ionu sedinthi
spap er:A. FLA IRi (
v) B.S c
aleofint
ensit
ies
N 2 N
inthesmoothedv o
lum e
sC 1
.GFLA IRi( v,10)
;C 2. G FLAIRi( v
,10);D 1
.
N
GFLAIRi (
v,2 0
);D 2.G2FLAIRiN
(
v,20)
.

th
resh
old
s,th
epr
obab
il
itym
apsf
rom OAS
ISc
anb
eus
edt
ocr
eat
eha
rds
eg-

m
ent
ati
onso
fle
sionp
res
enc
e.F
igu
re3
.1Gsh
owsas
li
ceo
fah
ards
egm
ent
ati
on

o
ver
laidonth
eFLA
IRim
age
.

3
.2.11 V
alida
tion w
ithgo
lds
tanda
rd:v
alida
tionse
t1

v
al
ida
tions
et1
,de
scr
ibedind
eta
ilinth
eMa
ter
ial
sse
cti
on,c
ons
ist
sof1
31 MR
I

s
tud
ies
:98s
tud
iesf
rom MSsub
jec
tsand3
3stud
iesf
romh
eal
thysub
jec
ts.T
o

fi
tth
emod
elandt
ome
asu
rep
erf
orm
anc
e,w
erequ
iredas
eto
fda
tainwh
ich

th
eou
tcom
eisa
sse
ssedu
sin
gag
olds
tand
ard m
easu
re. Th
ego
lds
tand
ard

w
asob
tain
edu
sin
gmanu
als
egm
ent
ati
onb
yat
echn
olo
gis
twi
th m
oreth
an

7
2
1
0ye
arso
fexp
eri
enc
eind
el
ine
atin
g wh
item
att
erl
esi
ons
. Th
ete
chn
olo
gis
t
sp
entb
etw
een3
0minu
test
oanh
ours
egm
ent
inge
achs
tudy
,dep
end
ingonth
e

l
esi
onl
oadandd
ist
ribu
tion
. Th
ema
jor
ityo
fth
estud
iesh
ada
tle
astm
ode
rat
e

p
ath
olo
gyandth
ere
for
etookb
etw
een4
5minu
test
oanh
our
. Th
ese
gmen
tat
ion
s
w
erem
adef
romth
eFLA
IRand T
1-w
eigh
tedv
olum
es.F
igu
re3
.1Dsh
owsa

m
anu
allys
egm
ent
eds
li
cef
orasub
jec
t. Th
eme
anv
olum
eofl
esi
onsf
or MS
3 3 3
sub
jec
tsinv
al
ida
tions
et1i
s11
.2cm (
IQR
:[1
.7cm,1
6.6cm])
.Itw
as

a
ssum
edth
atth
ehe
alth
ysub
jec
tsd
idn
oth
avean
yle
sion
s.
T
oev
alu
atep
erf
orm
anc
eofou
rmod
elw
ith
inv
al
ida
tions
et1
,wet
rain
ed

th
emod
el[
1]on2
0rand
omlys
ele
ctedsub
jec
ts(
15 MSsub
jec
tsand5h
eal
thy

sub
jec
ts)andt
est
edonth
erem
ain
ing1
11sub
jec
ts(
83 MSsub
jec
tsand2
8

h
eal
thysub
jec
ts)
. W
eus
edon
lyth
estud
iesf
romth
e11
1sub
jec
tsinth
ist
est

s
ett
oes
tim
ateth
evo
xel
-lev
elr
ece
ive
rop
era
torch
ara
cte
ris
tic(ROC
)cu
rveand

a
reaund
erth
ecu
rve(AUC
).Th
esep
erf
orm
anc
eme
asu
resa
rekn
ownt
obesu
s-

c
ept
ibl
etoin
stab
il
ity
.Toa
ccoun
tfo
rth
is
,wen
onp
aram
etr
ica
llyboo
tst
rapp
ed

w
ithr
epl
acem
entth
esub
jec
tst
oth
etr
ain
ingandt
est
ings
ets
. W
eth
enfi
tth
e

m
ode
lonth
etr
ain
ings
etandob
serv
edth
epe
rfo
rman
ceo
fth
emod
elinth
e

t
est
ings
et.
I
tiskn
ownth
atth
efu
llAUCsumm
ari
zest
estp
erf
orm
anc
eov
err
egi
onso
f

th
eROCsp
aceth
ata
ren
otc
lin
ica
llyr
elev
antf
orl
esi
ons
egm
ent
ati
on[
9]. On
ce

at
esth
asb
eenab
let
odi
stin
gui
sh w
el
lbe
twe
end
ise
aseandn
otd
ise
ase
,th
e

p
erf
orm
anc
eofth
ete
stf
orp
art
icu
larapp
li
cat
ion
s mu
stb
eev
alu
ated
,inwh
ich

c
aseon
ema
ybein
ter
est
edinon
lyasm
allpo
rti
ono
fth
eROCcu
rve[
94]
.In

th
isp
art
icu
larapp
li
cat
ion w
ear
ein
ter
est
edinu
sin
gth
ele
sions
egm
ent
ati
on
t
oid
ent
ifyl
esi
onsandt
opr
ovid
eac
cur
atee
stim
ati
onso
fle
sionv
olum
es. Th
e

7
3
m
eanl
esi
onv
olum
eofm
anu
all
esi
ons
egm
ent
ati
onsf
romv
al
ida
tions
et1i
s11
.2
3 3 3
cm (
IQR[
1.7cm,1
6.6cm])
.Fo
rth
een
tir
ebr
ain
,af
als
epo
sit
iver
ateo
f
3
.
01w
ouldc
orr
espondt
oav
olum
eof1
2.8cm o
fhe
alth
ybr
ainb
ein
gfa
lse
ly
id
ent
ifieda
sle
sion
, wh
ichi
smo
reth
anth
eme
anl
esi
onv
olum
einv
al
ida
tion

s
et1
. Th
ere
for
eweex
amin
edon
lyf
als
epo
sit
iver
ate
sbe
low1%
. W
epr
ovid
e

th
epa
rti
al ROCcu
rvew
ithboo
tst
rapp
ed9
5%c
onfid
enc
eband
sfo
rcl
ini
cal
ly
r
elev
antf
als
epo
sit
iver
ate
sof1%andb
elow
.

3
.2.12 V
alida
tion w
ithexpe
rtrank
ing
s:v
alida
tionse
t1

andv
alida
tionse
t2

F
orth
estud
iesinv
al
ida
tions
et2
,go
lds
tand
ards
egm
ent
ati
onsw
eren
ota
vai
l-

ab
le
.Toev
alu
ateth
epe
rfo
rman
ceo
f OAS
ISonv
al
ida
tions
et2
,th
reeexp
ert
s

(
aneu
ror
adi
olo
gis
t,n
eur
olo
gis
t,andr
adi
olo
gis
t)c
omp
ared OAS
ISs
egm
ent
a-

t
ion
stoth
osef
romL
esi
onTOADS
,anop
en-
sou
rcel
esi
ons
egm
ent
ati
ons
oftw
are

(h
ttp
://www
.ni
trc
.or
g/p
roj
ect
s/t
oad
s-c
rui
se/
),[
95,9
6,6
6].v
al
ida
tions
et2
,

d
esc
rib
edind
eta
ilinth
eMa
ter
ial
sse
cti
on,c
ons
ist
sof1
69 MR
Istud
ieso
f14
9

sub
jec
ts,2
0ofwh
omh
adf
oll
ow-upv
is
its
. Th
eses
tud
iesw
erea
cqu
iredu
sin
ga
v
ari
etyo
fim
agin
gpr
oto
col
s.

F
orth
e OAS
ISa
lgo
rithm
,th
eon
lyp
aram
ete
rth
at mu
stb
etun
ed wh
en

m
ovin
gtoan
ewd
ata
seti
sth
epopu
lat
ion
-lev
elth
resh
old
.Fo
rva
lid
ati
ons
et2

w
eus
edth
eco
effic
ien
tsth
atw
eret
rain
edonv
al
ida
tions
et1andth
enemp
ir
i-

c
allyad
jus
tedth
epopu
lat
ionl
eve
lth
resh
oldf
orv
al
ida
tions
et2
.Toad
jus
tth
is

th
resh
old
,wer
and
omlys
amp
led1
0sub
jec
tsf
romv
al
ida
tions
et2
. W
eapp
li
ed

th
resh
old
sbe
twe
en0
.10and0
.50(b
yin
crem
ent
sof0
.05
)toth
epr
obab
il
ity

7
4
m
aps
,ex
amin
edth
ese
gmen
tat
ion
,andemp
ir
ica
llych
oseath
resh
oldo
f0.
35f
or
v
al
ida
tions
et2
. Th
isth
resh
oldad
jus
tmen
tisv
eryf
astandt
ran
spa
ren
t. W
e

r
anth
ese
gmen
tat
ion
sfo
rth
e10sub
jec
tsinp
ara
ll
el
,ande
achs
egm
ent
ati
on

t
ookl
essth
an5 m
inu
tes
. N
ext
,weth
resh
old
edth
epr
obab
il
itym
apsa
tth
e
9d
iffe
ren
tth
resh
old
s, wh
icht
ookon
lys
econd
s.L
ast
,wel
ook
edth
rou
ghth
e

s
egm
ent
ati
onsandth
eor
igin
alim
age
stos
ele
ctth
eop
tim
al(m
ostr
eas
onab
le)
th
resh
old
,wh
icht
ookon
lyabou
ta m
inu
tef
ore
achsub
jec
t. Th
een
tir
epr
oce
ss

o
ftun
ingth
eth
resh
oldt
ookl
essth
ananh
ourandin
volv
edon
ly1
0minu
teso
f

m
anu
alim
ageex
amin
ati
on. Th
isp
roc
edu
reon
lyn
eed
stob
epe
rfo
rmedon
ce

wh
en m
ovin
gtoan
ewim
agin
gcen
tero
rstudy
.Fo
rth
ese
gmen
tat
ionc
omp
ar-

i
son
,wep
res
ent
edth
eth
reeexp
ert
swi
ths
egm
ent
ati
onsa
tth
eth
resh
oldv
alu
e

o
f0.
35ona
llo
fth
eim
age
sinv
al
ida
tions
et2a
swe
lla
satth
eth
resh
oldf
rom

v
al
ida
tions
et1w
ithaf
als
epo
sit
iver
ateo
f0.
005
,ath
resh
oldv
alu
eof0
.16
. W
e

w
il
lre
fert
oth
eth
resh
oldv
alu
eof0
.35a
sth
eemp
ir
ica
llyad
jus
tedth
resh
old

andth
eth
resh
oldv
alu
eof0
.16a
sth
eva
lid
ati
ons
et1th
resh
old
.

W
ecomp
aredbo
th OAS
ISs
egm
ent
ati
onst
oth
ese
gmen
tat
ion
spr
odu
ced

b
yth
eop
ens
our
ces
oftw
areL
esi
onTOADS
. W
eranL
esi
onTOADS w
ith T
1-

w
eigh
tedand FLA
IRinpu
tsandth
ede
fau
ltp
aram
ete
rs. W
ead
jus
tedth
e

sm
ooth
ingp
aram
ete
rfr
om0
.2t
o0.
4be
cau
sew
eemp
ir
ica
llyf
oundth
ist
oim
-

p
rov
eth
equ
ali
tyo
fth
ese
gmen
tat
ion
s.I
tisimpo
rtan
tton
oteth
atL
esi
on-

TOADSn
oton
lys
egm
ent
sle
sion
s,bu
tal
sos
egm
ent
sth
eoth
ert
issu
ecl
ass
eso
f
th
ebr
ain
.Fo
rth
isan
aly
sis
,weon
lyu
sedth
ele
sions
egm
ent
ati
ons
.

W
ede
sign
edanim
ager
atin
gsy
stemt
oev
alu
ateth
epe
rfo
rman
ceo
fth
etw
o

s
egm
ent
ati
ona
lgo
rithm
s.F
ore
acho
fth
e16
9stud
ies
,weh
adth
rees
egm
en-

t
ati
ons
:th
eLe
sionTOADSs
egm
ent
ati
on,th
e OAS
ISs
egm
ent
ati
on w
ithth
e

7
5
th
resh
oldf
romv
al
ida
tions
et1
,andth
e OAS
ISs
egm
ent
ati
onw
ithth
eemp
ir
i-
c
allyad
jus
tedth
resh
old
. W
eal
sor
and
omlys
ele
cted2
0ofth
e MR
Istud
iesand

c
rea
teddup
li
cat
eso
fth
eset
oas
ses
sra
tin
gre
liab
il
ity
,fo
rat
ota
lof1
89s
tud
ies
.

W
erand
omi
zedth
eord
erinwh
ichth
ese
gmen
tat
ion
swe
rep
res
ent
edt
oth
eex
-
p
ert
sandr
and
omlya
ssi
gnede
achs
egm
ent
ati
onal
ett
er:A
,B,o
rC,s
oast
o

b
lindth
era
tert
oth
ese
gmen
tat
iona
lgo
rithm
.
W
epr
esen
tede
acho
fth
e18
9 MR
Istud
iest
oanexp
eri
enc
ed MSn
eur
ora
-

d
iol
ogi
st.F
ore
achs
tudy
,th
eneu
ror
adi
olo
gis
tex
amin
edth
ese
tofth
rees
eg-

m
ent
ati
onsa
lon
gwi
thth
eor
igin
alFLA
IR,PD
,T1
-we
igh
ted
,andT
2-w
eigh
ted

v
olum
es. Th
eneu
ror
adi
olo
gis
tth
ens
cor
edth
epe
rfo
rman
ceo
fea
cho
fth
ese
g-

m
ent
ati
onsonac
ont
inu
ouss
cal
efr
om0t
o10
0,w
ith0b
ein
ganunu
sab
lel
esi
on

s
egm
ent
ati
onand1
00b
ein
gap
erf
ects
egm
ent
ati
on. Th
eneu
ror
adi
olo
gis
twa
s

p
res
ent
eda
llth
rees
egm
ent
ati
onss
imu
ltan
eou
sly
,soth
ats
cor
esw
erea
ssi
gned

r
ela
tiv
etoon
ean
oth
er.F
if
tyo
fth
estud
iesw
eres
ele
ctedt
obes
cor
edw
ithth
e

s
amesy
stemb
yan
eur
olo
gis
twi
thasub
spe
cia
ltyin MSandag
ene
ralr
adi
olo
-

g
istino
rde
rtoa
sse
ssr
ate
rag
reem
entam
ongth
eth
reer
ate
rs. Th
e50s
tud
ies

w
erec
omp
ris
edo
f45r
and
omlys
ele
cteds
tud
iesw
ith5o
fth
estud
iesr
epe
ated

t
oas
ses
sra
terr
el
iab
il
ity
.

Th
eneu
ror
adi
olo
gis
tal
soc
omp
aredands
cor
edth
e OAS
ISand L
esi
on-

TOADSs
egm
ent
ati
onsf
romth
estud
iesf
orth
e98 MSp
ati
ent
sinv
al
ida
tion

s
et1
. Th
isa
llow
sfo
rcomp
ari
sono
fth
epe
rfo
rman
ceo
fth
ese
gmen
tat
ion
son
v
al
ida
tions
et1andv
al
ida
tions
et2
.

7
6
3
.3 Expe
rimen
talre
sul
ts

3
.3.1 V
alida
tionse
t1:t
rain
ing w
ithgo
lds
tanda
rd

Th
e OAS
IS m
ode
lha
sane
stim
atedfu
ll AUCo
f98%(
95% C
I;[
96%
,99%
])
andap
art
ialAUCf
orc
lin
ica
llyr
elev
antf
als
epo
sit
iver
ate
sof1%andb
elowo
f

0
.59%(
95%C
I;[
0.5
0%,0
.67%
])inth
ete
sts
et.F
igu
re3
.4sh
owsth
evo
xel
-lev
el

p
art
ial ROCcu
rvef
orth
ete
sts
etw
ithboo
tst
rapp
ed9
5%c
onfid
enc
eband
s

f
orc
lin
ica
llyr
elev
antf
als
epo
sit
iver
ate
s. Th
epr
obab
il
itym
apth
resh
oldth
at

c
orr
espond
stoaf
als
epo
sit
iver
ateo
f1%i
s0.
10. Th
eve
rti
calax
iso
fth
epa
rti
al

ROCcu
rvesh
owsth
etru
epo
sit
iver
ate(
sen
sit
ivi
ty)f
orth
resh
old
sbe
twe
en0

and0
.10o
fth
epr
obab
il
itym
apandth
eho
riz
ont
alax
issh
owsth
efa
lsepo
sit
ive

r
ate(
1-sp
ecifi
cit
y)f
orth
eseth
resh
old
s.

Th
eco
effic
ien
tsf
romfi
ttin
gth
elo
gis
ticm
ode
l[1
]ov
era
ll1
31s
tud
iesin

v
al
ida
tions
et1
,at
ota
lof2
4mi
ll
ionv
oxe
ls
,ar
erepo
rtedinth
eApp
end
ix. Th
e

c
oeffi
cien
tsf
romth
efir
stands
econdfi
tofth
emod
ela
rep
rov
ided
. W
eal
so

a
sse
ssedth
eva
ria
tioninth
eco
effic
ien
tsb
ynonp
aram
etr
ica
llyboo
tst
rapp
ing

th
esub
jec
tsw
ithr
epl
acem
ent
. Th
eboo
tst
rapp
ed9
5%c
onfid
enc
ein
terv
alsf
or

th
eco
effic
ien
tsc
anb
efoundinth
eApp
end
ix. Th
eva
rian
ceo
fth
esec
oeffi
cien
ts

i
sla
rgeinc
omp
ari
sont
oth
ees
tim
ate
softh
eco
effic
ien
ts. Th
ein
stab
il
ityin

th
eco
effic
ien
tsd
oesn
otimp
actth
epe
rfo
rman
ceo
fOAS
IS,a
sil
lus
tra
tedinth
e

s
tab
il
ityo
fth
epa
rti
alROCcu
rve
.
Ch
oos
ingafin
alth
resh
oldv
alu
eaf
terth
ese
condp
rob
abi
li
tym
apsa
rem
ade

i
sat
rad
eoffb
etw
eens
ens
it
ivi
tyandsp
ecifi
cit
y. OAS
ISi
sflex
ibl
e,andth
e

7
7
F
i gu
re3 .4:P a
rti
al ROCcu rveforthev oxe
l-
leveld et
ecti
ono fle
sionsinth e
test
ings eto fval
idationset1f ordifferentthresholdsofth eprobabi
li
tym ap
s
producedfromOAS ISf o
rclin
ical
lyrel
ev antfa
lsepo s
itiv
er a
tesof1%andb e
low.
Boots
trapp ed9 5%c onfidencebandsar ealsoprovided. Thevert
ica
lax i
softh e
part
ialROCcu rvesh owsthetrueposi
tiver a
te(sensit
ivi
ty)foragiv
enth re
shold
o
fth ep robabil
itym apandth ehor
izont a
laxissh owsth efa
lsepos
i t
iverate(1
-sp e
cificit
y )forthi
sth re
sh o
ld.

app
rop
ria
tef
als
epo
sit
iver
atem
ayb
ese
lec
tedf
orap
art
icu
larapp
li
cat
ion
.Ta
-
b
le3
.2sh
owsth
eth
resh
oldv
alu
es,s
ens
it
ivi
ty,andd
ices
imi
lar
ityc
oeffi
cien
t[9
7]

f
orf
ourd
iffe
ren
tfa
lsepo
sit
iver
ate
sfo
rth
emod
elfi
tov
era
llo
fth
estud
iesin

v
al
ida
tions
et1
. OAS
ISd
ete
ctedl
esi
onsin m
anyo
fth
ehe
alth
ysub
jec
ts.T
a-

b
le3
.3sh
owsth
eme
anv
olum
eoff
als
epo
sit
ivel
esi
onsd
ete
ctedinth
ehe
alth
y
and MSsub
jec
tsf
orth
efou
rth
resh
oldv
alu
esf
romT
abl
e3.
2. Th
evo
lum
eof

f
als
epo
sit
ive
sfo
rbo
thth
e MSandh
eal
thysub
jec
tsi
scomp
arab
le
.

7
8
Tab
le3
.2:Binarys
egm en
tationth
resho
ldsw
ithfal
sepos
it
iver
ate
,sen
sit
ivi
ty
andDSCforval
ida
tionset1
F
als
eP os
it
iveR at
e S en
sit
ivi
ty Thre
sholdVa
lue DSC
1% 80% 0
. 1
0 0.5
5
0
.75% 76% 0
. 1
2 0.5
8
0
.5% 69% 0
. 1
6 0.6
1
0
.25% 58% 0
. 2
3 0.5
9

T
able3.3
:V o
lum eoff
alseposit
iveles
ioninh ea
lthyvo
lunte
e r
sand MSsubjec
ts
3 3
f
romv a
lida
tionset1(
incm) ;theactua
lm eanles
ionvolumeis0cmf o
rhe
althy
3 3 3
v
olunt
eersand1 1
.2cm ( IQR :[1
.7cm,1 6.6cm] )f
or MSsub j
ects
Thresh
oldV a
lue H ea
lthyM ean(IQR ) MS M ean(IQR)
0.1
0 8
.6( 4
.6,10
.6) 10.9(
7.6,13.6
)
0.1
2 6.7(3.1
,8.2) 8.0(5.2
,1 0
.3)
0.1
6 4.3(1.5
,5.7) 5.2(
3.0,7.0
)
0.2
3 2
.2(.7,2.
8) 2.5(
1.2,3.5
)

3
.3.2 V
alida
tionse
t1: neu
rorad
iolog
istra
tingre
sul
ts

F
orth
eneu
ror
adi
olo
gis
trank
ing
softh
e OAS
ISandL
esi
onTOADSs
egm
ent
a-

t
ion
sfo
rth
e98 MSsub
jec
tsinv
al
ida
tions
et1
,wep
erf
orm
edap
air
edt
-te
stt
o

a
sse
ssth
ediff
eren
ceinth
eme
anso
fth
eOAS
ISs
egm
ent
ati
onsandth
eLe
sion
-

TOADSs
cor
es. Th
isd
iffe
ren
cew
asf
oundt
obe1
2.6
,wi
tha9
5%c
onfid
enc
e
−12
in
terv
alo
f(9
.6,1
5.8
),p
-va
lue< 1
0 . Th
e OAS
ISemp
ir
ica
lth
resh
old w
as

r
ank
edh
igh
erth
anL
esi
onTOADSs
egm
ent
ati
onin7
3(9
5%C
I:[
64,8
1])o
fth
e

9
8stud
ieso
r74%(
95%C
I:[
65%
,82%
])
. W
enonp
aram
etr
ica
llyboo
tst
rapp
ed

w
ithr
epl
acem
entth
esub
jec
tst
opr
odu
ceth
econfid
enc
ein
terv
alsf
orth
erank
-
in
gs.

7
9
3
.3.3 V
alida
tionse
t2: neu
rorad
iolog
istra
tingre
sul
ts

T
abl
e3.
4con
tain
ssumm
arys
tat
ist
icsf
orth
esc
ore
sfr
omth
eneu
ror
adi
olo
gis
t
r
atin
gso
fth
eth
rees
egm
ent
ati
onsf
ora
ll1
89s
tud
ies
. Th
eOAS
ISv
al
ida
tions
et

1th
resh
olds
egm
ent
ati
onsandth
eLe
sionTOADSs
egm
ent
ati
onsh
avea mu
ch

l
owe
rfir
stqu
ant
il
eth
anth
e OAS
ISemp
ir
ica
lth
resh
olds
egm
ent
ati
ons
. F
or
th
isan
aly
sisw
efo
cusm
ain
lyonth
ediff
eren
ceb
etw
eenth
e OAS
ISemp
ir
ica
l

th
resh
oldandth
eLe
sionTOADSs
egm
ent
ati
on,a
sth
e OAS
ISv
al
ida
tions
et1

th
resh
oldd
idn
otp
erf
orm w
el
lonth
isn
ewd
atas
et. Th
isw
asexp
ect
ed,a
s

th
epr
obab
il
itym
apth
resh
oldn
eed
stob
ead
jus
tedt
oma
int
ainth
esam
efa
lse
po
sit
iver
ate wh
en m
ovin
gtoan
ewd
atas
et. W
epe
rfo
rmedap
air
edt
-te
st

t
oas
ses
sth
ediff
eren
ceinth
eme
anso
fth
e OAS
ISemp
ir
ica
lth
resh
olds
cor
es

andth
eLe
sionTOADSs
cor
es. Th
isd
iffe
ren
cew
asf
oundt
obe1
6.6
,wi
tha
−14
9
5%c
onfid
enc
ein
terv
alo
f(1
3.3
,20
.0)
,p-v
alu 0
e<1 . Th
e OAS
ISemp
ir
ica
l

th
resh
oldw
asr
ank
edh
igh
erth
anL
esi
onTOADSs
egm
ent
ati
onin1
46(
95%C
I:

[
135
,15
7])o
fth
e18
9ca
seso
r77%(
95%C
I:[
71%
,83%
])
. W
enonp
aram
etr
ica
lly
boo
tst
rapp
edw
ithr
epl
acem
entth
esub
jec
tst
opr
odu
ceth
econfid
enc
ein
terv
als

f
orth
erank
ing
s.

T
able3.4:Summ a rysta
tis
tic
sofimag
er a
tin
gso
fv a
lidat
ionse
t1forneu
rora-
d
iol
o g
iston1 8
9s tudi
es
OASIS OASIS L
esi
onTOADS
v
alida
tionset1Thr
eshold Emp
iri
c a
lTh re
sho
ld
Minimum 3.7 3.7 2.7
1stQu ant
ile 27
.3 55
.7 2
1.7
Median 42
.0 68
.3 5
1.0
Mean 43
.2 64
.1 4
7.5
3rdQu ant
il
e 57
.7 76
.3 7
1.0
Maximum 99
.3 99
.0 9
7.3

8
0
 T
oas
ses
sra
terr
el
iab
il
ityam
ongth
e20dup
li
cat
ed MR
Istud
ies
,wec
al-
cu
lat
edth
ein
tra
cla
ssc
orr
ela
tionc
oeffi
cien
t:0
.61(
95%C
I:[
0.6
9,0
.81
])
. Th
e

r
ank
ing
sfo
rth
eLe
sionTOADSim
age
sandth
eOAS
ISemp
ir
ica
lth
resh
oldw
ere

p
res
erv
edinth
edup
li
cat
erank
ing
sfo
r17o
fth
e20im
age
s(9
5%C
I:[
14,2
0])
.
W
enonp
aram
etr
ica
llyboo
tst
rapp
edw
ithr
epl
acem
entth
esub
jec
tst
opr
odu
ce

th
econfid
enc
ein
terv
alsf
orbo
thth
ein
tra
cla
ssc
orr
ela
tionc
oeffi
cien
tsandth
e
r
ank
ing
s.

3
.3.4 V
alida
tionse
t2:ra
terag
reemen
twi
thneu
rorad
i-

o
log
ist
,neu
rolog
ist
,andrad
iolog
ist

F
igure3.5
:N otchedboxp l
otoftheresu
ltsfr
omth en eu
ror
adi
olog
ist
,n euro
l-
og
ist
,andr adi
ologi
stim ag
erat
ingsforsegment
ati
onso fthe50 MR Istud
ies
fr
omv al
idat
ionset2:th eOASISval
idat
ionset1thresho
ldsegmenta
tions
,the
OASISempir
ical
lyad ju
stedth
resh
olds e
gm en
tat
ions
,andth eL e
sionTOADS
segmen
tat
ions
.

T
abl
e3.
5con
tain
ssumm
arys
tat
ist
icsf
orth
esc
ore
sfr
omth
eneu
ror
adi
olo
-

g
ist
,neu
rol
ogi
st,andr
adi
olo
gis
tra
tin
gso
fth
eth
rees
egm
ent
ati
onsf
orth
ese
t
o
f50s
tud
iess
ele
ctedt
oas
sesr
ate
rre
liab
il
ity
.Fi
gur
e3.
5sh
owsan
otch
edbo
x

p
lotf
ore
achr
ate
rofth
esefind
ing
s.F
romth
ebo
xpl
otw
ese
eth
atth
erei
s

8
1
as
tat
ist
ica
llys
ign
ific
antd
iffe
ren
ceb
etw
eenth
emed
ian
sfo
ral
lth
rees
egm
en-
t
ati
onsf
orth
eneu
ror
adi
olo
gis
tandn
eur
olo
gis
t. Th
erew
asn
otas
tat
ist
ica
lly

s
ign
ific
antd
iffe
ren
ceinth
emed
ian
softh
esc
ore
sfo
rth
eth
rees
egm
ent
ati
onsb
y

th
erad
iol
ogi
st.M
ore
ove
r,a
llth
reer
ate
rsind
ica
tedth
atth
e OAS
ISv
al
ida
tion
s
et1s
egm
ent
ati
onsandth
eLe
sionTOADSs
egm
ent
ati
onsh
avea mu
chl
owe
r

fi
rstqu
ant
il
eth
anth
e OAS
ISemp
ir
ica
lth
resh
olds
egm
ent
ati
ons
. Th
eou
tl
ier
s
inth
ebo
xpl
otsc
anb
eexp
lain
eda
sei
the
rer
ror
sinp
roc
ess
ing
,su
cha
sre
gis
-

t
rat
iono
rbada
rti
fac
ts,o
rass
tud
iesth
atn
oneo
fth
ese
gmen
tat
ion m
eth
ods

p
erf
orm
edw
el
lon
. W
edidn
otr
emo
veth
eses
tud
iesf
romth
ean
aly
sis
,be
cau
se

8
2
 Tabl
e3 .5
:M eanands tandardd evia
tionofth er a
tingfromth eneuro
r adio
lo g
ist
,n eu
r o
log
ist
,andr adio
log
istfor
OASISv a
lidat
i onset1thre
sh old
,OAS ISemp iri
calthresholdandLes
ionTOADSon5 0studi
esfromv a
lidat
ionset2;
meandifferenceb etwe
enOAS ISemp i
rica
lthr e
sholdandL es
ionTOADSandp erc
entageoftimesOAS ISw asranked
h
i ghe
rth anLe si
onTOADSonth eseim age
s
OASIS OAS IS Le
sionTOADS Mean Perc
entag
e
v
al
idat
ions et1 Emp i
rical Mean(SD ) Difference Rank
Mean(SD ) M e
an(SD ) (95%C I) (95%C I
)
Neuro
radiolo
gi s
t 4 6
.3(22 .0) 66
.1( 20
.2) 4 7.
3( 27.2
) 1 8
.7( 11.2,26.3
) 7 6%( 64%,88% )
Neuro
logis
t 48
.7(2 4.3
) 73.1(18.5) 5 6.6( 26
.0) 16
.5( 7.0
,2 5.9
) 6 6%(52%,78% )
Radio
logis
t 71
.6(1 9.6
) 74.1(17.9) 7 1.8( 16
.5) 2.3( -
4.2,8.8) 5 2%(38%,6 6% )

8
3
w
ewan
ttoa
sse
ssth
epe
rfo
rman
ceo
fOAS
ISinth
ese
ttin
gofan
ima
gep
roc
ess
ing
p
ipe
lin
e,wh
ereim
age
sma
yno
tbep
rop
erlyr
egi
ste
redo
rma
ycon
taina
rti
fac
ts.

A
gain
,wew
il
lfo
cusm
ain
lyonth
ediff
eren
ceb
etw
eenth
e OAS
ISemp
ir
-

i
calth
resh
oldandth
eLe
sionTOADSs
egm
ent
ati
on. W
epe
rfo
rmedap
air
ed
t
-te
stt
oas
ses
sth
ediff
eren
ceinth
eme
anso
fth
e OAS
ISemp
ir
ica
lth
resh
old

s
cor
esandth
eLe
sionTOADSs
cor
es. Th
esed
iffe
ren
cesc
anb
efoundinT
abl
e
5
. Th
eme
anf
orth
eOAS
ISemp
ir
ica
lth
resh
oldw
asg
rea
terth
anth
eme
anf
or

th
eLe
sionTOADSs
cor
esf
ora
llth
reer
ate
rs. Th
isd
iffe
ren
cew
asf
oundt
obe

s
tat
ist
ica
llys
ign
ific
antf
orbo
thth
eneu
ror
adi
olo
gis
tandn
eur
olo
gis
t,(p
-va
lue
s
−4 −3
<1
0 and< 1
0 ,r
esp
ect
ive
ly)
,bu
tno
tfo
rth
erad
iol
ogi
st,(p
-va
lue0
.5)
.

Th
eneu
ror
adi
olo
gis
tandth
eneu
rol
ogi
stt
end
edt
osp
readth
eirs
cor
esm
ore
,
andth
isa
llow
edb
ett
erc
omp
ari
sono
fth
ese
gmen
tat
iona
lgo
rithm
s. T
abl
e5

a
lsosh
owsth
epe
rcen
tag
eoft
imeth
e OAS
ISemp
ir
ica
lth
resh
old w
asr
ank
ed

h
igh
erth
anL
esi
onTOADSs
egm
ent
ati
oninth
e50s
tud
ies
. W
enonp
aram
et-

r
ica
llyboo
tst
rapp
edw
ithr
epl
acem
entth
esub
jec
tst
opr
odu
ceth
econfid
enc
e

in
terv
alsf
orth
erank
ing
s.

T
oas
ses
sra
terr
el
iab
il
ityam
ongth
e5dup
li
cat
ed MR
Istud
ies
,wec
alcu
lat
ed

th
ein
tra
cla
ssc
orr
ela
tionc
oeffi
cien
tandth
enumb
ero
ftim
esth
erank
ing
sfo
r

th
eLe
sionTOADSim
age
sandth
e OAS
ISemp
ir
ica
lth
resh
oldw
erep
res
erv
ed.

W
enonp
aram
etr
ica
llyboo
tst
rapp
edw
ithr
epl
acem
entth
esub
jec
tst
opr
odu
ce
th
econfid
enc
ein
terv
alsf
orbo
thth
ein
tra
cla
ssc
orr
ela
tionc
oeffi
cien
tsandth
e

r
ank
ing
s.F
orth
eneu
ror
adi
olo
gis
t,th
ein
tra
cla
ssc
orr
ela
tionc
oeffi
cien
tfo
rth
e

5r
epe
ateds
tud
iesi
s0.
55(
0.2
1,0
.82
)andth
enumb
ero
fpr
ese
rvedr
ank
ing
sis

4(
2,5
).F
orth
eneu
rol
ogi
st,0
.32(
-0.
10,0
.68
)and4(
2,5
).F
orth
erad
iol
ogi
st,

-
0.3
8(-
0.3
5,0
.71
)and2(
0,4
). Th
erep
eat
edr
ank
ing
sfo
rea
chr
ate
rfo
rth
e5

8
4
sub
jec
tsi
srepo
rtedinth
eApp
end
ix.
W
eca
lcu
lat
edth
era
tera
gre
emen
tfo
rth
erank
ingo
fth
e OAS
ISemp
ir
ica
l

th
resh
oldv
ersu
sLe
sionTOADS
.Wed
ecid
edt
ous
eth
erank
ing
softh
esc
ore
sto

a
sse
ssr
ate
rag
reem
entr
ath
erth
anth
esc
ore
sth
ems
elv
es,b
ecau
se,a
ssh
ownf
rom
th
ein
tra
cla
ssc
orr
ela
tionc
oeffi
cien
t,th
esc
ore
sar
eno
tve
ryr
el
iab
le
,wh
il
eth
e

o
rde
rinwh
ichth
eob
serv
ersr
ankth
ese
gmen
tat
ion
s,onth
eoth
erh
and
,isqu
ite
r
el
iab
le
. W
eca
lcu
lat
edth
ekapp
ast
ati
sti
ctoa
sse
ssth
ere
liab
il
ityo
fth
erank
ing
s

f
ore
achp
airo
fra
ter
sandn
onp
aram
etr
ica
llyboo
tst
rapp
ed w
ithr
epl
acem
ent

th
esub
jec
tst
opr
odu
ceth
econfid
enc
ein
terv
alsf
orth
ekapp
ast
ati
sti
cs. Th
e

k
app
ast
ati
sti
cfo
rth
era
tera
gre
emen
tbe
twe
enth
eneu
ror
adi
olo
gis
tandth
e

n
eur
olo
gis
twa
s0.
47(
0.2
0,0
.75
),th
eneu
ror
adi
olo
gis
tandr
adi
olo
gis
t0.
02(
-

0
.26
,0.
30)andth
eneu
rol
ogi
standr
adi
olo
gis
t-0
.09(
-0.
37,0
.19
).

3
.4 D
iscu
ssion

OAS
ISm
ayb
eus
edt
oas
sis
torev
enr
epl
acem
anu
als
egm
ent
ati
ono
f MSl
esi
ons

inth
ebr
ain
.Af
tert
rain
ingandad
jus
tmen
tofth
epopu
lat
ionl
eve
lth
resh
old
,

ou
rfu
llyau
tom
ati
cme
thodd
oesn
otr
equ
irehum
aninpu
tanda
void
sth
eva
ri
-
ab
il
ityin
trodu
cedb
ymanu
als
egm
ent
ati
on.U
sin
gth
eexp
li
citf
ormo
fth
est
a-
t
ist
ica
lmod
el
, OAS
ISc
ane
asi
lyb
ead
apt
edandt
rain
edf
orc
ase
swh
erem
ore

o
rfew
erim
agin
gsequ
enc
esa
rea
vai
lab
le
.

W
ithth
eOAS
ISm
ode
l,ar
eca
lib
rat
iono
fth
epopu
lat
ion
-lev
els
egm
ent
ati
on
th
resh
oldi
sne
ces
saryf
ore
achn
ewd
atas
etbu
tcanb
edon
eonaf
air
lyl
imi
ted

numb
ero
fsub
jec
ts,a
sinth
eex
amp
lef
romth
isp
ape
r.ar
eca
lib
rat
iono
fth
e
popu
lat
ion
-lev
els
egm
ent
ati
onth
resh
oldi
sne
ces
saryf
ore
achn
ewd
atas
etbu
t

8
5
c
anb
edon
eonaf
air
lyl
imi
tednumb
ero
fsub
jec
ts,a
sinth
eex
amp
lef
romth
is
p
ape
r. As
eto
fsub
jec
tsi
srequ
iredt
otun
eth
ispopu
lat
ionl
eve
lth
resh
old
,

th
ere
for
efu
llyau
tom
ati
cse
gmen
tat
iono
fas
ing
les
tudyf
roman
ewim
agin
g

c
ent
erm
ayn
otf
eas
ibl
ewi
thth
e OAS
IS m
ode
l. H
owev
er,inth
esec
ase
sth
e
th
resh
oldc
anb
ead
jus
tedv
eryqu
ick
ly m
anu
ally(
2-5m
inu
tes
)byv
isu
alin
-

sp
ect
iono
f3-
4sl
ice
sbyad
jus
tin
gju
ston
epa
ram
ete
r. Wh
enu
sin
gan ROC
cu
rvef
orc
las
sifi
cat
ion
,th
resh
old
sfo
rsubpopu
lat
ion
swi
thd
iffe
ren
tco
var
iat
e

v
alu
esm
ayn
eedt
obed
efin
edd
iffe
ren
tlyino
rde
rtok
eepf
als
epo
sit
iver
ate
s

th
esam
eac
ros
sth
osesubpopu
lat
ion
s[9
8]. Th
ere
for
e,i
twa
sexp
ect
edth
atth
e

ROCth
resh
oldw
ouldn
eedt
obead
jus
tedt
oma
int
ainth
esam
efa
lsepo
sit
ive

r
atef
romv
al
ida
tions
et1inv
al
ida
tions
et2
. Th
isth
resh
oldi
sth
eon
lytun
ing

p
aram
ete
rinOAS
ISth
atmu
stb
ead
jus
tedwh
enm
ovin
gtoan
ewd
atas
et,and

th
isad
jus
tmen
tisv
eryf
astandin
tui
tiv
etom
akeandd
oesn
otr
equ
ire mu
lt
ipl
e

i
ter
ati
onso
fse
gmen
tat
ion
s. W
ebe
li
eveth
at OAS
ISh
old
spr
omi
sef
oru
sein

mu
lt
icen
ter MR
Istud
ies
,wi
thad
jus
tmen
tofth
epopu
lat
ionl
eve
lth
resh
oldf
or

e
achs
ite
.

F
utu
rew
orkin
clud
esfu
rth
erv
al
ida
tiono
fOAS
ISund
erch
ang
esinim
agin
g

c
ent
erandp
rot
oco
landt
oal
sosh
owth
erep
rodu
cib
il
ityo
fth
eOAS
ISs
egm
en-

t
ati
ons
. On
ere
sou
rcef
orth
isi
sth
e MSL
esi
onS
egm
ent
ati
onCh
all
eng
e[6
7],a

c
omm
ond
atab
asef
or MSl
esi
ons
egm
ent
ati
ona
lgo
rithm
s. W
epl
ant
odofu
rth
er

v
al
ida
tionw
ithth
isd
atab
asea
swe
lla
swi
thv
olum
esf
romadd
it
ion
alim
agin
g
c
ent
ers
.Fo
rth
isan
aly
sisw
edidn
oth
aves
can
-re
scan MR
Iav
ai
lab
le
. Th
esea
re

c
ruc
ialf
ora
sse
ssin
gth
erep
rodu
cib
il
ityo
fth
eme
thod
,andw
epl
ant
oacqu
ire

th
eseinth
efu
tur
e.

8
6
 Inc
ont
ras
ttom
anyau
tom
ati
cse
gmen
tat
iont
echn
iqu
es, OAS
ISi
scompu
-
t
ati
ona
llyf
ast
. Wh
il
etr
ain
ingth
emod
elonth
e13
1stud
iesf
romv
al
ida
tion

s
et1t
ake
sfiv
ehou
rsonas
tand
ardw
ork
sta
tion
,th
isp
roc
essi
son
lyc
ondu
cted

on
ce. Th
ere
sul
tsf
romth
isa
resumm
ari
zeda
sth
etw
ose
tso
f21c
oeffi
cien
ts
in m
ode
l[1
]. A
lso
,th
emod
elm
ayb
etr
ain
edonf
ewe
rstud
ies
,assh
ownin

th
epa
rti
alROCan
aly
sisw
ith
inv
al
ida
tions
et1
;th
epe
rfo
rman
ceo
fth
emod
el
r
ema
inss
tab
lewh
ent
rain
edonsub
set
sof2
0stud
ies
.Us
ingth
isfi
ttedm
ode
lto

g
ene
rat
eap
rob
abi
li
tym
apo
fth
een
tir
ebr
ainf
romas
eto
fnewim
age
stak
es

on
ly3
0minu
tes
. Th
eset
ime
sar
efo
rst
and
ardw
ork
sta
tion
sanda
reexp
ect
edt
o

d
ropd
ram
ati
cal
lyw
ith mu
lt
i-c
orep
ara
ll
elc
ompu
tin
gandimp
rov
edt
echn
olo
-

g
ies
. Th
eGau
ssi
ansm
ooth
ingi
sth
esl
owe
sts
tepo
fth
eal
gor
ithm
,andth
ese

c
ompu
tat
ion
scanb
epa
ral
le
li
zedt
osub
stan
tia
llyd
ecr
eas
eth
etim
eofth
een
tir
e

a
lgo
rithmt
oapp
rox
ima
tely5 m
inu
tes
.

A
fte
rmak
ingth
eim
ager
atin
gsf
orv
al
ida
tions
et2
,th
eneu
ror
adi
olo
gis
twa
s

unb
lind
edandr
evi
ewedth
eth
rees
egm
ent
ati
ons
,pr
ovid
ingc
omm
ent
sabou
tth
e

s
tren
gth
sandw
eakn
ess
eso
fea
ch. Th
e OAS
ISemp
ir
ica
lth
resh
oldp
erf
orm
ed

mu
chb
ett
erth
anth
e OAS
ISv
al
ida
tions
et1th
resh
old
. Th
eneu
ror
adi
olo
gis
t

r
epo
rtedap
ref
eren
cef
orth
esm
oothn
esso
fth
e OAS
ISs
egm
ent
ati
onsinc
on-

t
ras
ttoth
eLe
sionTOADSs
egm
ent
ati
on,wh
icho
ftenapp
ear
edsp
eck
led
. Th
e

OAS
ISs
egm
ent
ati
onso
ftenh
ada
rti
fac
tsinth
epin
ealg
land
sandth
ech
oro
id

p
lexu
softh
even
tri
cle
s. Th
ism
ayb
eexp
lain
edb
yth
efa
ctth
at OAS
IS w
as
t
rain
edonFLA
IRim
age
sacqu
iredb
efo
reag
ado
lin
ium
-ba
sedc
ont
ras
tag
ent

w
asadm
ini
ste
redt
oth
epa
tien
t,wh
il
eth
eva
lid
ati
onw
asd
onew
ithFLA
IRim
-

a
gesth
atw
erea
cqu
ireda
fte
rgad
olin
iumadm
ini
str
ati
on.V
oxe
lsinth
ech
oro
id

p
lexu
sandp
ine
alg
land
s, wh
ichenh
anc
ewi
thg
ado
lin
ium
,we
reb
righ
terand

8
7
w
erethu
smi
scl
ass
ifieda
sle
sion
.Le
sionTOADSd
oesn
otm
akeas
imi
lare
rro
r,
a
sitimpo
sest
opo
log
ica
lcon
str
ain
tsth
atp
rec
lud
eth
eses
tru
ctu
resf
romb
ein
g

id
ent
ifieda
sle
sion
s.F
urth
err
efin
emen
tso
fOAS
IS m
aya
ccoun
tfo
rsu
chc
om-

p
lexch
ang
eso
fpr
oto
col
. Th
eLe
sionTOADSs
egm
ent
ati
onsw
erem
orev
ari
abl
e
th
anth
oseo
f OAS
ISandd
idn
otp
erf
ormw
el
lonc
ase
swi
thl
owl
esi
onl
oad
.

Th
e OAS
ISs
egm
ent
ati
onh
adsy
stem
ati
cer
ror
sinth
emed
ialf
ron
talc
ort
ex
andth
ebr
ain
stem
. Onth
eoth
erh
and
,Le
sionTOADSa
void
edf
als
epo
sit
ive
s

inth
ebr
ain
stemb
ecau
sei
ton
lys
egm
ent
sle
sion
sinth
ece
reb
rum
.Fi
gur
e3.
6

sh
owsas
li
cef
romasub
jec
twi
thanex
amp
leo
fal
esi
onth
atOAS
ISs
egm
ent
s

inth
ece
reb
ellum
.Fi
gur
e3.
6Ash
owsas
ing
les
li
ceo
fth
eFLA
IRv
olum
e,F
ig-

u
re3
.6Bsh
owsas
ing
les
li
ceo
fth
eT1
-we
igh
tedv
olum
e,F
igu
re3
.6Csh
ows

th
eLe
sionTOADSs
egm
ent
ati
ono
fth
esl
ice
,andF
igu
re3
.6Dsh
owsth
e OA
-

S
ISs
egm
ent
ati
ono
fth
esl
ice
.Le
sionTOADSd
oesn
ots
egm
entth
ece
reb
ellum
,

wh
ere
as OAS
ISd
oesn
otr
est
ric
tth
ear
easth
ati
tse
gmen
tsandi
sab
let
ofind

th
ele
sioninth
iss
li
ce.

OAS
ISi
sno
tana
tla
s-b
asedm
eth
odandth
ere
for
edo
esn
ott
akein
toa
ccoun
t

an
atom
ica
lin
form
ati
ondu
rin
gse
gmen
tat
ion
,su
cha
sti
ssu
ecl
ass
.Fu
rth
erin
-

c
orpo
rat
iono
fan
atom
ica
lin
form
ati
on,su
cha
sth
eti
ssu
ecl
asss
egm
ent
ati
ons

f
romL
esi
onTOADS
,ma
yhe
lpt
oav
oidl
esi
onsf
als
epo
sit
ive
sina
rea
s wh
ere

w
eha
vep
rio
rkn
owl
edg
eth
atl
esi
onp
res
enc
eisl
owand wh
ere OAS
IS m
ade

sy
stem
ati
cfa
lsepo
sit
ive
s,su
cha
sth
emed
ialf
ron
talc
ort
exandth
ebr
ain
stem
.
A
lso
,th
isc
ouldb
eus
edt
ohe
lp w
ithth
efa
lsepo
sit
ive
sinth
epin
ealg
land
s

andth
ech
oro
idp
lexu
softh
even
tri
cle
sinth
epo
st-
con
tra
stFLA
IRa
sth
esea
re

a
rea
swh
erel
esi
onsd
ono
toc
curin MS
.

Th
esm
ooth
edim
age
sus
edin OAS
ISa
res
imi
lart
oth
eus
eofsm
ooth
ed

8
8
F
igu
re3
.6:Examp
leofac e
reb
elluml e
sionc
l a
ssifiedus
ingOAS ISinv
al
ida
tion
s
et2:A
.FLA IRvo
lume;B .T1
-w ei
ghtedvolum e
;C .Les
ionTOADSsegmenta
-
t
ion
;D.OASISempi
ric
allyad
justedthresh
olds e
gm en
tat
ion.

im
age
sfo
rinh
omo
gen
eit
yco
rre
cti
onin MR
I.F
orinh
omo
gen
eit
yco
rre
cti
on,an
im
agei
ssm
ooth
edt
osupp
res
sth
ede
tai
lso
fth
eim
ageandth
enth
eor
igin
al

im
agei
sdiv
idedb
yth
issm
ooth
edim
ageino
rde
rtoc
orr
ectth
eim
ageinh
o-

m
ogen
eit
y[9
9]. Ou
rme
thodd
iffe
rsf
romth
isinth
atw
edon
otd
ivid
eth
e

o
rig
ina
lim
ageb
yth
esm
ooth
edv
olum
e.In
ste
adw
eus
eth
esm
ooth
edv
olum
e

a
sac
ova
ria
teinou
rmod
el
. W
eal
sou
se mu
lt
ire
solu
tionsm
ooth
edv
olum
es,in

c
ont
ras
ttoju
ston
esm
ooth
edv
olum
efo
rco
rre
cti
on.
O
the
rme
thod
sofc
aptu
rin
ginh
omo
gen
eit
iesm
ayb
eus
edinth
e OAS
IS

m
ode
lasana
lte
rna
tiv
etoth
esm
ooth
edv
olum
es.A
lte
rna
tiv
esm
ooth
ersm
ay

8
9
b
eus
edin
ste
ado
fth
eGau
ssi
ank
ern
eland m
ayb
emo
reapp
rop
ria
teino
the
r
app
li
cat
ion
s. W
ede
cid
edt
ous
eth
eGau
ssi
anfi
lte
rbe
cau
sei
tisw
ide
lyu
sed
,

c
anb
eapp
li
edt
oan
yim
age
,andi
sre
lat
ive
lyc
ompu
tat
ion
allyf
ast
. Th
eOAS
IS

m
ode
lin
gfr
amew
orki
sve
ryfl
exib
le
,how
eve
r,andc
anb
ead
apt
edf
oro
the
r
m
eth
odso
fcap
tur
ingth
ebi
asfi
eldandr
egi
ona
lin
ten
sit
yva
ria
tion
.

W
eus
edth
e15
thp
erc
ent
il
eofFLA
IRin
ten
sit
iesinth
ebr
aint
ocr
eat
eth
e
b
raint
issu
ema
sk.O
the
rse
gmen
tat
ion
scanb
eus
edt
orem
oveth
eCSF
.We

u
sedth
e15
thp
erc
ent
il
eofFLA
IRin
ten
sit
iesb
ecau
sei
tisf
astandp
erf
orm
ed

w
el
linth
isapp
li
cat
ion
.

L
esi
onsth
ata
reh
ypo
int
ens
eonFLA
IR,b
ecau
seo
fhi
ghf
reew
ate
rcon
ten
t,

a
ren
otd
ete
ctedb
yOAS
IS.Th
eme
thod m
ode
lson
lyc
and
ida
tev
oxe
ls
,th
etop

1
5pe
rcen
tofv
oxe
lsinth
ece
reb
ralm
att
er-m
ask
edFLA
IRv
olum
e,t
omin
imi
ze

th
enumb
ero
ffa
lsepo
sit
ive
s.Inth
eFLA
IRv
olum
e,su
chl
esi
onsa
rech
ara
cte
r-

i
zedb
yhypo
int
ens
it
iesinth
ecen
tero
fal
esi
onandh
ype
rin
ten
sit
iesa
roundth
e

ed
ges
. Th
ere
for
eth
ecen
tero
fth
ele
sion
sisex
clud
edf
romth
ecand
ida
tev
ox-

e
ls
.Fu
tur
ewo
rkin
clud
esexp
and
ingth
eOAS
ISm
ode
ltos
egm
entth
esel
esi
ons
.

Th
isc
ouldb
edon
ebyfi
ttin
gan
oth
erOAS
IS m
ode
ltr
ain
edon
lyonl
esi
onv
ox-

e
lsth
atapp
earh
ypo
int
ens
einFLA
IRl
esi
ons
. Th
ebin
arys
egm
ent
ati
onsf
rom

th
eor
igin
alOAS
IS m
ode
landth
ism
ode
lcou
ldth
enb
ecomb
inedt
opr
odu
cea

c
omp
let
ele
sions
egm
ent
ati
on.

L
ikeo
the
rvo
xel
-ba
sed m
eth
ods
, OAS
ISi
ssen
sit
ivet
oma
jorm
isr
egi
str
a-
t
ion
swi
thinan MR
Istudy
. H
owev
er,inp
artb
ecau
sei
tin
corpo
rat
essp
ati
al

sm
ooth
ing
, OAS
ISi
sno
tsen
sit
ivet
omin
ore
rro
rsinr
egi
str
ati
on. Bys
imu
lta
-

n
eou
slyc
omp
arin
gda
taf
rommu
lt
ipl
esequ
enc
esandon
lyc
ons
ide
rin
gcand
ida
te

v
oxe
ls
,OAS
ISi
sab
let
odi
stin
gui
shb
etw
eena
rti
fac
tsandl
esi
on.

9
0
 OAS
ISu
sesav
oxe
l-
lev
elm
ode
lfo
ras
ses
sin
gth
eou
tcom
e. Th
eas
sump
tion
o
find
epend
enc
ebe
twe
env
oxe
lsi
simp
erf
ect
,asl
esi
onsc
ons
isto
fclu
ste
rso
f

v
oxe
ls
.Inth
isw
orkw
eus
esm
ooth
inginth
esm
ooth
edv
olum
esandsm
ooth
ing

o
fth
epr
edi
ctedp
rob
abi
li
tie
softh
emod
elt
oin
corpo
rat
eth
esp
ati
aln
atu
reo
f
th
eda
ta.N
eve
rth
ele
ss,fu
rth
erin
corpo
rat
iono
fne
ighbo
rin
gvo
xelin
form
ati
on

i
swa
rran
ted
.

9
1
Chap
ter4

Acompa
risono
fsupe
rvi
sed
mach
inelea
rninga
lgo
rithm
sand
fea
turev
ecto
rsfo
r MSle
sion
segmen
tat
ionu
sing mu
ltimoda
l
s
truc
tura
l MR
I

4
.1 In
troduc
tion

M
ach
inel
earn
ingi
sapopu
larp
ersp
ect
ivef
orm
inin
gandan
aly
zin
gla
rgec
ol-

l
ect
ion
sofm
edi
cald
ata[
100
,10
1,1
02]
. W
efo
cusonth
eex
ten
ttowh
ichth
e

ch
oic
eofm
ach
inel
earn
ingo
rcl
ass
ific
ati
ona
lgo
rithmandth
efe
atu
reex
tra
cti
on

9
2
fun
cti
onimp
actp
erf
orm
anc
einon
epr
obl
emf
rom m
edi
calr
ese
arch–sup
er-
v
ised mu
lt
ipl
esc
ler
osi
s(MS
)le
sions
egm
ent
ati
onins
tru
ctu
ralm
agn
eti
cre
so-

n
anc
eim
agin
g(MR
I).Th
eev
alu
ati
ono
fth
ecl
ass
ific
ati
ona
lgo
rithm
semp
loy
ed

insup
erv
isedl
esi
ons
egm
ent
ati
on m
eth
odsi
sno
ton
lyafun
cti
ono
fcl
ass
ifi-
c
ati
ona
ccu
racy
. D
epend
ingonth
eapp
li
cat
ion
,compu
tat
ion
aleffi
cien
cyand

in
terp
ret
abi
li
tym
ayb
eva
lueda
tth
eco
sto
fcl
ass
ific
ati
ona
ccu
racy
. Th
ere
for
e,
ou
rev
alu
ati
ona
lsoin
clud
esth
ecompu
tat
ion
alt
imeandr
esou
rce
srequ
iredb
y

e
acha
lgo
rithmandth
ein
terp
ret
abi
li
tyo
fth
ere
sul
tsp
rodu
cedb
yth
eal
go-

r
ithm
.Comp
ari
sono
fma
chin
ele
arn
ingt
echn
iqu
esh
asb
eenp
erf
orm
edino
the
r

app
li
cat
ion
s[1
03,1
04,1
05]
,bu
tno
ttoou
rkn
owl
edg
ein mu
lt
ipl
esc
ler
osi
sle
sion

s
egm
ent
ati
on.A
lsom
anyo
fth
ecu
rren
tlya
vai
lab
lec
omp
ari
son
sdon
otc
ons
ide
r

c
ompu
tat
ion
alt
ime
.

MSi
sal
ife
-lon
gch
ron
icd
ise
aseo
fth
ecen
tra
lne
rvou
ssy
stemth
ati
sdi
ag-

n
osedp
rim
ari
lyiny
oun
gadu
ltswh
owi
llh
avean
earn
orm
all
ifeexp
ect
ancy
.

B
ecau
seo
fth
is
,th
ebu
rdeno
fth
edi
sea
sei
sgr
eat
,wi
thl
arg
eec
onom
ic
,so
cia
l

and m
edi
calc
ost
s.B
etw
een2
50,
000and4
00,
000p
eop
leinth
e Un
itedS
tat
es

h
aveb
eend
iagn
osedw
ith MS
,andth
ees
tim
atedannu
alc
osto
fth
edi
sea
sei
s

o
vers
ixb
il
liond
oll
ars
. Th
erei
scu
rren
tlyn
ocu
ref
or MS
,bu
tman
yth
erap
ies

ex
istf
ort
rea
tin
gsymp
tom
sandd
ela
yin
gac
cumu
lat
iono
fpe
rman
entd
isab
il
ity

(h
ttp
://www
.nind
s.n
ih.
gov
/di
sord
ers
/mu
lt
ipl
esc
ler
osi
s/d
eta
ilmu
lt
ipl
esc
ler
osi
s.h
tm)
.

MSi
sch
ara
cte
riz
edb
ydem
ylin
atin
gle
sion
sth
ata
rep
red
omin
ate
lyl
oca
tedin
th
e wh
item
att
ero
fth
ebr
ain
,and MR
Iofth
ebr
aini
ssen
sit
ivet
oth
esel
e-

s
ion
s[1
]. Qu
ant
ita
tiv
e MR
Ime
tri
cs,su
cha
sth
enumb
erandv
olum
eofl
esi
ons
,
a
reimpo
rtan
tcl
ini
calt
ool
sfo
rre
sea
rchin
toth
epa
thoph
ysi
olo
gyandn
atu
-
r
alh
ist
oryo
f MS[
65]
.Inp
rac
tic
e,l
esi
onbu
rdeni
sde
term
inedb
ymanu
alo
r

9
3
s
emi
-au
tom
atedex
amin
ati
onandd
el
ine
ati
ono
f MR
I,wh
ichi
stim
econ
sum
ing
,
c
ost
ly
,andp
ron
etol
arg
ein
ter
-andin
tra
-ob
serv
erv
ari
abi
li
ty[
62]
. Th
ere
for
e

d
eve
lopm
ento
fau
tom
ated MSl
esi
ons
egm
ent
ati
on m
eth
odsi
sana
ctiv
ere
-

s
ear
chfi
eld[
106
,65
]. Th
epr
obl
emo
fau
tom
ated MSl
esi
ons
egm
ent
ati
on mu
st
b
eadd
res
sedb
ya m
eth
odth
ati
sbo
ths
ens
it
iveandsp
ecifi
ctowh
item
att
er

l
esi
ons
,andwh
ichg
ene
ral
ize
sac
ros
ssub
jec
tsandim
agin
gcen
ter
s.
M
anym
ach
inel
earn
inga
lgo
rithm
sha
veb
eend
eve
lop
edf
orau
tom
ateds
eg-

m
ent
ati
ono
f MSl
esi
onsins
tru
ctu
ral MR
I.Ov
er8
0pap
ersh
aveb
eenpub
li
shed

onth
etop
icinth
ela
st1
5ye
ars
,andy
etn
oso
lut
iont
oth
isp
rob
lemh
asem
erg
ed

a
ssup
eri
ort
ooth
erm
eth
ods[
106
].E
achl
esi
ons
egm
ent
ati
on m
eth
odinth
eli
t-

e
ratu
rei
sth
ecompo
sit
iono
fac
las
sifi
cat
iona
lgo
rithmandf
eatu
reex
tra
cti
on

fun
cti
onapp
li
edt
oon
eorm
any MR
Imod
ali
tie
s. A
sdiff
eren
tme
thod
sus
e

d
iffe
ren
tda
tas
etsandp
erf
orm
anc
eme
tri
cs,th
eex
ten
tto wh
ichth
ecl
ass
ifi-

c
ati
ona
lgo
rithm
,th
efe
atu
reex
tra
cti
onfun
cti
on,andth
ein
terp
layb
etw
een

th
ecl
ass
ific
ati
ona
lgo
rithmandf
eatu
reex
tra
cti
onfun
cti
onimp
act
sth
epe
rfo
r-

m
anc
eofth
esem
eth
odsi
sunkn
own
. T
oin
ves
tig
ateth
is
,weex
amin
e wh
ich

f
act
orsimp
rov
ecl
ass
ific
ati
onp
erf
orm
anc
eth
rou
ghth
ecompo
sit
iono
fnin
esu
-

p
erv
isedc
las
sifi
cat
iona
lgo
rithm
swi
ths
ixf
eatu
reex
tra
cti
onfun
cti
ons
. W
eus
e

v
oxe
lin
ten
sit
iesf
ormth
eT1
-we
igh
ted(T
1-w
),T
2-w
eigh
ted(T
2-w
)andflu
id-

a
ttenu
atedin
ver
sionr
eco
very(FLA
IR) MR
Imod
ali
tie
stot
rainandv
al
ida
te

p
erf
orm
anc
eofth
ecomb
ina
tion
sofc
las
sifi
ersandf
eatu
reex
tra
cti
onfun
cti
ons
.
W
ear
eno
tpr
opo
sin
gan
ewl
esi
ons
egm
ent
ati
onm
eth
od.R
ath
erth
ans
ear
chin
g

f
orth
eop
tim
alm
eth
od,w
eexp
lor
eth
epr
obl
emandp
res
entou
rin
sigh
tsin
to

th
etoo
lsand m
eth
odso
fapp
roa
ch.

Ou
rfind
ing
sar
eth
at,f
orth
eemp
loy
edf
eatu
reex
tra
cti
on m
eth
ods
,th
e

9
4
p
art
icu
larc
las
sifi
cat
iona
lgo
rithmi
s mu
chl
essimpo
rtan
tth
anth
eca
refu
lde
-
v
elopm
ento
fth
efe
atu
res
. Th
esefind
ing
sar
eno
tun
iqu
etoth
isp
rob
lem
.Hand

(
200
6)a
sse
rtsth
at,inp
rac
tic
e,inc
las
sifi
cat
ion
,simp
lec
las
sifi
erst
ypi
cal
lyy
ie
ld

p
erf
orm
anc
ealm
osta
sgoodo
rbe
tte
rth
an m
ores
oph
ist
ica
tedc
las
sifi
ers[
107
].
Th
isi
sat
tribu
tedt
osou
rce
sofun
cer
tain
tyind
atath
ata
reg
ene
ral
lyn
otc
on-

s
ide
redinth
ecl
ass
ica
lsup
erv
isedc
las
sifi
cat
ionp
arad
igm
.Handr
efe
rst
ous
ing
c
omp
lexc
las
sifi
cat
iona
lgo
rithm
sas“
thei
llu
siono
fpr
ogr
ess
”. Ou
rfind
ing
s

suppo
rtth
isch
ara
cte
riz
ati
on.

4
.2 Expe
rimen
tal me
thod
s

4
.2.1 S
tudypopu
lat
ionandexpe
rimen
tal me
thod
s

W
econ
sid
er MR
Istud
iesw
ithT
1-w
,T2
-wandFLA
IRv
olum
esf
rom9
8pa
tien
ts

w
ith MS
.Th
e3DT
1-MPRAGEim
age
s(r
epe
tit
iont
ime(TR
) =1
0ms
;ech
o

t
ime(TE
) =6m
s;fl
ipan
gl )α =8◦;in
e(FA ver
siont
ime(T
I) =8
35m
s,

r
eso
lut
ion =1
.1 mm× 1
.1 mm× 1
.1 mm
),2D T
2-wFLA
IRim
age
s(TR =

1
100
0ms
;TE =6
8ms
;TI =2
800m
s;in
-pl
aner
eso
lut
ion =0
.83 mm× 0
.83

mm
;sl
iceth
ickn
ess =2
.2 mm
)and T
2-wv
olum
es(TR =4
200m
s; TE =8
0

m
s;r
eso
lut
ion =0
.83 mm × 0
.83 mm× 2
.2 mm
)we
rea
cqu
iredona3t
esl
a

MR
Isc
ann
er(Ph
il
ipsM
edi
calSy
stem
s,B
est
,Th
eNe
the
rland
s)equ
ipp
edw
ith

an8
-ch
ann
elph
aseda
rra
yhe
adc
oil
.

9
5
4
.2.2 Imagep
rep
roce
ssing

W
epr
epr
oce
ssedth
e MR
Iim
age
sus
ingth
etoo
lsp
rov
idedin M
edi
calIm
ageP
ro-
c
ess
ingAn
aly
sisandV
isu
ali
zat
ion(M
IPAV
)[2
8],TOADS
-CRU
ISE(h
ttp
://ww

w
.ni
trc
.or
g/p
roj
ect
s/t
oad
s-c
rui
se/
),andJ
avaIm
ageS
cien
ceT
oolk
it(J
IST
)[2
7]

s
oftw
arep
ack
age
s. W
efir
str
igid
lya
lign
edth
eT1
-wim
ageo
fea
chsub
jec
tin
to
th
eMon
tre
alN
eur
olo
gic
alIn
sti
tut
e(MN
I)s
tand
ardsp
ace(v
oxe
lre
solu
tion1

mm3)
. W
eth
enr
egi
ste
redth
eFLA
IRandT
2-wim
age
sofe
achsub
jec
ttoth
e

a
lign
edT
1-wim
age
s. W
eal
soapp
li
edth
eN3inh
omo
gen
eit
yco
rre
cti
ona
lgo
-
r
ithm[
19]t
oal
lim
age
sandr
emo
vedex
tra
cer
ebr
alv
oxe
lsu
sin
gSPECTRE
,a

sku
ll
-st
ripp
ingp
roc
edu
re[
88]
. Ab
raint
issu
ema
ski
scr
eat
edf
romth
eex
tra
c-

e
reb
ralv
oxe
lrem
ova
lma
skb
yrem
ovin
gvo
xel
sfa
ll
ingb
elowth
e15
thp
erc
ent
il
e

o
fth
eFLA
IRin
ten
sit
ieso
verth
ema
sk[
7]. Th
isb
raint
issu
ema
skr
emo
ves

c
ereb
rosp
ina
lflu
idinth
even
tri
cle
sandou
tsid
eth
ebr
ain
.

4
.3 S
tat
ist
ica
l me
thod
s

Ou
raimi
stoex
amin
eth
eex
ten
tto wh
ichth
ecl
ass
ific
ati
ona
lgo
rithmand

th
efe
atu
reex
tra
cti
onfun
cti
onimp
act
sth
epe
rfo
rman
ceo
fle
sions
egm
ent
ati
on
m
eth
ods
. T
odos
o,w
ecomp
arec
ompo
sit
ion
sofsup
erv
isedc
las
sifi
cat
iona
l-

g
ori
thm
sandf
eatu
reex
tra
cti
onfun
cti
onsf
orth
ecl
ass
ific
ati
ono
fle
sionv
oxe
ls

v
ersu
she
alth
yti
ssu
eins
tru
ctu
ral MR
Istud
ies
. Af
eatu
reex
tra
cti
onfun
cti
oni
s

afun
cti
onth
ata
ctsonth
eob
serv
edin
ten
sit
iesf
romth
e MR
Imod
ali
tie
sandp
ro-

du
cesaf
eatu
rev
ect
or.F
ore
achv
oxe
lofth
ebr
ain
,weh
avea“
si
lve
rst
and
ard
”

m
anu
all
esi
ons
egm
ent
ati
onu
sedt
otr
ainandv
al
ida
teth
ele
sions
egm
ent
ati
on

9
6
m
eth
od. M
anu
all
esi
ons
egm
ent
ati
onsa
rec
ons
ide
redas
ilv
ers
tand
ard
,asop
-
po
sedt
ogr
oundt
ruth
,asth
erei
s mu
chin
ter
-andin
tra
-ob
serv
erv
ari
abi
li
ty

am
ong
stexp
erts
egm
ent
ati
ons
. W
eex
amin
ele
sions
egm
ent
ati
on m
eth
odsth
at

a
reth
ecompo
sit
iono
fac
las
sifi
cat
iona
lgo
rithmandaf
eatu
reex
tra
cti
onfun
c-
t
ion
.He
re,ou
rgo
ali
sno
ttofindanth
eop
tim
all
esi
ons
egm
ent
ati
on m
eth
od;

w
ein
ste
ads
ear
chf
orin
sigh
tbyev
alu
atin
gth
epe
rfo
rman
ceo
veras
eto
fpo
ssib
le
c
las
sifi
ersandex
tra
cti
onfun
cti
ons
.

4
.3.1 Supe
rvi
sedc
las
sifica
tiona
lgo
rithm
s

V
oxe
lsw
ith
inab
raina
resp
ati
allyc
orr
ela
ted
.Toin
clud
esp
ati
alin
form
ati
on,

w
eal
soin
clud
efun
cti
onso
fvo
xeln
eighbo
rhood
sasf
eatu
resinou
rvo
xel
-lev
el

c
las
sifi
ers
. Th
eex
ten
tto wh
ichth
ere
sidu
alsa
res
ti
llc
orr
ela
teda
fte
rth
ese
f
eatu
resa
rein
clud
edo
rtowh
atex
ten
tth
isin
form
ati
onc
anb
eus
edt
ofu
rth
er

imp
rov
epr
edi
cti
onr
ema
inop
enp
rob
lem
s.

W
epr
ovid
eash
ortd
esc
rip
tiono
fth
esup
erl
earn
er,a
sth
isi
sno
tas
tan
-

d
ardc
las
sifi
cat
iont
echn
iqu
eemp
loy
edinth
eneu
roim
agin
gli
ter
atu
re. Th
esu
-

p
erl
earn
eri
sa m
eth
odf
orc
omb
inin
gcl
asse
stim
ati
onsf
romd
iffe
ren
tcl
ass
i-

fi
cat
iona
lgo
rithm
s,b
ywe
igh
tin
gth
ecl
ass
ifie
rsa
cco
rdin
gtoth
eirp
red
ict
ion

p
erf
orm
anc
eus
ingac
ros
s-v
al
ida
tionl
ossfun
cti
on[
108
,10
9,1
10,1
11]
, wh
ich

i
sre
fer
redt
ointh
eli
ter
atu
rea
sen
semb
lel
earn
ing
,mod
els
tac
kin
g,o
rsup
er
l
earn
ing
. Th
esup
erl
earn
era
ssi
gnse
achc
las
sifi
cat
iona
lgo
rithmac
oeffi
cien
t

w
eigh
t,αi∈(
0,1
),w
ith iαi=1
. Am
ored
eta
il
edd
esc
rip
tiono
fth
esup
er

l
earn
erando
fth
eoth
ersup
erv
isedc
las
sifi
cat
iona
lgo
rithm
sus
edinth
isan
aly
sis

c
anb
efoundinth
eApp
end
ix.

9
7
 T
abl
e4.
1sh
owsasumm
aryo
fth
ecl
ass
ific
ati
ona
lgo
rithm
sapp
li
edt
oea
ch
o
fth
efe
atu
rev
ect
ors
,in
clud
ingth
e Rp
ack
ageu
sedt
oapp
lyth
eal
gor
ithm

and
,wh
enapp
li
cab
le
,th
etun
ingp
aram
ete
rva
lue
sth
atw
eres
ear
chedo
ver
. W
e

p
erf
orm
eda
llm
ode
lin
ginth
eRen
vir
onm
ent(v
ers
ion2
.15
.3,RF
ound
ati
onf
or
S
tat
ist
ica
lCompu
tin
g,V
ienn
a,Au
str
ia)w
ithth
epa
cka
gesAn
aly
zeFMR
I[1
12]
,

ROCR[
113
], MASS[
39]
,cl
ass[
39]
,nn
et[
39]
,mc
lus
t[1
14,1
15]
,e1
071[
116
],
r
and
omF
ore
st[
117
],andSup
erL
earn
er[
118
].

9
8
 T
abl
e4 .1: Asumm aryo fthesup erv
isedcl a
ssificati
ona lg
ori
thm s
. V alue
sf orth etuningp ar
am et
ersforeach
a
lgo
rithmw ereselectedu sing10-
foldcros
sv a
lidati
ononth evox
els
inthet ra
iningsetandvalidat
ionoftheal
gori
thms
w
aspe r
form edonas epar at
eset.
Algo r
ithm Rp ackage TuningP aramet
ers
Lo g
i s
ticR e g
ression defau
lts
Line a
rD i
scrim inantAn a
lysi
s MASS defau
lts
Qu adraticD iscriminantAn a
lysi
s MASS defau
lts
Gau ss
i an Mixtu reM odel mclust defau
lts
Suppo r tV ectorM a
chine e1071 cost
:1 /8
,1 /4,1 /
2,1,2,4,and8
(w ithlineark ernel)
Rand omF orest randomF ore
st numb e
ro ftree
s=5 00
m
try=1 :d imensionofthef ea
turevecto
r
k-N eares
tN e
i ghbor class k=1 ,10,100

9
9
Neu ra
lN etwo rk nn e
t size=1 ,5,10
Sup erL earner SuperL earn
er allalgor
ithms
 Table4.2: Asumm aryofthesixfe
atu
rev e
ctor
s
Fea
tu reVe ct
or V oxe
lInt ens
iti
e s(T1-w,T 2
-w,FLA IR) Vo
xelSel
ect
ion D
imen
sion
Pr
ocedur
e
Unn o
rm al
ized Ob served 3
Norm a
lized Norm a
lized 3
VoxelSelect
ion N o
rm al
ized X 3
Sm oothed N o
rm al
ized X 9
Sm oothedv olum es
,n∈{2 1,41
} 9
Mom ent
s N
o rmali
zed X 21
th
j L oc a
lm om entvolumes,j∈{1 ,2,3},n∈{21,41},
Sm oothedand N orm a
lized X 27
Mom ent
s Sm oothedv olum es
, n∈{2 1,41
}
th
j Localm omen tvolume
s,j∈{1 ,
2,3},n∈{2 1,
41}

1
00
4
.3.2 F
eatu
reex
trac
tionfunc
tion
sandv
ecto
rs

Inth
iss
ect
ionw
ein
trodu
ceth
esixf
eatu
reex
tra
cti
onfun
cti
onsandth
eve
cto
rs
th
esefun
cti
onsp
rodu
ce.InF
igu
re4
.1,w
eex
amin
e3-d
imen
sion
als
cat
terp
lot
s

o
fth
ein
ten
sit
ieso
fth
efe
atu
resth
atf
ormth
efe
atu
rev
ect
ors
.No
teth
atwh
il
e

m
anyo
fth
efe
atu
rev
ect
orsa
reinah
igh
erd
imen
sion
,inth
isfi
gur
ewea
re
on
lyab
let
osh
ow3
-dim
ens
ion
s.S
cat
terp
lot
softh
eT1
-w,T
2-wandFLA
IR

in
ten
sit
iesandfun
cti
onso
fth
esein
ten
sit
iesf
or1
0,0
00r
and
omlys
amp
ledv
oxe
ls

o
f5r
and
omlys
amp
ledsub
jec
t’s MR
Istud
ies(
ato
talo
f50
,00
0vo
xel
s)a
re

sh
own
;ea
chpo
intinth
epl
otr
epr
esen
tsas
ing
lev
oxe
lfr
oma MR
Istudy
. W
e
w
il
lre
fert
oth
isfi
gur
eth
rou
ghou
tth
iss
ect
ion
.Tab
leA
.3c
ont
ain
sasumm
ary

o
fth
efe
atu
rev
ect
orsin
trodu
cedinth
iss
ect
ion
.

4
.3.2
.1 Unno
rma
lized

Th
eunn
orm
ali
zedf
eatu
rev
ect
orc
ont
ain
sth
eob
serv
edv
oxe
lin
ten
sit
ies(
aft
er

im
agep
re-p
roc
ess
ing
)fo
rav
oxe
lvf
romth
eT1
-w,T
2-wandFLA
IRv
olum
es.

F
igu
re4
.1Dsh
owsap
loto
fth
eob
serv
edv
oxe
lin
ten
sit
iesf
orth
efiv
esub
jec
ts

f
orth
eth
reev
olum
es.L
esi
onsapp
eara
shyp
erin
ten
sit
iesonth
eFLA
IRand

T
2-wv
olum
esanda
shypo
int
ens
it
iesonth
eT1
-wv
olum
e.

4
.3.2
.2 No
rma
lized

W
eno
rma
li
zev
oxe
lin
ten
sit
iesb
ytr
ans
form
ingth
emin
tos
tand
ards
cor
eso
ver

th
ebr
aint
issu
ema
sk[
93]
. Th
eno
rma
li
zedf
eatu
rev
ect
orc
ont
ain
sth
eno
rma
l-

i
zedv
oxe
lin
ten
sit
iesf
romth
eth
reeim
agin
gmod
ali
tie
s.F
igu
re4
.1Esh
owsa

p
loto
fth
eno
rma
li
zedv
oxe
lin
ten
sit
iesf
romth
eth
reem
oda
li
tie
s.F
igu
re4
.2A

1
01
sh
owsas
li
ceo
fth
eFLA
IRv
olum
eaf
terth
eno
rma
li
zat
ionp
roc
edu
reandF
ig-
u
re4
.2Bsh
owsth
emanu
all
esi
ons
egm
ent
ati
onf
orth
iss
li
ce.

F
LAIR

C
A B
T1
-we
igh
ted

T2
-we
igh
ted

Unno
rma
l
ized
(D) No
rma
l
ized
(E) Vo
xelSe
lec
tion
(F)

A
B

C Gaus
sianKe
rne
l Th
irdMomen
t F
irs
tMoment
Ne
ighbo
rhood:21vo
xel
s(G
) Ne
ighborhood
:5vo
xel
s(H
) Ne
ighborhood
:3vo
xel
s(I
)

F
i gure4 .1
:S ca
tterplo tsofth eT 1-w,T 2
-wandFLA IRv oxelin tens
itiesand
functionso fth e
seint ensi
tiesfor1 0,0
0 0r and omlys ampledv o x
elsfrom5r an-
domlys ampledsubject’s MR Istudies
.E achpo intinth epl o
tr epresentsas in g
le
voxelfromas tudy.(A -C )C olo
rk eyforth esep lo
ts:(A )th eFLA IRv o
lum efor
anax ialslicefromas in g
lesub ject
’s MR Is tudy,(B )th et echnician’sm anu a
l
segm entationforthiss l
iceand(C )th ec olo
r sth atareu sedinth ep lot
sc orre
-
spondin gt othissl
ice.L esionv o
x e
lsarep ink ,v oxel
sw ithin1 mmo fal esion
voxelar eorange,voxelsw ithin2mmo fal esionv ox e
lareb lueanda l
lo therv ox
-
e
lsinth ebr a
inarec o
l oredg rey
. Thearrow sinth efigureind icateth eorderth a
t
thef eature
sa recreated.F o
rth eunn o
rm a
lizedin tens
it
i e
sth ereisn op laneth a
t
cans ep ar
atel e
sionv oxelsfr omn on-
les
i onv o xe
ls,bu taftern orm aliz
ationand
w
ithth eadd i
tionoffe aturesthatincluden eighbo rhoodinf orm at
ion,ap lan eis
ablet osepa r
atelesi
onandn on
-le
sionv oxelsw ithimp roveda c curacy.

4
.3.2
.3 V
oxe
lse
lec
tion

W
ese
lec
tcand
ida
tel
esi
onv
oxe
lst
olow
erc
ompu
tat
ion
alt
imeandr
est
ric
tth
e

m
ode
lin
gsp
ace
.Asm
ostl
esi
onv
oxe
lsapp
eara
shyp
erin
ten
sit
iesinth
eFLA
IR
v
olum
e,w
eapp
lyth
ebr
aint
issu
ema
skt
oth
eFLA
IRv
olum
eands
ele
ctth
e

1
02
F
i gure4.2: Anax i
alslic
ef r
omas inglesubjec
to fth eFLA IRv o
lum ewithth e
norm a
lizat
ionp rocedure
,m anua
ll e
sions egmentat
ion,n eighbo rh oodfunctions
ofth eFLA IRv o
lum e,andanex amp leofac lass
ifi ca
tionr esult.(A )FLA IR
volum e
;(B )m anuallesionsegm en
tation
;(C )FLA IRsm oothedv olumew itha
neighborhoodn=4 1
;(D )FLA IRfi rstloca
lm om entv o
lum ewithn ei
ghborhood
n =5 ;(E )FLA IRs econdl oca
lm om entv o
lum ew i
thn eighbo rh oodn = 5
;(F )
FLA IRth i
rdl ocalm omentv olumew ithn e
ighborh oodn =5 . Th esm ooth ed
volum e
sa ctonl argeneighborhoods
,wh i
lethel oca
lm om entv olum esacto v e
r
sm al
lern e
ighborhood s
;(G )Th ep robabi
litym app roduc edforth elogi
sticr e-
gress
ioncl a
ssifieronth esm oothedfe a
turev e
ctor;(H )Th escaleo fintensit
i e
s
inth ep r
ob abi
li
tym ap
.

8
5thp
erc
ent
il
eandabo
veo
fvo
xel
sinth
ebr
aint
issu
ema
ska
scand
ida
tev
oxe
ls

f
orl
esi
onp
res
enc
e.F
igu
re4
.1Fsh
owsth
eno
rma
li
zedv
oxe
lin
ten
sit
iesf
oron
ly

th
ecand
ida
tev
oxe
ls
. Th
evo
xels
ele
cti
onp
roc
edu
rei
sno
tne
ededf
ors
imp
le
m
eth
odsbu
tisn
eed
edf
orm
orec
omp
lexa
lgo
rithm
s.

1
03
4
.3.2
.4 Smoo
thed

Th
esm
ooth
edf
eatu
rev
ect
orc
ont
ain
svo
xelin
ten
sit
iesf
romth
esm
ooth
edv
ol-
um
es,wh
icha
refun
cti
onso
fea
chv
oxe
landi
tsn
eighbo
rs. Th
esm
ooth
edv
ol-

um
esa
ctonr
ela
tiv
elyl
arg
ene
ighbo
rhood
sanda
red
esi
gnedt
ocap
tur
ean
atom
i-

c
alin
form
ati
onandr
esidu
alin
ten
sit
yinh
omo
gen
eit
ies(
forad
eta
il
edd
iscu
ssi
on
s
ee[
7])
. L
etth
ene
ighbo
rhoodo
fsi
zenb
eth
en×n×nn
eighbo
rhoodo
f
v
oxe
lsc
ent
ereda
tv. Tw
osm
ooth
edv
olum
esf
ore
achim
agin
gmod
ali
tya
re

c
rea
tedb
y3-d
imen
sion
alG
aus
siansm
ooth
ingo
fth
eno
rma
li
zedin
ten
sit
iesf
or
th
emod
ali
tyo
verth
ene
ighbo
rhoodo
fsi
zenw
ith
inth
ebr
aint
issu
ema
sk;

inth
isapp
li
cat
ion w
ech
osen=2
1and4
1. W
eus
edth
eFSLt
oolf
slm
ath
s

(h
ttp
://www
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rib
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/fs
l)t
ocr
eat
eth
esm
ooth
edv
olum
es. Du
etoth
e
h
ighd
imen
siono
fth
isf
eatu
rev
ect
or,w
ecann
otv
isu
ali
zein
ten
sit
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romth
e

en
tir
eve
cto
r.F
igu
re4
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owsth
evo
xelin
ten
sit
ieso
fth
esm
ooth
edv
olum
es

f
orth
eth
reem
oda
li
tie
sfo
ran
eighbo
rhoodo
f21v
oxe
lsf
orc
and
ida
tev
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ls

f
romth
evo
xels
ele
cti
onp
roc
edu
re.F
igu
re4
.2Csh
owsas
li
ceo
fth
esm
ooth
ed

v
olum
efo
rth
eFLA
IR,n
eighbo
rhoodo
fn=4
1.

4
.3.2
.5 Momen
ts

Inc
ont
ras
ttoth
esm
ooth
edv
olum
es, wh
icha
ctonr
ela
tiv
elyl
arg
ene
ighbo
r-

h
ood
s,th
elo
calm
omen
tvo
lum
esa
red
esi
gnedt
oin
corpo
rat
esp
ati
alin
form
a-

t
ionf
romn
earb
yne
ighbo
rin
gvo
xel
s,a
sas
ing
lel
esi
oni
styp
ica
llyc
omp
ris
ed

o
f mu
lt
ipl
eclu
ste
redv
oxe
ls
. Th
elo
calm
omen
tvo
lum
esa
rec
rea
tedb
ytak
ing
th
th
ej samp
lem
omen
tfo
rea
chv
oxe
lvo
verth
ene
ighbo
rhoodo
fsi
zeno
fth
e
th
n
orm
ali
zedv
olum
eov
erth
ebr
aint
issu
ema
sk(
thej s
amp
lem
omen
tfo
ra

1
04
 r j
s
eto
frpo
int
sisd
efin
edt
obe1
r =1 Xi)
i . H
erew
eus
ej∈{1
,2,
3}f
orth
e

s
amp
lem
omen
tsandn=3and5f
orth
ene
ighbo
rhoods
ize
. Du
etoth
ehi
gh
d
imen
siono
fth
isf
eatu
rev
ect
or,w
eag
ainc
ann
otv
isu
ali
zein
ten
sit
iesf
romth
e

en
tir
eve
cto
r.F
igu
re4
.1Hsh
owsth
evo
xelin
ten
sit
ieso
fth
eth
irdl
oca
lmom
ent

v
olum
esf
orth
eth
reem
oda
li
tie
swi
than
eighbo
rhoodo o
fn=5vxe
lsf
orc
an-
d
ida
tev
oxe
ls
.Fi
gur
e4.
1Ish
owsth
evo
xelin
ten
sit
ieso
fth
efir
stl
oca
lmom
ent

v
olum
esf
orth
eth
reem
oda
li
tie
swi
than
eighbo
rhoodo
fn=3v
oxe
lsf
orc
and
i-

d
atev
oxe
ls
.Fi
gur
e4.
2sh
owsanax
ials
li
cef
romasub
jec
tofth
elo
calm
omen
t
v
olum
efo
rth
eFLA
IRw
ithan
eighbo
rhoodo
fn =5
;Fi
gur
e4.
2Dsh
owsth
e

fi
rstl
oca
lmom
entv
olum
e,F
igu
re4
.2Eth
ese
cond
,andF
igu
re4
.2Fth
eth
ird
.

Inth
elo
calm
omen
tvo
lum
esth
econ
tra
stb
etw
eenl
esi
onando
the
rti
ssu
eis

in
cre
ased
.

4
.3.2
.6 Smoo
thedand momen
ts

Th
esm
ooth
edand m
omen
tsf
eatu
rev
ect
orc
ont
ain
sth
ein
ten
sit
iesf
romth
e

sm
ooth
edf
eatu
rev
ect
orandth
emom
ent
sfe
atu
rev
ect
or. Th
isv
ect
orc
ont
ain
s

th
eno
rma
li
zedv
oxe
lin
ten
sit
iesandin
ten
sit
iesf
romth
esm
ooth
edv
olum
esand

l
oca
lmom
entv
olum
esf
orc
and
ida
tev
oxe
lsf
romth
evo
xels
ele
cti
onp
roc
edu
re.

4
.3.3 T
rain
ingandv
alida
tions
tud
iesw
ith manua
lle
sion

segmen
tat
ion
s

F
ore
acho
fth
e98 MR
Istud
iesw
eha
vea m
anu
all
esi
ons
egm
ent
ati
on m
adeb
y

at
echn
ic
ianw
ith m
oreth
an1
0ye
arso
fexp
eri
enc
eind
el
ine
atin
gwh
item
att
er
l
esi
ons
. An
eur
orad
iol
ogi
stw
ithm
oreth
an1
0ye
arso
fexp
eri
enc
ein MR
Iof MS

1
05
p
ati
ent
srev
iew
edth
emanu
als
egm
ent
ati
onsandf
oundth
emt
obea
ccep
tab
le
.
Th
emanu
als
egm
ent
ati
onsw
erem
adeon
lyf
orwh
item
att
erl
esi
onsandw
ere

m
adeu
sin
gth
eFLA
IRandT
1-wv
olum
es.T
oas
ses
sth
epe
rfo
rman
ceo
fth
e

a
lgo
rithm
sone
acho
fth
efe
atu
rev
ect
ors
,wer
and
omlya
ssi
gned4
9ofth
e MR
I
s
tud
iest
oat
rain
ings
etandth
erem
ain
ing4
9stud
iesw
ereu
sedf
orv
al
ida
tion
.

W
efitth
eal
gor
ithm
sonas
eto
f50
0vo
xel
ssamp
ledf
rome
acho
fth
etr
ain
ing
MR
Istud
ies(
forat
ota
lof2
4,5
00v
oxe
ls)
. Th
isw
asd
oneino
rde
rtor
edu
ce

th
etim
ene
ededt
ofite
acha
lgo
rithm
,asm
anyo
fth
eal
gor
ithm
swi
thtun
ing

p
aram
ete
rsr
equ
iredasub
stan
tia
lam
oun
toft
imet
ofitonl
arg
ers
etso
fvo
xel
s.

W
ein
ves
tig
ateth
eeff
ectonp
erf
orm
anc
eandc
ompu
tat
ion
alt
imeo
fth
isand

fu
rth
erd
own
samp
lin
ginth
eRe
sul
tss
ect
ion
.Va
lue
sfo
rth
etun
ingp
aram
ete
rs

f
ore
acha
lgo
rithmw
eres
ele
ctedu
sin
g10
-fo
ldc
ros
sva
lid
ati
ononth
evo
xel
sin

th
etr
ain
ings
et. W
eva
lid
atedonth
een
tir
ebr
ainv
olum
efo
rea
cho
f49s
tud
ies

inth
eva
lid
ati
ons
et.T
abl
e4.
3sh
owsasumm
aryo
fth
etr
ain
ings
et,th
etr
ain
ing

s
eta
fte
rth
evo
xels
ele
cti
onp
roc
edu
reandth
eva
lid
ati
ons
ets
.

1
06
 T
abl
e4 .3
: Asumm aryofthetrainingset
,train
ingseta
fte
rth evoxe
lsele
ctionprocedurehasbeenapp l
ied,andth
e
v
al
idati
onset.Subject
sw ererand omlyass
ignedtothetr
ainingorval
idati
ons et
.A lltra
ining
,includingtun
ingof
a
lgo
rithmp ar
am e
terswith1 0
-fo
ldc ros
sv a
lida
tion
,w a
sperformedonth etra
iningset.

1
0
Tra
iningSet Tra
iningS e
tw i
thV oxe
lS e
lection V a
lidat
ionS et

7
Numb e
ro fSubjec
ts 4
9 49 49
Numb e
ro fLes
ionV oxels(% ) 2 88(1.2%) 27
3( 7
.5% ) 45
8,407(0.8% )
Tot
alNumb e
rofV oxel
s 24500 3664 5 4
,751,5
0 1
4
.3.4 Mea
sure
sofou
tcomeandag
reemen
t

Inth
eRe
sul
tss
ect
ion
,wer
epo
rtth
epa
rti
alR
ece
ive
rOp
era
tin
gCh
ara
cte
ris
tic
(pROC
)cu
rveands
cal
edp
art
ialA
reaUnd
erth
eCu
rve(pAUC
)asm
easu
reso
f

a
lgo
rithma
ccu
racy
. Th
epROCandpAUCa
rec
alcu
lat
edf
orf
als
epo
sit
iver
ate
s

o
f10%andb
elowonth
eva
lid
ati
ons
et,u
sin
gth
emanu
all
esi
ons
egm
ent
ati
ons
a
sa“
si
lve
rst
and
ard
”oft
ruth
. Th
esc
aledpAUCi
scompu
tedb
ydiv
idin
gth
e

pAUCb
yth
efa
lsepo
sit
iver
ateo
f10%[
119
]andt
ake
sva
lue
sbe
twe
en0and1
,

w
ithav
alu
eof1c
orr
espond
ingt
ope
rfe
ctc
las
sifi
cat
iono
fle
sionandn
on-
les
ion

v
oxe
ls
. W
eal
sor
epo
rtth
eDi
ces
imi
lar
ityc
oeffi
cien
t(DSC
)asa m
easu
reo
f
a
gre
emen
tam
ong
stth
ebin
arys
egm
ent
ati
onsp
rodu
cedb
yea
cha
lgo
rithm
.To

c
alcu
lat
eth
e DSC w
eth
resh
oldth
epr
obab
il
itym
apf
ore
acha
lgo
rithma
ta

f
als
epo
sit
iver
ateo
f0.
5%inth
eva
lid
ati
ons
et. Th
e DSCi
sa m
easu
reo
fth
e

o
ver
lapo
ftw
ose
ts[
97]
,wi
thaDSCo
f0c
orr
espond
ston
oov
erl
apandaDSC

o
f1c
orr
espond
stop
erf
ecto
ver
lap
. Th
eeffi
cien
cyo
fth
eal
gor
ithm
s,inth
e
f
ormo
fcompu
tat
ion
alt
imef
orfi
ttin
gth
eal
gor
ithm
sonth
etr
ain
ings
etand

m
akin
gpr
edi
cti
onsonth
eva
lid
ati
ona
rer
epo
rted
. W
eal
soex
amin
eth
eeff
ect

o
fdown
samp
lin
gth
etr
ain
ings
etonfi
ttim
e,p
erf
orm
anc
eandth
esup
erl
earn
er

c
oeffi
cien
twe
igh
ts.

4
.4 Re
sul
ts

4
.4.1 C
las
sifica
tionpe
rfo
rmance

F
igu
re4
.3sh
owsth
epROCcu
rve
sfo
rfa
lsepo
sit
iver
ate
supt
o10%f
orth
enin
e
c
las
sifi
cat
iona
lgo
rithm
sor
gan
izedb
yth
efe
atu
rev
ect
ors
,wi
thap
lotf
ore
ach

1
08
 Unno
rma
lized No
rma
lized

.0

.0
1

1
Log
i s
it
ic
Neura
lNe t
SVM
QDA

.8

.8
LDA

0
GMM
kNN

te

te
RandomFo res
t

iveRa

iveRa
SuperLeaner

.6

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Ident
ity

0
t

t
i

i
ruePos

ruePos
.4

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0

0
T

T
.2

.2
0

0
.0

.0
0

0
0
.00 0
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Fa
lsePos
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iveRa
te Fa
lsePo
si
ti
veRa
te
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Voxe
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thed
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lsePos
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0

0
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Fa
lsePos
it
iveRa
te Fa
lsePo
si
ti
veRa
te F
E

F
i gure4.3: Th ep ar
tia
lR ece
iver Operat
in gCh aracter
ist
ic(pROC )cu rve
sf or
thec lass
ificationa l
gorithmsf orfals
epo sit
iver atesupt o10%inth ev al
id a-
t
i onse t
. Th ed iagonallineissh ownone achp lotinb l
a ckforr e
feren c
e,and
representsac lass
ifierth atperformsasw e
llasch anc e
. Ap lotisp re
s entedf or
eacho fth esixf e
aturev ecto
rs:(A )unn orm a
lized,(B )n orm a
li
zed,(C )vox el
sele
ction,(D )sm oothed,(E )m om ent
s,and(F )sm oothedand m omen ts. Th e
perfo
rm anc eofthesimp lercla
ssificat
ionalgorithm sonth efeaturevect or
sw ith
featuresincludingsp a
tialinfo
rm at
iona resupe r
iortoth atofth em orec ompl ex
c
l as
sifiersonth eorig
inalfeaturesonth eunn orm a
lizedfeatur
ev ector
.

1
09
o
fth
esixv
ect
ors
:unn
orm
ali
zed(F
igu
re4
.3A
),n
orm
ali
zed(F
igu
re4
.3B
),v
oxe
l
s
ele
cti
on(F
igu
re4
.3C
),sm
ooth
ed(F
igu
re4
.3D
),m
omen
ts,(F
igu
re4
.3E
)and

sm
ooth
edand m
omen
ts(F
igu
re4
.3F
). W
eal
sor
epo
rts
cal
edpAUCf
orf
als
e

po
sit
iver
ate
sof1
0%f
ore
achf
eatu
rev
ect
orinF
igu
re4
.4. Th
esp
readinth
e
pROCcu
rve
sinF
igu
re4
.3andth
esc
aledpAUCinF
igu
re4
.4c
ome
smo
ref
rom

th
ediff
eren
tfe
atu
rev
ect
orsth
anth
ecl
ass
ific
ati
ona
lgo
rithm
s. Wh
enfi
ttin
gth
e
a
lgo
rithm
sonth
eunn
orm
ali
zedf
eatu
rev
ect
or,a
lgo
rithm
spe
rfo
rmb
ett
erand

w
ors
ere
lat
ivet
oon
ean
oth
er.InF
igu
res4
.3andF
igu
re4
.4w
ese
eth
atm
ore

c
omp
lexa
lgo
rithm
s,su
cha
sth
esup
erl
earn
er,G
aus
sian m
ixtu
rem
ode
l,n
eur
al

n
etw
ork
,andr
and
omf
ore
st,p
erf
ormb
ett
erth
ans
imp
lera
lgo
rithm
s. W
edefin
e

c
omp
lex
itya
safun
cti
ono
fana
lgo
rithm
’sd
eci
sionbound
ary–f
orex
amp
lea
l-

g
ori
thm
swi
thl
ine
ard
eci
sionbound
ari
esa
rer
ela
tiv
elys
imp
lerth
ana
lgo
rithm

w
ithn
onl
ine
ard
eci
sionbound
ari
es[
120
].A
fte
rno
rma
li
zat
ionandth
eadd
it
ion

o
ffe
atu
resth
atin
clud
ene
ighbo
rin
gin
form
ati
on,th
epe
rfo
rman
ceo
fth
eal
go-

r
ithm
sbe
gint
ocon
ver
ge.A
llo
fth
eal
gor
ithm
spe
rfo
rmw
ors
eonth
emom
ent
s

f
eatu
rev
ect
orth
anth
esm
ooth
edf
eatu
rev
ect
or,ev
enth
ough
tth
edim
ens
iono
f

th
emom
ent
sfe
atu
rev
ect
ori
s mu
chh
igh
erth
anth
ato
fth
esm
ooth
edf
eatu
re

v
ect
or(
21v
ersu
s9)
.Inth
isapp
li
cat
ionandint
erm
sofp
red
ict
ivep
erf
orm
anc
e,

th
esm
ooth
edv
olum
esa
reb
ett
erf
eatu
resf
orc
las
si
fyin
gle
sion
sth
anth
elo
cal

m
omen
tvo
lum
es. A
lso
,tw
oofth
eal
gor
ithm
s,th
eGau
ssi
an m
ixtu
rem
ode
l

andth
ek-n
ear
estn
eighbo
rs,h
avead
ecr
eas
edp
erf
orm
anc
ere
lat
ivet
ooth
er
a
lgo
rithm
sonth
eva
lid
ati
ons
etinth
esm
ooth
edand m
omen
tsf
eatu
rev
ect
or.

Th
epe
rfo
rman
ceo
fth
esimp
lerc
las
sifi
cat
iona
lgo
rithm
sonth
edev
elop
ed

f
eatu
rev
ect
orsi
ssup
eri
ort
oth
ato
fth
emo
rec
omp
lexc
las
sifi
ersonth
eob
-

s
erv
ed MR
Iin
ten
sit
iesinth
eunn
orm
ali
zedf
eatu
rev
ect
or.InF
igu
re4
.3w
ese
e

1
10
 Sca
ledpAUCbyFea
tureSpace

.9
0
.8
0
.7
0
ledpAUC
.6
0
.5
ca
0

Log
i s
ti
c
S

Neura
lNet
SVM
.4
0

QDA
LDA
GMM
.3
0

kNN
RandomFore
st
SuperLea
rne
r
.2
0

Unno
rma
l
ized No
rma
l
ized Voxe
l Smoo
thed Momen
ts Smoothed
Se
lect
ion and Momen
ts

F
igure4.
4: Thesca
ledp ar
tia
lA reaUndertheCu rve(pAUC)foreachalgo
rithm
oneachfea
turevector
. Thedifferenc
esinscal
edpAUCc om e
sm o
refromdiff e
r-
ence
sinfeatureve
ctorsthandifferen
cesinclas
sificat
iona
lg o
rithms
. Thesc a
led
pAUCo fthesimplercla
ssifi
cationalgo
rithmsinth edev
elopedfeatu
revect o
rs
ar
el a
rge
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rec omplexcl
ass
ifi e
rsontheo rig
inalf
eatur
e sin
theunnorm a
li
zedfeatur
ev e
ctor
.

th
atth
ebe
stp
erf
orm
inga
lgo
rithm
sonth
eunn
orm
ali
zedf
eatu
rev
ect
or,th
e

sup
erl
earn
erand G
aus
sian m
ixtu
rem
ode
l,exh
ibi
tin
fer
iorp
erf
orm
anc
etoa
ll
a
lgo
rithm
sonth
edev
elop
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eatu
rev
ect
ors
. Anin
tui
tionf
orth
isr
esu
ltf
rom

th
eda
tai
spr
ovid
edinth
epl
otso
fFi
gur
e4.
1.F
igu
re4
.1Dsh
owsap
loto
f

th
ein
ten
sit
iesf
romth
eunn
orm
ali
zedT
1-w
,T2
-wandFLA
IRv
olum
es. Th
ere

i
snop
lan
eth
atc
ans
epa
rat
ele
sionv
oxe
lsf
romn
on-
les
ionv
oxe
ls
. Th
ism
ay

b
eth
ere
asona
stowh
yal
gor
ithm
swi
thn
onl
ine
ard
eci
sionbound
ari
esp
erf
orm

1
11
b
ett
eronth
eunn
orm
ali
zedf
eatu
rev
ect
or.A
fte
rno
rma
li
zat
ioninF
igu
re4
.1E
,
ap
lan
eisab
let
osep
ara
tel
esi
onandn
on-
les
ionv
oxe
lsw
ithimp
rov
eda
ccu
racy
.

W
ithth
eadd
it
iono
fth
esm
ooth
edandm
omen
tvo
lum
es(F
igu
re4
.1G
-H)
,cl
as-

s
ific
ati
ona
ccu
racyi
sfu
rth
erimp
rov
ed.
N
oteth
atm
anyo
fth
eal
gor
ithm
srequ
iredar
ang
eofu
ser
-supp
li
edtun
-

in
gpa
ram
ete
rs(T
abl
e4.
3). W
ein
ves
ted mu
cht
imeind
ecid
ingwh
ichtun
ing
p
aram
ete
rst
oal
lowth
eal
gor
ithm
stos
ear
cho
ver
,asu
sin
gth
ein
cor
rec
tpa
-

r
ame
ter
sgr
eat
lyd
imin
ish
edth
epe
rfo
rman
ceo
fth
esea
lgo
rithm
s.A
sth
erea
re

aninfin
itenumb
ero
fpa
ram
ete
rsth
anc
anb
ese
arch
ed,w
ecann
eve
rbec
ert
ain

th
atw
eha
ved
ecid
eduponth
eop
tim
alp
aram
ete
rs,andth
ere
for
ewep
ref
er

u
sin
gal
gor
ithm
sth
ata
rec
omp
let
elyin
form
edb
yth
eda
ta.

4
.4.2 A
lgo
rithmag
reemen
t

T
oas
ses
sth
eag
reem
entinth
ecl
assl
abe
las
sign
edt
oav
oxe
lbye
acha
lgo
rithm
,

w
erepo
rtth
eDSCf
ora
llp
air
sofb
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1
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1
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1
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1
18
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F
igure4 .7
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1
19
v
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4
.4.6 In
terp
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In
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1
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igure4 .
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121
].

Th
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aus
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1
21
an
aly
sisandth
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ixtu
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n
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ly

p
rov
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th
atth
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igu
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rac
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ont
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ime
.

4
.5 D
iscu
ssion

Inth
isp
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r,w
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ves
tig
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ten
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ass
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,

th
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ithmandf
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m
ent
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e
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e

1
22
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lfe
atu
resa
rea
vai
lab
le
[12
2].A
llo
fth
eal
gor
ithm
spe
rfo
rmb
ett
eronth
e

sm
ooth
ed,m
omen
tsandsm
ooth
edand m
omen
tsf
eatu
rev
ect
ors
,th
anth
eyd
o

1
23
onth
efe
atu
rev
ect
orsw
ithl
owe
rdim
ens
ion
.Iti
sal
sou
sefu
lton
ote
,th
atinth
is
app
li
cat
ion
,th
esm
ooth
edv
olum
eswh
ichu
seamu
chl
arg
ern
eighbo
rhooda
rea

b
ett
erf
eatu
resf
orc
las
si
fyin
gle
sion
sth
anth
elo
calm
omen
tvo
lum
es,wh
ichu
se

in
form
ati
oninasm
all
ern
eighbo
rhood
. Wh
il
eon
emi
ghtexp
ectp
erf
orm
anc
eto
b
ehi
ghe
ronth
emom
entv
olum
esth
anth
esm
ooth
edv
olum
es,a
sth
edim
ens
ion

i
shi
ghe
rinth
esp
aceo
fth
emom
entv
olum
es,i
tha
sbe
ensh
ownth
atth
eadd
i-
t
iono
fno
isyf
eatu
resc
and
imin
ishc
las
sifi
cat
ionp
erf
orm
anc
e.[
122
]Anumb
er

o
fim
agesm
ooth
ersc
anb
eus
edt
oin
corpo
rat
esp
ati
alin
form
ati
on. W
ech
ose

th
esm
ooth
edv
olum
esandl
oca
lmom
entv
olum
est
oil
lus
tra
teasm
ooth
ero
ver

ar
ela
tiv
elyl
arg
ene
ighbo
rhoodandr
ela
tiv
elysm
alln
eighbo
rhood
,re
spe
ctiv
ely
.

W
ere
ferth
ere
ade
rtoth
eli
ter
atu
reonim
agesm
ooth
inginbo
thc
ompu
terv
i-

s
ionandn
eur
oim
agin
gfo
ra m
orec
omp
let
edi
scu
ssi
ono
fsm
ooth
ers
,ar
evi
ew

o
fwh
ichc
anb
efoundin“Th
eIm
ageP
roc
ess
ingH
andbook
”[1
23]
.

W
epe
rfo
rmeda
llm
ode
lin
ginth
eRen
vir
onm
ent
,us
ingth
est
and
ardimp
le-

m
ent
ati
onso
fea
cho
fth
ecl
ass
ific
ati
ona
lgo
rithm
s.I
fac
las
sifi
cat
iona
lgo
rithm

w
ithah
ighc
ompu
tat
ion
alt
imeexh
ibi
tedanimp
rov
emen
tinc
las
sifi
cat
iona
c-

cu
racyo
vero
the
ral
gor
ithm
s,th
isa
lgo
rithmc
ouldb
eta
ilo
redt
oredu
cec
om-

pu
tat
ion
alt
ime
. Th
erea
rem
anyt
echn
iqu
est
oredu
cec
ompu
tat
ion
alt
ime
,

su
cha
smo
rec
ompu
tat
ion
allyeffi
cien
ttr
ain
ingandt
est
ingimp
lem
ent
ati
ons

[
124
,12
5,1
26]
,th
eus
eofp
ara
ll
elc
ompu
tat
iono
rgr
aph
icsp
roc
ess
ingun
its
[12
7],

andp
rog
ramm
ingino
the
rlan
gua
gessu
cha
sPy
thon[
128
].Inth
eapp
li
cat
ion
o
fle
sions
egm
ent
ati
on,w
edidn
otob
serv
eanimp
rov
emen
tinc
las
sifi
cat
ion

a
ccu
racyth
atw
ould m
eri
timp
rov
ingc
ompu
tat
ioneffi
cien
cy.

An
oth
erc
onc
erni
sth
ebeh
avi
oro
fth
ecl
ass
ifie
rsonunb
alan
cedd
ata
.Man
y

o
fth
ecl
ass
ific
ati
ona
lgo
rithm
semp
loy
edinth
ean
aly
sish
aveb
eensh
ownt
o

1
24
p
erf
ormpoo
rlyonunb
alan
cedt
rain
ingd
ata
,su
cha
sk-n
ear
estn
eighbo
rs,n
eur
al
n
etw
ork
s,andsuppo
rtv
ect
orm
ach
ine
s[1
29,1
30]
. In T
abl
e3 w
esh
owth
e

d
ist
ribu
tiono
fth
ele
sionandn
on-
les
ionv
oxe
lsinth
etr
ain
ings
et.F
orf
eatu
re

ex
tra
cti
onfun
cti
onsw
ith
outth
evo
xels
ele
cti
onp
roc
edu
re,1
.2%o
fth
evo
xel
s
c
ont
ainl
esi
ons
.Fo
rfe
atu
reex
tra
cti
onfun
cti
onw
ithv
oxe
lse
lec
tion
,7.
5%o
fth
e

v
oxe
lsc
ont
ainl
esi
on. Wh
il
evo
xels
ele
cti
onw
asp
erf
orm
edt
olow
erc
ompu
tat
ion
t
ime
,itc
ana
lsob
eth
ough
tofa
sa m
eth
odo
fba
lan
cin
gth
etr
ain
ingd
atas
et.

I
tiss
imi
lart
oth
eme
thodo
fdown
-s
iz
ing[
130
],wh
erer
and
ome
lem
ent
softh
e

o
ver
-s
izedc
las
sar
erand
omlye
lim
ina
tedf
romth
etr
ain
ings
et. On
ediff
eren
ce

i
sth
atinth
evo
xels
ele
cti
onp
roc
edu
re,v
oxe
lsw
eren
otr
emo
veda
trand
om,

bu
twe
rer
emo
vedu
sin
gath
resh
oldonth
eFLA
IRv
olum
es.O
the
rme
thod
sfo
r

b
alan
cin
gth
etr
ain
ings
etc
oulda
lsob
eapp
li
edt
ole
sions
egm
ent
ati
on.

Th
erei
sal
arg
eli
ter
atu
reonsup
erv
ised m
ach
inel
earn
inga
lgo
rithm
sfo
r

s
egm
ent
ati
ono
f MSl
esi
onsins
tru
ctu
ral MR
I.F
romth
isl
ite
ratu
rei
tisd
if
-

fi
cul
ttod
ete
rmin
eth
eex
ten
tto wh
ichth
ecl
ass
ific
ati
ona
lgo
rithmandth
e

f
eatu
reex
tra
cti
onfun
cti
onimp
act
sth
epe
rfo
rman
ceo
fth
ele
sions
egm
ent
a-

t
iona
lgo
rithm
s. E
acho
fth
eme
thod
srepo
rtsd
iffe
ren
tpe
rfo
rman
cem
etr
ics

ond
iffe
ren
tda
tas
ets
. Th
ema
jor
ityo
fsup
erv
ised m
ach
inel
earn
inga
lgo
rithm
s

inth
eli
ter
atu
rea
reac
ompo
sit
iono
fas
ing
lec
las
sifi
cat
iona
lgo
rithmandf
ea-

tu
reex
tra
cti
onfun
cti
on.M
osto
fth
efe
atu
rev
ect
orsf
roml
esi
ons
egm
ent
ati
on

m
eth
odsinth
eli
ter
atu
rec
ont
ainin
ten
sit
yno
rma
li
zedv
oxe
lin
ten
sit
ies
,th
e
m
ostpopu
laro
fwh
ichi
shi
sto
gramm
atch
ing[
131
].O
the
rcomm
onf
eatu
resa
re

fun
cti
onso
fne
ighbo
rhood
sofanim
agev
oxe
l[1
32,1
33,1
34,1
35,8
0,7
,13
6]o
r

l
oca
tionin
form
ati
onf
romanan
atom
ica
lat
las[
132
,13
7,1
38,1
39,1
35]
. Th
e

1
25
sup
erv
isedc
las
sifi
cat
iona
lgo
rithmu
sedb
yth
esem
eth
odsin
clud
eneu
raln
et-
w
ork
s[1
33,7
2,1
40,1
41,1
42]
,k–n
ear
estn
eighbo
rs[
132
,14
3],b
aye
sianc
las
sifi
ers

[
138
,79
],p
rin
cip
alc
ompon
entan
aly
sisc
las
sifi
cat
ion[
135
],P
arz
enw
ind
owc
las
-

s
ifie
rs[
77]
,mod
els
tac
kin
g[8
0,1
36]
,cl
ass
ific
ati
onb
asedon M
ark
ovR
and
om
F
ie
lds[
134
,81
],sup
erv
isedl
earn
ingo
fop
tim
alsp
ect
ralg
rad
ien
ts[
82],and

r
and
omf
ore
sts[
137
]. K
amb
er(
199
5)d
oesc
omp
aref
ourd
iffe
ren
tcl
ass
ific
a-
t
ion m
eth
ods
:a m
inimumd
ist
anc
ecl
ass
ifie
r,aB
aye
sianc
las
sifi
er,anunp
run
ed

d
eci
siont
ree
,andap
run
edd
eci
siont
reeandf
oundth
atth
eBa
yes
ianc
las
-

s
ifie
rpe
rfo
rmedb
est
.[1
39] Th
eon
lyf
eatu
resu
sedinth
eme
thodp
ropo
sed

b
yKamb
era
reth
e MR
Ivo
xelin
ten
sit
iesanda
tla
sde
riv
edp
rio
rpr
obab
il
it
ies

o
fav
oxe
lcon
tain
ingl
esi
on;th
eme
thodu
sesn
eith
erin
ten
sit
yno
rma
li
zat
ion

n
orfun
cti
onso
fth
eim
agein
ten
sit
ies
. M
anyo
fth
eaf
orem
ent
ion
edl
esi
ons
eg-

m
ent
ati
on m
eth
odsu
sed
iffe
ren
tim
agep
re-p
roc
ess
ings
tep
s.Inth
isw
ork w
e

ev
alu
ateth
eimp
acto
fcl
ass
ific
ati
ona
lgo
rithm
sandf
eatu
reex
tra
cti
onfun
cti
ons

onc
las
sifi
cat
ionp
erf
orm
anc
e. Ou
rda
tai
sre
sl
icedt
o1mmi
sot
rop
icr
eso
lut
ion
,

ac
omm
onr
eso
lut
ionf
orm
anyim
agep
roc
ess
inga
lgo
rithm
s,ev
enf
ord
ataa
c-

qu
ireda
tal
owe
rnom
ina
lre
solu
tion
.Asp
re-p
roc
ess
ings
tep
sma
yal
soinflu
enc
e

c
las
sifi
cat
ionr
esu
lts
,fu
tur
ewo
rki
sne
ededt
oin
ves
tig
ateth
isimp
act
.

W
ein
ves
tig
ateth
ech
oic
eofsup
erv
isedc
las
sifi
cat
iona
lgo
rithmandf
eatu
re

ex
tra
cti
onfun
cti
ononth
epe
rfo
rman
ceo
fle
sions
egm
ent
ati
on m
eth
ods
. Ou
r

find
ing
sar
eth
atth
epa
rti
cul
arc
las
sifi
cat
iona
lgo
rithmi
sle
ssimpo
rtan
tth
an
th
eca
refu
ldev
elopm
ento
fth
efe
atu
rev
ect
ors
.Fo
rth
eemp
loy
edf
eatu
reex
tra
c-

t
ion m
eth
ods
,cl
ass
ific
ati
ona
lgo
rithm
swi
thal
ine
ard
eci
sionbound
ary(
log
ist
ic

r
egr
ess
ionandl
ine
ard
isc
rim
inan
tan
aly
sis
)pe
rfo
rmedequ
allyw
el
lasc
las
sifi
ers

1
26
w
ithn
onl
ine
ard
eci
sionbound
ari
es.A
lso
,th
epe
rfo
rman
ceo
fth
esimp
lerc
las
-
s
ific
ati
ona
lgo
rithm
swi
thth
efe
atu
rev
ect
orsc
ont
ain
ingadd
it
ion
alf
eatu
resi
s

sup
eri
ort
oth
ato
fth
emo
rec
omp
lexc
las
sifi
ersonth
eor
igin
alf
eatu
res
.

1
27
Chap
ter5

Re
lat
ing mu
lti
-sequence
long
itud
ina
lin
ten
sityp
rofi
les
andc
lin
ica
lcov
aria
tesin
inc
iden
t mu
ltip
lesc
lero
sisle
sion
s

5
.1 In
troduc
tion

S
tru
ctu
ralm
agn
eti
cre
son
anc
eim
agin
g(MR
I)c
anb
eus
edt
ode
tec
tle
sion
sin

th
ebr
ain
sof mu
lt
ipl
esc
ler
osi
s(MS
)pa
tien
ts. Th
efo
rma
tiono
fth
esel
esi
ons
i
sac
omp
lexp
roc
essin
volv
inginfl
amm
ati
on,t
issu
edam
age
,andr
epa
ir–t
o

a
llo
fwh
ich MR
Iha
sbe
ensh
ownt
obes
ens
it
ive
. Th
eMcD
ona
ldc
rit
eri
afo
r

d
iagn
osi
sof MSemph
asi
zeth
ekeyr
oleo
fdi
ssem
ina
tiono
fle
sion
sinth
ecen
tra
l

n
erv
oussy
stemon MR
Ino
ton
lyinsp
ace
,bu
tal
soint
ime[
4]. Ch
ara
cte
riz
ing
th
elon
gitud
ina
lbeh
avi
oro
fle
sion
sons
tru
ctu
ral MR
Iisth
ere
for
elik
elyt
obe

1
28
impo
rtan
tfo
rmon
ito
rin
gdi
sea
sep
rog
res
sionandr
espon
set
oth
erap
yandf
or
und
ers
tand
ingth
eet
iol
ogyo
fth
edi
sea
se. Su
rpr
is
ing
ly
,th
erei
spoo
ras
soc
i-

a
tionb
etw
eenc
lin
ica
lfind
ing
sandth
erad
iol
ogi
calex
ten
tofin
volv
emen
ton

MR
Ius
ingt
rad
it
ion
alv
olum
etr
icm
easu
res
,aph
enom
enonr
efe
rredt
oasth
e
c
lin
ico
-rad
iol
ogi
calp
arad
ox[
5].H
erew
eadd
res
sth
isp
arad
oxb
ymod
el
ingth
e

a
sso
cia
tionb
etw
eenth
elon
gitud
ina
lbeh
avi
oro
fle
sion
saf
terin
cid
enc
eon MR
I
andc
lin
ica
lco
var
iat
esandd
ise
ase
-mod
ify
ingt
rea
tmen
t.

P
rev
iou
swo
rkt
och
ara
cte
riz
eth
elon
gitud
ina
lbeh
avi
oro
fle
sion
sons
tru
c-

tu
ral MR
Iandt
ofu
rth
err
ela
teth
esech
ang
est
ocl
ini
calin
form
ati
onh
ason
ly

in
volv
eds
ing
les
tru
ctu
ral MR
Isequ
enc
es.Inth
ewo
rko
f[1
44,1
45]and[
146
],

l
ong
itud
ina
lle
sionb
eha
vio
risch
ara
cte
riz
edon
lyonth
ein
ten
sit
yno
rma
li
zed

p
rot
ond
ens
ity(PD
)vo
lum
e,u
sin
gbi
-we
ekly MR
Istud
ies
.Al
thou
ghth
eyd
id

n
otr
ela
teth
esech
ang
est
ocl
ini
calc
ova
ria
tes
,itw
asf
oundth
atth
emax
ima
l

in
sul
twi
thinal
esi
ono
ccu
rreda
tth
ecen
tero
fth
ele
sion
,th
atl
owe
rin
it
ial

in
ten
sit
ywi
thinal
esi
onw
asp
red
ict
iveo
frep
air
,andth
atm
ostl
esi
ona
ctiv
ity

d
idn
otl
astb
eyond1
0we
eks
.Mo
rer
ecen
tly
,[1
47]ex
amin
edth
ech
ang
eov
era

2
-ye
arp
eri
odinn
orm
ali
zedT
1-w
eigh
ted(T
1)in
ten
sit
ywi
thinn
ewl
esi
ons
,and

c
omp
aredth
esech
ang
esinp
edi
atr
icandadu
lt
-on
set MSp
ati
ent
s. Ag
ene
ral
-

i
zedl
ine
arm
ixed
-eff
ect
smod
elw
asu
sedt
ore
lat
ecl
ini
calc
ova
ria
tes
,su
cha
s

d
ise
asedu
rat
ionandt
rea
tmen
ts,t
och
ang
esinin
ten
sit
yinth
e MR
I.Th
eon
ly

s
tat
ist
ica
llys
ign
ific
antr
ela
tion
shipw
asth
atth
eT1in
ten
sit
yinl
esi
onsin
cre
ased
b
etw
eenin
cid
enc
eand1
-ye
arf
oll
ow-up
,andth
isr
eco
veryw
asm
orep
ron
oun
ced

inch
ild
ren
. W
orkh
asa
lsob
eend
onet
ore
lat
elon
gitud
ina
lch
ang
esinl
esi
on

in
ten
sit
ytos
amp
les
izec
alcu
lat
ion
sfo
rcl
ini
calt
ria
ls
.[1
48]u
sedth
ech
ang
ein

th
e25
thp
erc
ent
il
eofin
ten
sit
y-n
orm
ali
zedPDs
ign
alw
ith
inal
esi
ono
vert
ime

1
29
t
oes
tim
aten
ece
ssa
rys
amp
les
ize
sfo
rcl
ini
calt
ria
lso
fdiff
erin
glen
gth
s. Th
e
2
5th
,50
th,and7
5thp
erc
ent
il
eso
f mu
lt
ipl
e MR
Isequ
enc
esw
erea
sse
ssed
,and

i
twa
sfoundth
atth
e25
thp
erc
ent
il
eofth
eno
rma
li
zedPDy
ie
ldedth
esm
all
est

s
amp
les
izer
equ
irem
ent
s. Al
imi
tat
iono
fth
eses
tud
iesi
sth
ate
achu
seson
ly
on
e MR
Isequ
enc
etoch
ara
cte
riz
eth
ebeh
avi
oro
fth
ele
sion
s, wh
ichi
gno
res

in
form
ati
onkn
ownt
obea
vai
lab
leinth
eoth
ers
equ
enc
es[
149
].
H
ere
,wed
esc
rib
etw
omod
elst
ound
ers
tandth
ere
lat
ion
shipb
etw
eenc
lin
ica
l

c
ova
ria
tesandth
elon
gitud
ina
lin
ten
sit
ypr
ofil
esinl
esi
ont
issu
efr
omth
eT1
,T2
,

T
2-w
eigh
tedflu
id-
att
enu
atedin
ver
sionr
eco
very(FLA
IR)
,andPDs
equ
enc
es.

Th
efir
sti
sap
rin
cip
alc
ompon
entan
aly
sis(PCA
)andr
egr
ess
ion m
ode
land

th
ese
condc
ons
ist
soffun
cti
on-
on-
sca
larr
egr
ess
ion m
ode
ls[
150
]. W
eus
e mu
lt
i-

s
equ
enc
e MR
Istud
iesa
cqu
ireda
tth
eNa
tion
alIn
sti
tut
eofN
eur
olo
gic
alD
ise
ase

andS
trok
e(N
INDS
),w
ithsub
jec
tsb
ein
gsc
ann
edona
ver
ageon
ceev
ery3
7da
ys

(
sd5
2.3
,ran
ge[
13,8
89]
)yi
eld
ingana
ver
ageo
f21s
can
spe
rsub
jec
t(sd8
.0,

r
ang
e[1
0,3
7])
. Inth
e PCAandr
egr
ess
ion m
ode
l,w
efir
str
edu
ceth
eda
ta

t
oas
cal
ar,v
oxe
l-
lev
elb
iom
ark
erf
orid
ent
ify
ings
lowandp
ers
ist
ent
,lon
g-t
erm

in
ten
sit
ych
ang
es(wh
ichw
ewi
llr
efe
rtof
romth
ispo
intona
sin
ten
sit
ych
ang
es

f
ors
imp
li
cit
y)w
ith
inl
esi
ont
issu
e. Th
eab
il
ityo
fth
ebi
oma
rke
rtoid
ent
ify

th
esech
ang
esi
sth
env
al
ida
tedinanexp
ertr
ate
rtr
ialw
ithtw
ora
ter
s,an
eur
o-

r
adi
olo
gis
tandan
eur
olo
gis
t.A
fte
rth
isv
al
ida
tion
,wer
ela
teth
ebi
oma
rke
rto

c
lin
ica
lin
form
ati
oninav
oxe
l-
lev
elm
ixed
-eff
ect
sre
gre
ssi
onf
ram
ewo
rk.Inth
e
fun
cti
on-
on-
sca
larr
egr
ess
ion
,wed
ire
ctlyr
ela
teth
een
tir
elon
gitud
ina
ltr
aje
c-

t
ori
esf
rome
achs
equ
enc
etoth
ecl
ini
calc
ova
ria
tes
. Th
isa
llow
sfo
ras
ses
smen
t

o
fhowth
ecl
ini
calin
form
ati
onr
ela
test
oth
ein
ten
sit
ypo
int
satth
epo
st-
les
ion

in
cid
enc
etim
epe
riod
sat wh
ichth
esea
sso
cia
tion
soc
cur
,un
lik
einth
ePCA

1
30
r
egr
ess
ion m
ode
l.

5
.2 Ma
ter
ialand me
thod
s

Inth
iss
ect
ion
,wefi
rstd
esc
rib
eth
eim
agea
cqu
is
it
ionandp
rep
roc
ess
ing
,fo
l-
l
owedb
yth
epa
tien
tdem
ogr
aph
ics
.Nex
t,w
ebr
ieflyd
esc
rib
eth
elon
gitud
ina
l

l
esi
onin
ten
sit
ypr
ofil
esinth
esub
sec
tionL
esionP
rofi
les,w
itha m
orec
omp
let
e

d
esc
rip
tiono
fth
epip
elin
efo
rex
tra
ctin
gth
esep
rofi
lesp
rov
idedinth
eApp
end
ix.

W
eth
enin
trodu
cetw
omod
elsf
ors
tudy
ingth
ere
lat
ion
shipb
etw
eenth
ele
sion

p
rofi
lesandth
ecl
ini
calin
form
ati
oninth
esub
sec
tion
sPr
inc
ipa
l Comp
onen
t

Ana
lys
isand R
egr
ess
ion andF
unc
tion
-on
-Sc
ala
rRe
gre
ssion
s. Th
esub
sec
tion

P
rin
cip
al Comp
onen
t Ana
lys
isand R
egr
ess
ion a
lsoin
clud
esth
eexp
ertr
ate
r

t
ria
lofth
evo
xel
-lev
elb
iom
ark
erf
orid
ent
ify
ingin
ten
sit
ych
ang
esw
ith
inl
esi
on

t
issu
e. A
llan
aly
sis
,ex
cep
tfo
rim
agep
rep
roc
ess
ing
,wa
spe
rfo
rmedinth
eR

en
vir
onm
ent[
151
]us
ingth
eRp
ack
ageo
ro.n
if
ti[
152
].

5
.2.1 Imageacqu
isi
tionandp
rep
roce
ssing

Wh
ole
-br
ain2DFLA
IR,PD
,T2
,and3DT
1vo
lum
esw
erea
cqu
ired
ina1
.5t
esl
a

(T
) MR
Isc
ann
er(S
ign
aEx
cit
eHDx
t; GEH
eal
thc
are
,Mi
lwauk
ee,W
isc
ons
in)

u
sin
gth
ebodyc
oilf
ort
ran
smi
ssi
on. Th
e2DFLA
IR,PD
,andT
2vo
lum
esw
ere

a
cqu
iredu
sin
gfa
st-
spin
-ech
osequ
enc
es,andth
e3D T
1vo
lum
ewa
sacqu
ired
u
sin
gag
rad
ien
t-e
chos
equ
enc
e. Th
e PDand T
2vo
lum
esw
erea
cqu
ireda
s

sh
ortandl
onge
cho
esf
romth
esam
esequ
enc
e. Th
esc
ann
ingp
aram
ete
rsw
ere

c
lin
ica
llyop
tim
izedf
ore
acha
cqu
iredim
age
.
F
orim
agep
rep
roc
ess
ing
,weu
seM
edi
calIm
ageP
roc
ess
ing An
aly
sisand

1
31
V
isu
ali
zat
ion(h
ttp
://m
ipa
v.c
it
.nih
.go
v)andth
eJa
vaIm
ageS
cien
ceT
oolk
it
(h
ttp
://www
.ni
trc
.or
g/p
roj
ect
s/j
ist
)[2
7]. W
ein
terpo
lat
eal
lim
age
sfo
rea
ch

sub
jec
tate
achv
is
itt
oav
oxe
lsi
z f1mm3andr
eo igid
lyc
o-r
egi
ste
ral
lvo
lum
es
l
ong
itud
ina
llyanda
cro
sss
equ
enc
est
oth
eMon
tre
alN
eur
olo
gic
alIn
sti
tut
est
an-

d
ardsp
ace[
153
]. W
erem
oveex
tra
cer
ebr
alv
oxe
lsu
sin
gasku
ll
-st
ripp
ingp
roc
e-

du
re[
154
]. W
eau
tom
ati
cal
lys
egm
entth
een
tir
ebr
ainu
sin
gth
eT1andFLA
IR
im
age
s[6
6]t
opr
odu
cea m
asko
fno
rma
l-app
ear
ing wh
item
att
er(NAWM
),

o
rwh
item
att
erex
clud
ingl
esi
ons
.Af
terp
rep
roc
ess
ing
,stud
iesw
erem
anu
ally

qu
ali
tyc
ont
rol
ledb
yar
ese
arch
erw
itho
verf
oury
ear
sexp
eri
enc
ewi
ths
tru
ctu
ral

MR
I(EMS
).S
tud
iesw
ith m
oti
ono
roth
era
rti
fac
tsw
erer
emo
ved
.

5
.2.2 Pa
tien
tdemog
raph
ics

F
orth
isan
aly
sis
,weu
se6
0sub
jec
tss
cann
eda
tth
eNINDS
,wi
thth
eea
rl
ies
t

s
canp
erf
orm
edin2
000andth
emo
str
ecen
tsc
anp
erf
orm
edin2
008
. Th
ree
sub
jec
tsw
ereex
clud
eddu
rin
gth
eexp
ertv
al
ida
tionb
ecau
sei
twa
sfoundth
at

th
elon
gitud
ina
lre
gis
tra
tionh
adf
ail
ed,c
aus
ingo
ver
allpoo
rse
gmen
tat
iono
f

l
esi
ont
issu
e.A
fte
rex
clu
siono
fth
esesub
jec
tsandsub
jec
tsth
atd
idn
oth
ave

v
oxe
lsw
ithin
cid
entl
esi
onsth
atm
etap
resp
ecifi
edin
clu
sionc
rit
eri
a(sub
jec
ts

s
cann
eda
tle
aston
cew
ith
in4
0da
yso
fle
sionin
cid
enc
eanda
tle
aston
ce2
00

d
aysa
fte
rle
sionin
cid
enc
e),th
erew
ere3
4sub
jec
tsl
eftinth
ean
aly
sis
. Th
e
3
4sub
jec
tsin
clud
edinth
ean
aly
sish
adana
ver
ageo
f21s
can
sea
ch(
sd8
.0,

r
ang
e[1
0,3
7])
. F
igu
re5
.1sh
owsth
etim
epo
int
sat wh
iche
acho
fth
e34

sub
jec
tsw
ass
cann
ed. E
achr
owo
fth
epl
otc
orr
espond
stoasub
jec
t,and
e
achpo
intinth
epl
otr
epr
esen
tsan MR
Istudy
,wi
tht
imef
romth
esub
jec
t’s

1
32
b
ase
lin
evi
sitiny
ear
sal
ongth
eho
riz
ont
alax
is
. Th
eto
talf
oll
ow-upt
imep
er
sub
jec
twa
sona
ver
age2
.2y
ear
s(sd1
.2,r
ang
e[0
.9,5
.5]
). Th
eme
ana
geo
fth
e

sub
jec
tsa
tba
sel
inew
as3
7ye
ars(
sd1
0.1
,ran
ge[
18,
60]
). A
tba
sel
ine
,th
ere

w
ere3
0sub
jec
tsw
ithr
elap
sin
g-r
emi
ttin
g MS(RRMS
)and4sub
jec
tsw
ith
s
econd
ary
-pr
ogr
ess
ive MS(SPMS
). Th
erew
ere2
0fem
ale
sand1
4ma
les
,14

sub
jec
tsond
ise
ase
-mod
ify
ingt
rea
tmen
t,and2sub
jec
tswh
ore
ceiv
eds
ter
oid
s
a
tth
eba
sel
inev
is
it
. Th
edi
sea
se-m
odi
fyin
gtr
eatm
ent
sandu
seo
fst
ero
idsf
or

m
anyo
fth
esesub
jec
tsch
ang
eda
tsub
sequ
entf
oll
ow-upv
is
its
.

5
.2.3 Le
sionp
rofi
les

F
igu
re5
.2sh
owsanex
amp
leo
fth
elon
gitud
ina
l, mu
lt
i-
sequ
enc
e MR
Istud
ies

u
sedf
orth
isan
aly
sis
.Fo
rou
ran
aly
sis
,weu
sein
ten
sit
ypr
ofil
esf
romv
oxe
lsth
at

a
red
ete
cteddu
rin
gasub
jec
t’sf
oll
ow-upp
eri
od. Th
efir
str
owo
fFi
gur
e5.
2

sh
owsth
e mu
lt
ipl
e MR
Isequ
enc
esa
ton
etim
epo
int(
froml
eftt
ori
ght
,th
e

FLA
IR,T
2,PD
,andT
1sequ
enc
es)
.Ine
achs
equ
enc
e,ar
edbo
xsh
owsana
rea

w
ithal
esi
onth
atd
eve
lop
sdu
rin
gth
efo
llow
-upp
eri
od. Th
esub
sequ
ent4r
ows

o
fth
efigu
resh
owth
elon
gitud
ina
lbeh
avi
orw
ith
inth
isr
edbo
x.E
achc
olumn
o
fth
efigu
resh
owsad
iffe
ren
t MR
Istudy
,st
art
inga
t98d
aysa
fte
rba
sel
inein

th
efa
rle
ftc
olumnandg
oin
gun
ti
l34
3da
ysa
fte
rba
sel
ine
. Th
ele
sioninth
e

r
edbo
xisfi
rstob
serv
ed1
75d
aysa
fte
rba
sel
ine
.

Th
epip
elin
efo
rex
tra
ctin
gth
elon
gitud
ina
lvo
xel
-lev
ell
esi
onp
rofi
lesf
rom

th
eco
ll
ect
iono
f mu
lt
i-
sequ
enc
est
ruc
tur
al MR
Iisd
ivid
edin
tof
ours
tep
s:(
1)

id
ent
ify
ingv
oxe
lsw
ithn
ewl
esi
onf
orm
ati
on,(
2)in
ten
sit
yno
rma
li
zat
ion
,(3
)

t
empo
rala
lignm
ent
,and(
4)t
empo
ralin
terpo
lat
ion
. W
ebr
ieflyd
esc
rib
eth
ese

1
33
 MR
IStud
iesbySub
jec
t

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● ● ●●●● ● ● ●●●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●

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● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ●●●●●●● ●●● ●● ● ●● ●● ●

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● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ●

● ● ● ● ● ● ● ●● ● ● ●●●●● ● ● ● ● ● ●●● ●●● ●●●

● ● ●●●●● ● ● ● ●●●●●●●

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● ● ●● ●● ●●●● ● ● ● ● ● ● ● ●

0 1 2 3 4 5
T
imef
rombase
l
ine(
inyea
rs)

F
igure5.1
: Th etimepoint
satwh i
che achofthe34sub j
ect
sincludedinth
e
ana
lys
isw asscanned
.E achrowofthepl o
tisasubje
ct,ande a
chpointinthe
p
lotrep
resentsan MRIstudy
. Thehor
izontalax
isr
epresen
tsthetimefromthe
sub
ject
’sb a
sel
inevis
itinyear
s.

s
tep
she
reandin
clud
eanex
tend
edd
esc
rip
tiono
fal
lst
epsinth
isp
ipe
lin
ein

th
eApp
end
ix.F
orth
efir
sts
tepo
fid
ent
ify
ingth
ele
siont
issu
e,w
edi
stin
gui
sh

b
etw
eena
rea
sth
atc
ont
ainv
aso
gen
iced
ema(wh
ichw
ewi
llr
efe
rtos
imp
lya
s

“
edem
a”)anda
ctu
all
esi
ont
issu
e, wh
ichbo
th m
ani
fes
tasa
rea
sofabn
orm
al
s
ign
alin
ten
sit
y,e
spe
cia
llyonth
eT2
-we
igh
teds
equ
enc
es.F
orth
isan
aly
sis
,we

1
34
a
rein
ter
est
edon
lyina
rea
swi
tht
issu
edam
age
,asoppo
sedt
oth
ene
ighbo
rin
g
ed
ema
. W
ecomb
inetw
opr
evi
ous
lyd
eve
lop
edl
esi
ons
egm
ent
ati
on m
eth
ods
,

SuBL
IMEandOA
ISIS
,tofindn
ewl
esi
onv
oxe
lsandd
ist
ingu
ishb
etw
eened
ema

andl
esi
ont
issu
e[9
,7]
. Th
erowl
abe
led“S
egm
ent
ati
on”inF
igu
re5
.2sh
ows
th
eed
emaandl
esi
ont
issu
ese
gmen
tat
ionf
ore
achs
tudya
tth
etim
epo
intin

wh
ichth
ele
sionw
asd
ete
cted
. Th
esub
sequ
entan
aly
sisi
spe
rfo
rmedon
lyon
th
ele
siont
issu
einn
ewl
esi
onv
oxe
ls
.

F
orin
ten
sit
yno
rma
li
zat
ion
,wepu
tth
eun
itsf
rome
achim
agin
gsequ
enc
e

in
tos
tand
ardd
evi
ati
onsabou
tth
eme
ano
fin
ten
sit
iesw
ith
inth
eNAWM m
ask

[
66]f
orth
esequ
enc
e,u
sin
gth
eme
thod
olo
gyo
f[9
3]and[
155
].A
fte
rse
gmen
ta-

t
ionandn
orm
ali
zat
ion
,th
ein
ten
sit
yno
rma
li
zedl
ong
itud
ina
lpr
ofil
esf
romth
e

l
esi
oninF
igu
re5
.2f
ora
llf
ours
equ
enc
esc
anb
ese
eninth
efir
stc
olumno
f

F
igu
re5
.3.F
romt
opt
obo
ttominth
efir
stc
olumno
fFi
gur
e5.
3weh
aveth
e

p
rofi
lesf
rom1
50r
and
omlys
amp
ledv
oxe
lsf
romth
ele
sioninF
igu
re5
.2f
orth
e

FLA
IR,T
2,PD
,andT
1sequ
enc
es.E
achl
ineinth
epl
otr
epr
esen
tsth
elon
gi-

tud
ina
lpr
ofil
efr
omas
ing
lev
oxe
l. Th
ex-
axi
ssh
owsth
etim
eind
aysf
romth
e

b
ase
lin
evi
sit
,wi
thth
epo
into
fle
sionin
cid
enc
eden
otedb
yav
ert
ica
lda
shed

l
ine
,andth
ey-
axi
ssh
owsth
eno
rma
li
zeds
equ
enc
ein
ten
sit
ies
.

Inth
isw
ork
,wea
rein
ter
est
edinth
ele
siondyn
ami
cson
lya
fte
rle
sionin
-

c
iden
ce,s
owep
erf
orml
ine
arin
terpo
lat
ionw
ith
inth
ewind
owa
fte
rle
sionin
ci-

d
enc
eandupt
o20
0da
yspo
st-
inc
iden
ce. W
ese
lec
tth
eendpo
into
f20
0da
ys,
a
sith
asb
eenp
rev
iou
slyf
oundth
atn
ew T
2le
sion
ssh
owth
emo
std
ram
ati
c

ch
ang
esinin
ten
sit
yfo
rth
reet
ofou
rmon
ths[
146
],andw
eop
ttob
econ
serv
a-

t
iveandin
clud
esom
eda
tab
eyondth
isr
epo
rteds
tab
il
iza
tionpo
int
.Vo
xel
sar
e

s
ele
ctedf
orth
ean
aly
sisi
fth
esub
jec
tha
satl
eas
ton
evi
sit2
00d
ayso
rmo
re

1
35
a
fte
rle
sionin
cid
enc
e,anda
tle
aston
evi
sitw
ith
in4
0da
yso
fin
cid
enc
e.O
fth
e
6
0sub
jec
tsinth
isan
aly
sis
,34h
avev
oxe
lpr
ofil
esm
eet
ingth
isin
clu
sionc
rit
eri
a,

a
fte
rrem
ovin
gth
eth
reesub
jec
tsf
orpoo
rlon
gitud
ina
lre
gis
tra
tion
. W
elin
ear
ly

in
terpo
lat
eov
erag
rido
f0t
o20
0da
ysinin
crem
ent
sof5d
ayss
oth
ata
llp
rofi
les
a
reob
serv
edonth
esam
etim
egr
id. W
eden
oteth
eve
cto
rofob
serv
ati
onsf
rom

av
oxe
lov
erth
ist
imeg
ridf
ors
equ
enc
eSinv
oxe
lvf
orsub
jec
tiinl
esi
onla
t
N
r
egi
ste
reds
tudyt
imet(
sin
cel
esi
onin
cid
enc
e)a
sSi
lv(t)
,fo
rS=FLA
IR,T
1,
N
T
2,andPD
.Th
enw
ele
tSi
lvb
eth
elon
gitud
ina
lco
ll
ect
iono
fth
esein
terpo
lat
ed
N N
v
alu
es,n
ame
lyth
e1×4
1ve
cto
rSi
lv={Si
lv(
t):t∈(
0,5
,..
.,
200
)}. Th
ese
cond

c
olumno
fFi
gur
e5.
3sh
owsth
etempo
ral
lyr
egi
ste
redandl
ine
arlyin
terpo
lat
ed
N
p
rofi
les
,Si
lv,o
verth
epe
riodo
f0t
o20
0da
ysf
orth
ele
sioninF
igu
re5
.2f
orth
e

s
ame1
50r
and
omlys
amp
ledv
oxe
lsa
ssh
owninth
efir
stc
olumn
.

5
.2.4 P
rinc
ipa
lcomponen
tana
lys
isandreg
res
sion
s

Inth
iss
ect
ion
,weou
tl
ineth
ePCAandr
egr
ess
ionm
ode
lin
gapp
roa
chf
ors
tudy
-

in
gth
ere
lat
ion
shipb
etw
eenth
elon
gitud
ina
lle
sionp
rofi
lesandd
emo
graph
ics
,

d
ise
ase
,andt
rea
tmen
t. W
ebe
ginb
yde
scr
ibin
gth
evo
xel
-lev
elb
iom
ark
erf
or
id
ent
ify
ingin
ten
sit
ych
ang
esw
ith
inl
esi
ont
issu
e.N
extw
ede
scr
ibeth
eva
lid
a-
t
iono
fth
isb
iom
ark
erw
ithanexp
ertr
ate
rtr
ialw
ithtw
ora
ter
s,an
eur
orad
iol
-

o
gis
tandan
eur
olo
gis
t.L
ast
,wed
esc
rib
ea m
ixed
-mod
elr
egr
ess
ionf
ram
ewo
rk

f
orr
ela
tin
gth
evo
xel
-lev
elb
iom
ark
ert
ocl
ini
calc
ova
ria
tes
.

1
36
5
.2.4
.1 B
ioma
rke
r

W
ebe
ginb
yde
scr
ibin
gth
evo
xel
-lev
elb
iom
ark
erf
orid
ent
ify
ing
int
ens
itych
ang
es
w
ith
inl
esi
ont
issu
e. Th
ebi
oma
rke
risth
esc
oreonth
efir
stp
rin
cip
alc
ompo
-

n
ent(PC
),a
fte
rpe
rfo
rmin
gPCAonth
elon
gitud
ina
lle
sionp
rofi
les
.Top
erf
orm

PCAonth
elon
gitud
ina
lle
sionp
rofi
les
,wefi
rstc
onc
aten
ateth
epr
ofil
esf
ore
ach
v
oxe
lfr
omth
efou
rsequ
enc
est
oge
the
r.F
ore
achs
equ
enc
eanda
tea
chv
oxe
l,w
e
N
h
avea1×4
1ve
cto
rofl
ong
itud
ina
lin
ten
sit
ies
,Si
lv.L
etI
ilvd
eno
teth
e1×1
64
N
d
imen
sion
alv
ect
oro
fth
efou
rcon
cat
ena
tedp
rofi
les
,Si
lv,f
romsub
jec
til
esi
on

landv
oxe
lv. M
orep
rec
ise
ly
,

N N N N
I
ilv={FLA
IRi
lv,T
1i ,T
lv 2
i ,PD
lv i
lv} (
5.1
)

th
and w
eind
exth
een
tri
esI
i (
lv j
), wh
erej=1,
...
,16
4isth
ej en
tryo
fth
e

c
onc
aten
atedv
ect
or.N
oteth
atw
efir
str
emo
veth
eme
anf
romth
econ
cat
ena
ted

p
rofi
lesandth
enp
erf
ormaPCAonth
esec
onc
aten
atedp
rofi
les
.Le
tφk d
eno
te

ekthPC
th ,wh
ereφk i
sal
soind
exedb
yj. Th
ere
lat
ion
shipb
etw
eenth
esc
ore

ekthPC
onth ,th
eon
e-d
imen
sion
alv
alu
eξi
lv(k)
,andth
eob
serv
edt
raj
ect
ory

f
orI
ilv(
j)i
s:

K
I
ilv(
j)= ξ
i (
lv k)
φk(
j). (
5.2
)
k=1

W
efo
cusonth
efir
stPC
, φ1,andth
esc
oreonth
isc
ompon
ent
,ξi
lv(1
). Th
efir
st

PCi
sfoundt
oid
ent
ifyin
ten
sit
ych
ang
esa
tth
evo
xel
-lev
elw
ith
inl
esi
ons
.Po
si
-

t
ivev
alu
eso
fξi
lv(1
)co
rre
spondt
oar
etu
rno
fth
evo
xelt
oin
ten
sit
yva
lue
scl
ose
r

t
oth
ato
fno
rma
l-app
ear
ingt
issu
eandn
ega
tiv
eva
lue
sofξ
i (
lv 1
)co
rre
spondt
o

1
37
th
evo
xel
sma
int
ain
ingin
ten
sit
yva
lue
scl
ose
rtoth
osea
tle
sionin
cid
enc
e. Th
is
b
iom
ark
er,ξ
i (
lv 1
),c
oll
aps
esth
efu
llp
rofi
lesa
tea
chv
oxe
lfr
omth
efou
rse
-

qu
enc
esin
toas
ing
les
cal
ar. W
eus
eth
esc
oreonth
efir
stPCinth
isan
aly
sis
,as
th
eoth
erPC
sexp
lainon
ly2
5%o
fth
eva
ria
tioninth
eda
tA,w
eren
otf
oundt
o

b
eas
soc
iat
edw
ithan
ybi
olo
gic
alp
roc
ess
es,anda
rethu
slik
elydu
etos
cann
er-

r
ela
tedando
the
rno
ise
.Toa
sse
ssth
eva
riab
il
ityinbo
thth
eme
anandth
efir
st
PC
,weboo
tst
rapth
isp
roc
edu
reb
yre
samp
lin
gsub
jec
tsw
ithr
epl
acem
ent1
000

t
ime
s[1
56]
.

5
.2.4
.2 Expe
rtv
alida
tiono
fbioma
rke
r

W
eus
eexp
ertv
al
ida
tiont
ode
term
ineth
equ
ali
tyo
fth
ele
siont
issu
ese
gmen
ta-

t
ion(
exc
lud
inged
ema
)asw
el
lasth
eab
il
ityo
fth
ebi
oma
rke
rtoid
ent
ifya
rea
s

o
fsl
ow,l
ong
-te
rmin
ten
sit
ych
ang
e.F
orth
isv
al
ida
tion w
eus
etw
ora
ter
s,a

n
eur
orad
iol
ogi
stw
ith1
1ye
arso
fre
sea
rchexp
eri
enc
ein MS(DSR
)andan
eu-

r
olo
gis
twi
th4y
ear
sofr
ese
archexp
eri
enc
ein MS(MKS
).F
ore
achl
esi
on,w
e

fi
rstd
ete
rmin
eth
eax
ials
li
ceo
fth
eim
ageth
atc
ont
ain
sth
ela
rge
stnumb
ero
f

v
oxe
lsw
ithabn
orm
als
ign
alin
ten
sit
y. Th
enf
ore
achl
esi
onth
etw
ora
ter
sar
e

p
res
ent
edth
efo
llow
ing
:(1
)th
efu
llax
ials
li
cef
orth
eFLA
IR,T
2, PD
,and
T
1vo
lum
esth
atc
ont
ain
sth
ela
rge
stnumb
ero
fvo
xel
swi
thabn
orm
als
ign
al

in
ten
sit
y;(
2)th
een
tir
eco
ll
ect
iono
flon
gitud
ina
lsc
ansf
orabo
xcon
tain
ingth
e

abn
orm
als
ign
alin
ten
sit
yinth
eFLA
IR,T
2,PD
,andT
1vo
lum
esf
orth
isax
ial

s
li
ce;(
3)th
ese
gmen
tat
iono
fth
ele
sionanded
emat
issu
ewi
thinth
isbo
x;(
4)

th
ebi
oma
rke
rfo
rth
evo
xel
sse
gmen
teda
sle
siont
issu
ewi
thinth
isbo
xanda

s
cal
efo
rth
ein
ten
sit
iesw
ith
inth
isim
age
;(5
)th
een
tir
eco
ll
ect
iono
flon
gitu
-
d
ina
lsc
ansf
orth
eFLA
IR,T
2,PD
,andT
1we
igh
tedv
olum
esw
ith
inth
isbo
x

1
38
w
ithth
esc
oref
orth
efir
stPCo
ver
laidonth
eim
age
sfo
rea
chs
cana
fte
rle
sion
in
cid
enc
e. Th
era
ter
sar
eth
ena
skedt
ora
teth
equ
ali
tyo
fth
ele
siont
issu
e

s
egm
ent
ati
onandth
ebi
oma
rke
rfo
rid
ent
ify
inga
rea
sofin
ten
sit
ych
ang
eson

anin
teg
ers
cal
efr
om1t
o4,w
ithe
achr
atin
gco
rre
spond
ingt
oth
efo
llow
ing
:
(
1)f
ail
ed m
ise
rab
ly;(
2)s
omer
ede
emin
gfe
atu
res
;(3
)pa
ssedw
ith m
ino
rer
ror
s;

and(
4)p
ass
ed. Ex
amp
leso
fth
eim
age
spr
esen
tedt
oth
era
ter
sfo
rea
chl
esi
on
th
atr
ece
ivedar
atin
gof1th
rou
gh4f
orth
esc
oreonth
efir
stPCb
ybo
thr
ate
rs

a
rep
rov
idedinth
eApp
end
ix.F
ort
y-s
evenl
esi
onsa
res
ele
cteda
trand
omt
obe

r
epe
atedinth
ean
aly
sist
oas
ses
sin
tra
-ra
terr
el
iab
il
ity
.

W
erepo
rtth
emed
iano
fth
era
tin
gso
fth
ele
sions
egm
ent
ati
onandth
e

b
iom
ark
erf
ore
achr
ate
rov
era
lll
esi
ons
.Toa
sse
ssb
etw
een
-ra
terandw
ith
in-

r
ate
rre
liab
il
ity
,wer
epo
rtth
eCoh
en’
sκc
oeffi
cien
tso
vera
llo
fth
ele
sion
sand

f
orth
ese
tofr
epe
atedl
esi
onsr
esp
ect
ive
ly
,fo
rbo
thth
era
tin
gofth
ebi
oma
rke
r

andth
ele
sions
egm
ent
ati
on. W
eal
sor
epo
r o
tκfrth
era
tin
gofth
ele
sion

s
egm
ent
ati
onandth
ebi
oma
rke
rfo
ral
lle
sion
s,f
ore
achr
ate
r,t
ode
term
inei
f

th
equ
ali
tyo
fth
ese
gmen
tat
ionandth
equ
ali
tyo
fth
ebi
oma
rke
rar
ere
lat
ed. W
e

n
onp
aram
etr
ica
llyboo
tst
rapb
ysub
jec
twi
thr
epl
acem
ent1
000t
ime
stop
rodu
ce

th
econfid
enc
ein
terv
alsf
orth
emed
iano
fth
era
tin
gsf
ore
achr
ate
randth
eκ

c
oeffi
cien
ts.

5
.2.4
.3 Reg
res
sion mode
l

Th
ecl
ini
calin
form
ati
onf
ore
achsub
jec
tth
atw
econ
sid
era
tea
chs
tudyv
is
it

c
ons
ist
sof MSd
ise
asesub
typ
e,a
ge,s
ex,anind
ica
toro
ftr
eatm
entw
iths
ter
oid
s,

anind
ica
toro
fdi
sea
se-m
odi
fyin
gtr
eatm
ent
,andd
ist
anc
etoth
ebound
aryo
f

ana
reao
fabn
orm
als
ign
alin
ten
sit
y. Anex
amp
leo
fdi
stan
cet
oth
ebound
ary

1
39
o
fana
reao
fabn
orm
als
ign
alin
ten
sit
ycanb
ese
eninth
esev
enthr
owo
fth
e
F
igu
re5
.2. W
ecen
tera
gea
tth
eme
ana
geo
f36y
ear
sov
era
llo
fth
evo
xel
-lev
el

ob
serv
ati
ons
. Du
rin
gth
eob
serv
ati
onp
eri
od,m
anyo
fth
esub
jec
tsw
ereen
rol
led

inc
lin
ica
ltr
ial
satN
INDSt
ote
stv
ari
ousexp
erim
ent
alth
erap
ies
. Ou
rind
ica
tor
o
fdi
sea
se-m
odi
fyin
gtr
eatm
entind
ica
test
rea
tmen
twi
than
yofth
eFoodand

D
rugAdm
ini
str
ati
on-
app
rov
edt
rea
tmen
ts,in
clud
ingin
ter
fer
onb
eta1
-a(
int
ra-
mu
scu
laro
rsub
cut
ane
ous
),in
ter
fer
onb
eta1
-b,andg
lat
iram
era
cet
ate
,asw
el
l

a
sexp
erim
ent
alth
erap
y.A
sman
yofth
eco
var
iat
esch
ang
eov
ert
ime
,wem
ode
l

th
ere
lat
ion
shipb
etw
eenth
ele
sionp
rofi
lesandth
eva
lueo
fth
eco
var
iat
eatth
e

t
imeo
fle
sionin
cid
enc
efo
rth
epa
rti
cul
arp
rofi
les
.Fo
rth
efo
llow
ingan
aly
sis
,

w
eha
veat
ota
lof5
7,9
08v
oxe
lsf
rom3
15l
esi
onsin3
4sub
jec
ts.

W
enowin
trodu
ceal
ine
arm
ixed
-eff
ect
smod
elt
ore
lat
eth
ebi
oma
rke
r,th
at

i
sth
esc
oreonth
efir
stPC
,toth
ecl
ini
calc
ova
ria
tes[
157
]. W
eus
eth
eva
lue

o
fth
eco
var
iat
eatth
etim
eofl
esi
onin
cid
enc
efo
rth
epa
rti
cul
arp
rofi
les
,wh
ich

c
anv
aryw
ith
insub
jec
t. Thu
s,f
oradd
edp
rec
is
ion
,th
eco
var
iat
esth
atch
ang
e

o
vert
imea
reind
exedb
yth
esub
jec
tind
exi
,le
sionind
exlandv
oxe
lind
ex

v,a
svo
xel
sfr
omth
esam
ele
sion m
ayh
aved
iffe
ren
ttim
eso
fin
cid
enc
e.F
or

ex
amp
le
,th
esexo
fth
esub
jec
tdo
esn
otch
ang
ebyt
imeo
fle
sionin
cid
enc
e,s
o

i
tison
lyind
exedb
yi.Inc
ont
ras
t,a
geo
fth
esub
jec
tch
ang
esw
ithv
oxe
lle
sion

in
cid
enc
eandi
sind
exedb
yi,landv. W
eal
soaddr
and
omeff
ect
sfo
rsub
jec
t

andl
esi
on, wh
ich w
eden
oteb
ybiandb
l,r
esp
ect
ive
ly
,wi
thbo
thf
oll
owin
ga
2 2
n
orm
ald
ist
ribu
ti :b
on i ∼ N(
0,σ
i)andb
l∼ N(
0,σ
l), wh
ereσ2 d
eno
testh
e

v
ari
anc
eofth
erand
omeff
ect
s. W
econ
sid
erth
efo
llow
ingb
asi
cmod
elf
orth
e

a
sso
cia
tionb
etw
eenth
ebi
oma
rke
r,ξ
i (
lv 1
),andth
eco
var
iat
es:

1
40
 ξ
i (
lv 1
)=β0+β1SPMSilv+β2 D
ist
anc
eilv+β3A
geilv+β4 (A
ge− 4
)+i
lv

+β5S
ter
oid
silv+β6M
alei+β7T
rea
tmen
tilv+b
i+b
l+ i
lv

W
eas
sum
eth
atth
eer
rort
erm
sar
eind
epend
entandid
ent
ica
llyd
ist
ribu
ted
,
2
w
ithe
achf
oll
owin
gan
orm
ald
ist
ribu
tion
, lv∼ N(
i 0,σ).Inth
emod
el
,th
e

t
ermSPMSi
sanind
ica
toro
fbe
ingd
iagn
osedw
ithSPMSwh
ereth
ecomp
ari
son
g
roupi
sbe
ingd
iagn
osedw
ithRRMS
.No
teth
atth
eag
ete
rmh
asb
eenc
ent
ered

a
tth
eme
ana
geo
f36y
ear
s. Th
ete
rm(A
ge− 4
) lv=A
+i geilv·
1(A
gelv>4
i )is

asp
lin
ete
rmf
orc
ent
ereda
geo
ver4y
ear
s(o
rag
eov
er4
0ye
ars
),wh
ichw
asin
-

c
lud
edinth
emod
ela
fte
rvi
sua
li
zin
gth
ere
lat
ion
shipb
etw
eenth
ebi
oma
rke
rand
a
ge. W
eal
soin
ves
tig
ateds
imp
lerm
ode
lsw
ithth
esam
emix
ed-
effe
ctss
tru
ctu
re,

bu
twh
erew
econ
sid
erede
achc
ova
ria
tes
epa
rat
ely
.

T
ote
stf
ora
sso
cia
tion
s,w
eus
etw
opr
ocedu
res
.Fi
rst
,wep
erf
ormap
ara
-

m
etr
icboo
tst
rapp
ingp
roc
edu
re[
156
],ands
econdw
eca
lcu
lat
ep-v
alu
esu
sin
g

an
orm
alapp
rox
ima
tionf
orth
edi
str
ibu
tiono
fth
efix
ed-
effe
ctsinth
emix
ed-

eff
ect
smod
el[
158
]. W
eus
e10
00boo
tst
raps
amp
lesf
orth
eboo
tst
rapp
roc
edu
re.

W
epe
rfo
rmth
epa
ram
etr
icboo
tst
rapb
ecau
ses
ter
oidu
seandd
ise
asesub
typ
e

o
fSPMSd
idn
ota
lwa
ysapp
earinn
onp
aram
etr
icboo
tst
raps
amp
les
. Ac
om-
p
let
ede
scr
ipt
iono
fth
isp
roc
edu
rei
sfoundinth
e App
end
ix. W
eal
sou
seth
e

n
orm
alapp
rox
ima
tion
,asth
isapp
rox
ima
tionh
asb
eenf
oundt
obear
eas
onab
le

app
rox
ima
tionf
orth
edi
str
ibu
tiono
fth
efix
ed-
effe
ctsin m
osts
ett
ing
s[1
58]
.

1
41
5
.2.5 Func
tion
-on
-sca
larreg
res
sion
s

Th
epr
evi
ousm
ode
lisana
ttemp
ttoc
oll
aps
eth
ein
form
ati
onf
romth
efou
r
p
rofi
les(
acr
osss
equ
enc
esandt
ime
)in
toas
ing
les
cal
ara
tea
chv
oxe
l.A
san

a
lte
rna
tiv
e,w
eal
sofi
tatw
o-s
tepfun
cti
on-
on-
sca
larr
egr
ess
ion m
ode
l[1
50]
,

wh
erew
ecanin
ves
tig
ateth
ere
lat
ion
shipb
etw
eenth
eco
var
iat
eso
fin
ter
estand
th
epr
ofil
eate
acht
imepo
int
. W
efitafun
cti
on-
on-
sca
larr
egr
ess
ion m
ode
l

f
ore
achs
equ
enc
esep
ara
tely
.Fo
rsimp
li
cit
yofn
ota
tion
,wen
owu
setf
orth
e

r
egi
ste
redt
ime
,asoppo
sedt
ot. Th
eou
tcom
einth
emod
eli
sth
efu
lll
esi
on

in
ten
sit
ypr
ofil
e:

N
Si
lv(t
)=β0(
t)+β1(
t)SPMS
ilv+β2(
t)D
ist
anc
eilv+β3(
t)A
gei
lv

+β4(
t)(A
ge− 4)
+ilv+β5(
t)S
ter
oid
slv+β
i 6(
t)M
ale
i

+β7(
t)T
rea
tmen
tlv+
i lv(
i t)

f
orS=FLA
IR,T
1,T
2,andPD
.Tofi
tth
emod
el
,weu
seatw
o-s
tepfun
cti
on-

on
-sc
ala
rre
gre
ssi
onimp
lem
ent
edinth
eRp
ack
ager
efund[
159
]. Th
epr
ocedu
re
fi
rstfi
tsas
cal
ar-
on-
sca
larr
egr
ess
iona
tea
chind
ividu
alt
imepo
int
. Th
enth
e

r
esu
lt
ingc
oeffi
cien
tfun
cti
onsa
resm
ooth
edo
vert
imeu
sin
gacub
icsp
lin
eba
sis

w
ithanau
tom
ati
cal
lys
ele
ctedp
ena
ltyonth
ese
condd
eriv
ativ
e.

T
oas
ses
sth
eva
riab
il
ity
inth
eco
effic
ien
tfun
cti
onsandp
rov
ideboo
tst
rapp
ed,

po
int
-wi
se9
5%c
onfid
enc
ein
terv
als
,wen
on-p
aram
etr
ica
llyboo
tst
rapb
ysub
-

j
ectu
sin
g10
00r
esamp
ledd
ata
set
s. Wh
ens
amp
lesd
ono
tcon
tainsub
jec
ts
w
ithac
ova
ria
te,f
orex
amp
leth
eind
ica
toro
fst
ero
ids
,wer
emo
veth
iss
amp
le

1
42
f
romth
eboo
tst
rapandr
epl
acei
twi
than
oth
ers
amp
le
. Th
ediff
eren
ceb
etw
een
th
efun
cti
on-
on-
sca
larr
egr
ess
ionandth
ePCAr
egr
ess
ion m
ode
listh
atPCA

c
oll
aps
esth
een
tir
etempo
ralin
ten
sit
ypr
ofil
eofth
evo
xelin
toas
cal
ar. By

c
ont
ras
t,th
efun
cti
on-
on-
sca
larr
egr
ess
ionin
ves
tig
ate
sth
eas
soc
iat
iona
tev
-
e
ryt
imepo
int
. Wh
il
efun
cti
on-
on-
sca
larr
egr
ess
ioni
smo
rec
omp
reh
ens
iveand

in
terp
ret
abl
e,i
tism
oreapp
rop
ria
te wh
enth
erea
res
tron
gfun
cti
ona
leff
ect
s
th
ata
ren
otc
aptu
redb
yasm
allnumb
ero
fpr
inc
ipa
lcompon
ent
s,du
etoth
e

po
ten
tia
lfo
rde
cre
aseds
tat
ist
ica
lpow
er

5
.3 Re
sul
ts

5
.3.1 P
rinc
ipa
lcomponen
tana
lys
isandreg
res
sion

5
.3.1
.1 B
ioma
rke
r

InF
igu
re5
.4Aw
esh
owth
eme
anp
rofi
lesf
ore
achs
equ
enc
eov
erth
ere
gis
-

t
ered2
00d
ayp
eri
od,andinF
igu
re5
.4Bw
esh
owth
efir
stPC
,φ1,f
ore
ach

s
equ
enc
eov
erth
ere
gis
ter
ed2
00d
ayp
eri
od,wh
ereth
efir
stPCi
sdiv
idedin
to

d
iffe
ren
tsequ
enc
esf
orpu
rpo
seso
fpr
esen
tat
ion
. Th
esubfi
gur
esf
orbo
thth
e
m
eanandth
efir
stPCsh
owth
eboo
tst
rapp
ed9
5%c
onfid
enc
ein
terv
als
. Th
e

fi
rstPCexp
lain
s75%(
95%C
I:[
72%
,76%
])o
fth
eva
ria
tioninth
econ
cat
ena
ted

l
ong
itud
ina
lpr
ofil
es.

T
oin
terp
retth
ePC
s,w
ere
cal
lth
atth
eno
rma
li
zat
ionp
roc
edu
repu
tsth
e

v
olum
esin
toun
itso
fst
and
ardd
evi
ati
onsabo
veth
eme
ano
fth
eNAWM
.Th
ere
-
f
oreav
alu
eof0onth
eim
agec
orr
espond
stoth
eav
era
gev
alu
eofNAWMf
rom

th
epa
rti
cul
ar MR
Isc
an. Th
eme
anp
rofi
lesf
orth
eFLA
IR,T
2,andPDa
re

1
43
a
llabo
ve0th
rou
ghou
tth
etim
ecou
rse
,asl
esi
onsa
reh
ype
rin
ten
seonth
eses
e-
qu
enc
es.Inc
ont
ras
t,th
eme
anp
rofi
lef
orth
eT1s
equ
enc
eisb
elow0
,asl
esi
ons

a
reh
ypo
int
ens
eonth
iss
equ
enc
e. Th
efir
stPCf
orth
eFLA
IR,T
2,andPDi
s

n
ega
tiv
eth
rou
ghou
tth
etim
ecou
rse
,wi
thv
alu
esc
los
ert
o0a
tle
sionin
cid
enc
e
(
tim
e0)
.Po
sit
ives
cor
esonth
isPCind
ica
tead
ecr
eas
einth
esi
gna
linth
ese

s
equ
enc
es,wh
ichc
orr
espond
stoar
etu
rno
fth
evo
xelt
oin
ten
sit
yva
lue
scl
ose
r
t
oth
ato
fno
rma
l-app
ear
ingt
issu
e. Inc
ont
ras
t,n
ega
tiv
esc
ore
sind
ica
teth
e

v
oxe
lma
int
ain
ingin
ten
sit
yva
lue
scl
ose
rtoth
osea
tle
sionin
cid
enc
e,w
ith m
ore

h
ypo
int
ens
ityth
anth
eav
era
gep
rofi
le
.Sim
ila
rly
,fo
rT1th
efir
stPCi
spo
sit
ive

th
rou
ghou
tth
etim
ecou
rse
,wi
thv
alu
esc
los
ert
o0a
tle
sionin
cid
enc
e.P
osi
tiv
e

s
cor
esonth
isPCind
ica
tein
cre
aseds
ign
alonth
eT1
.Asl
esi
onsa
reh
ypo
int
ens
e

onth
eT1
,th
isa
lsoind
ica
tesar
etu
rno
fth
evo
xelt
oin
ten
sit
yva
lue
scl
ose
rto

th
ato
fno
rma
l-app
ear
ingt
issu
e.N
ega
tiv
esc
ore
sag
ainc
orr
espondt
oth
evo
xel
s

m
ain
tain
ingin
ten
sit
yva
lue
scl
ose
rtoth
osea
tle
sionin
cid
enc
e.

W
eth
ere
for
econ
sid
erth
esc
oreonth
efir
stPCt
obeab
iom
ark
ero
fin
ten
sit
y

ch
ang
esw
ith
inth
ele
siona
tth
evo
xell
eve
l.Inth
ela
str
owo
fFi
gur
e5.
2wes
ee

th
ePCs
cor
eso
rth
ebi
oma
rke
rfr
omth
ele
sionth
ati
ssh
owninth
efigu
re. W
e

s
eeth
atth
epo
sit
ives
cor
esind
ica
tea
rea
softh
ele
sionth
atr
etu
rnt
ova
lue
sof

n
orm
al-
app
ear
ingt
issu
e, wh
il
eth
ene
gat
ives
cor
essh
owa
rea
sth
atr
ema
ina
t

th
ein
ten
sit
yva
lue
satl
esi
onin
cid
enc
e.

5
.3.1
.2 Expe
rtv
alida
tiono
fbioma
rke
r

W
eus
eexp
ertv
al
ida
tiont
ode
term
ineth
equ
ali
tyo
fth
ele
sions
egm
ent
ati
on(
ex-

c
lud
inged
emat
issu
e)andth
eab
il
ityo
fth
ebi
oma
rke
rtoid
ent
ifya
rea
sofs
low
,
l
ong
-te
rmin
ten
sit
ych
ang
e. Th
edi
str
ibu
tion
softh
era
tin
gsf
orth
etw
ora
ter
s

1
44
f
orbo
thth
ele
sions
egm
ent
ati
onandth
ebi
oma
rke
rar
esh
owninF
igu
re5
.5.
Th
efir
str
owo
fpl
otsinF
igu
re5
.5sh
owsth
edi
str
ibu
tiono
fth
era
tin
gsf
orth
e

l
esi
ons
egm
ent
ati
onandth
ese
condr
owsh
owsth
era
tin
gsf
orth
ebi
oma
rke
r.

P
lot
sinth
ele
ftc
olumna
rer
atin
gsb
yth
eneu
ror
adi
olo
gis
t,andp
lot
sonth
e
r
igh
tco
lumna
rer
atin
gsb
yth
eneu
rol
ogi
st. Th
emed
ianr
atin
gfo
rbo
thth
e

l
esi
ons
egm
ent
ati
onandth
ebi
oma
rke
rbyth
eneu
ror
adi
olo
ista
re4(
95% C
I:
[
4,4
])
, wh
ichi
sar
atin
gofp
ass
ed,th
ehi
ghe
stpo
ssib
ler
atin
g. Th
emed
ian

r
atin
gfo
rbo
thth
ele
sions
egm
ent
ati
onandth
ebi
oma
rke
rbyth
eneu
rol
ogi
st

a
re3(
95%C
I:[
3,3
])
,wh
ichi
sar
atin
gofp
ass
edw
ith m
ino
rer
ror
s.N
oteth
at

c
rit
eri
afo
ras
sign
ings
cor
esw
eren
otd
iscu
ssedb
etw
eenth
etw
ora
ter
spr
iort
o

th
eirr
esp
ect
ivean
aly
ses
.

Th
eκc
oeffi
cien
tsf
orth
ewi
thin
-andb
etw
een
-ra
tera
gre
emen
tfo
rbo
thth
e

l
esi
ons
egm
ent
ati
onandth
esc
ore
sonth
ebi
oma
rke
rar
esh
ownin T
abl
e5.
1.

Th
eva
lue
sfo
rth o
eκceffi
cien
tran
geb
etw
een0and1
,wi
thav
alu
eof1ind
ica
t-

in
gto
tala
gre
emen
tand0ind
ica
tin
gnoa
gre
emen
t. Th
ewi
thin
-ra
tera
gre
emen
t

f
orth
ele
sions
egm
ent
ati
onandth
esc
oreonth
ebi
oma
rke
rar
ehi
ghe
rfo
rth
e

n
eur
orad
iol
ogi
stth
anth
eneu
rol
ogi
st. Th
erei
son
ly m
ode
sta
gre
emen
tbe
twe
en

th
eneu
ror
adi
olo
gis
tandn
eur
olo
gis
tonbo
thr
atin
gs,w
ithaκc
oeffi
cien
tof0
.29

(
95%C
I:[
0.1
8,0
.41
])f
orth
ele
sions
egm
ent
ati
onand0
.24(
95%C
I:0
.11
,0.
39)

f
orth
esc
oreonth
ebi
oma
rke
r. Th
isi
sdu
e,inp
art
,toth
efa
ctth
atth
eneu
rol
-

o
gis
tsp
readr
atin
gso
fth
estud
iesb
etw
een3and4
,wh
il
eth
eneu
ror
adi
olo
gis
t
g
avem
orer
atin
gso
f4.

Th
eκc
oeffi
cien
tfo
rth
eag
reem
entb
etw
eenth
era
tin
gofth
ele
sions
egm
en-

t
ati
onandth
ebi
oma
rke
ris0
.97(
95%C
I:0
.93
,1.
00)f
orth
eneu
ror
adi
olo
gis
t
and0
.68(
95%C
I:0
.58
,0.
78)f
orth
eneu
rol
ogi
st. Th
ehi
ghc
orr
ela
tionb
etw
een

1
45
th
eser
atin
gs,e
spe
cia
llyf
orth
eneu
ror
adi
olo
gis
t,ind
ica
testh
atth
equ
ali
tyo
f
th
ese
gmen
tat
ionimp
act
sth
equ
ali
tyo
fth
era
tin
gofth
ebi
oma
rke
r.C
omm
ent
s

f
romth
era
ter
smi
rro
redth
isfind
ing
,asm
anyo
fth
elows
cor
esf
orbo
thth
e

l
esi
ons
egm
ent
ati
onandth
ebi
oma
rke
rwe
redu
eto
:(1
)mi
ssin
gth
efir
stt
ime
po
into
fle
sionin
cid
enc
eands
egm
ent
ingi
tasn
ewl
esi
ona
tal
ate
rtim
epo
int
;

(
2)n
ots
egm
ent
ingth
een
tir
ele
sion
;and(
3)p
art
softh
esam
ele
sionb
ein
g
s
egm
ent
ed(unn
ece
ssa
ri
ly)a
tdiff
eren
ttim
epo
int
s.A
sbo
thth
era
tin
gsf
orth
e

l
esi
ons
egm
ent
ati
onandth
esc
oreonth
ebi
oma
rke
rwe
reh
igh
,th
equ
ali
tyo
fth
e

l
esi
ons
egm
ent
ati
ond
oesn
otapp
eart
oben
ega
tiv
elyimp
act
ingth
eme
thod
.

1
46
 F
LAIR T2 PD T1

T
ime 98 119 175 210 238 266 280 343

F
LAIR

T2

PD

T1

Edema
Segmen
tat
ion Les
ion

D
is
tan
ce 6vo
xel
s

0vo
xel
s

PC1S
cor
e 35
B
ioma
rke
r 0

-54

Figure5 .2
: Th efirstrowo fth efi gureshow sanax ialsli
cef romth e mult
iple
MR Isequences
,1 75d aysa f
terb a
seline(froml e
fttoright,theFLA IR ,T 2
,PD ,
andT 1sequences
).Ine a chs equenc e
,ar edbo xshowsana r
eaw ithal e
sionthat
developsdu r
ingth efo
llow -upp er
iod.Inth esubsequentr owso fthefi gur
e,w e
sh owth elong
itudinalb ehavi o
rw ithinth i
sr edbo x
.E achcolumno fth efigure
representsad iffe
rent MR Is tudy,s tar
tinga t9 8da y
sa fte
rb a
s e
lineinth efar
leftc o
lumnandg o
ingun t
il3 4 3d aysafterb a
sel
ine. Al es
ioni sfi rstident
ified
inth isareaat1 75d ays. Th efi rstfourr owssh owth elongitudinalb ehav
iorof
theFLA IR,T 2,PD ,andT 1s equen c
es. Then extrowsh ow sth esegm entat
ion
oftheed emaandl e
siont issue. Th ef o
llowingr owsh owsth ed istancetoth e
bound aryofabn orm a
l MR Is igna
l.T 14
h
e7las
tr owsh owsth es coreonth efirst
PC,wh ichidentifiesareaso fl es
ionr epairandp erm anentd am age.
 ty FLA
IR T
empo
ral
lyReg
iste
redFLA
IR

ty
i

i
tens

tens
10 D
is
tancetoBounda
ry

10
Inc
idence
Sma
l
les
t La
rge
st
izedin

izedin
5

5
l

l
rma

rma
0

0
no

no
0 200 400 600 0 50 100 150 200
t
ime(
inda
ys) t
imef
romle
sioninc
idence(
inda
ys)

T2 T
empo
ral
lyReg
iste
redT2
ty

ty
i

i
tens

tens
Inc
idence D
is
tancetoBounda
ry
5 10

5 10
Sma
l
les
t La
rge
st
izedin

izedin
l

l
rma

rma
0

0
no

no
0 200 400 600 0 50 100 150 200
t
ime(
inda
ys) t
imef
romle
sioninc
idence(
inda
ys)

PD T
empo
ral
lyReg
iste
redPD
y

y
10

10
t

t
i

i
s

Inc
idence D
is
tancetoBounda
ry
ten

ten

Sma
l
les
t La
rge
st
zedin

zedin
5

5
0

0
i

i
l

l
rma

rma
−5

−5
no

no

0 200 400 600 0 50 100 150 200

t
ime(
inda
ys) t
imef
romle
sioninc
idence(
inda
ys)

T1 T
empo
ral
lyReg
iste
redT1
y

y
t

t
i

i
s

s
2

2
ten

ten
zedin

zedin
−2

−2
i

i
l

l
rma

rma

D
is
tancetoBounda
ry
−6

−6

Inc
idence Sma
l
les
t La
rge
st
no

no

0 200 400 600 0 50 100 150 200

t
ime(
inda
ys) t
imef
romle
sioninc
idence(
inda
ys)

F
i gure5 .
3: Th efi rstc o
lumno fth efi gureshow sth efulllon g
itudinalprofil
e s
froma l
lf ours equ en
ces( f
romt opt obottom ,th e FLA IR,T 2
, PD ,and T 1
sequen ce
s). Thep rofi
lesarefrom1 50r andomlys amp ledv oxel
sfr omthelesion
inF igu r
e5 .2,andf ordisplaypu rpo s
esth ep er
iodsb e
tw eene achstudyh ave
beenl inea
rlyin terpolat
ed. E achl ineinth ep lotr epresentsthel ongi
tudinal
profilefromas in glevoxel
. Th ex-axissh owsthetim eind a y
sf r
omth esubje
ct’s
base
lin evis
it,th etimeo fles
ionin cidenceisd enotedb yad ashedline,andth e
y-ax
issh ow sthen o
rm a
lizedsequen ceintens
iti
e s
. Th esecondc olumnsh owsth e
sam ev oxe
lsa f
tert empo ra
la l
ignm entandl inearinterpolationo v
e rthe200d ay
peri
oda f
terin c
id ence
,th etim ep eriodu s
edinth i san a
ly s
is. Thep rofil
esa re
color
edb yd i
stan cetoth ebound aryo fabn o
rm al MR Isign a
l.

1
48
 A B
Mean PC1

.10
0
ty
4
i
tens

FLA
IR
izedin

.00
2

T2
PD
0
l
rma

T1
0
no

.10
−2

−0

0 50 100 150 200 0 50 100 150 200

t
imef
romles
ioninc
idence(
inda
ys) t
imef
romles
ioninc
idence(
inda
ys)

F
i gu
re5.4
:P anelAo fthefi guresh owsthem eanprofilesforeachofth eim ag
in g
sequenc
eso ve
rth eregis
t e
red2 00d ayperiod,andp ane
lBsh owsth efi rs
tPC
foreachoftheim ag
ings equence
s. Th efir
stPCexp l a
in s7 5%ofthev ari
ationin
theconcaten
atedlongitudina
lp rofile
s.Alon gthex
- axisforbothplotsisplotted
thetimeind ayssincelesiond e
t e
ction
. Th e95%c onfid enc
eintervalsinbo th
pane
lsareob ta
inedusing1 000n onparametricboo
ts trapedsamples.

1
49
 Neu
ror
adio
log
is
t Neu
rolog
is
t
4 84
.2% 4 35
.2%

L
esion 3 7
.2% 3 35
.9%

Segmenta
tion2 3
.9% 2 17
.8%

1 4
.6% 1 11
.2%
0

50

100

150

200

250

300

50

100

150

200

250

300
Numbe
rofS
tud
ies Numbe
rofS
tud
ies

4 84
.2% 4 39
.8%

B
iom
arke
r 3 7
.2% 3 34
.2%

2 3
.6% 2 11
.2%

1 4
.9% 1 14
.8%
0

50

100

150

200

250

300

50

100

150

200

250

300
Numbe
rofS
tud
ies Numbe
rofS
tud
ies

fa
i
led mise
rab
ly(1) passedwi
th m
ino
rer
rors(3
)
someredeemingfea
tures(2
) passed(4
)

F
igure5.5
: Th efirstrowo fplotsshowsthedi s
tributionsofth eratingsfo
rth e
l
esi
ons egm en
tati
on,andth esecondrowsh ow sth er a
tingsforth ebiomarker
.
P
lot
sinth el e
ftcolumna rer at
ingsbyth en euroradiolog
ist
,andp lotsonthe
r
ightc o
lumna rer at
ingsb ythen eur
ologis
t.E achp lotsh owsth enumb erof
s
tudiesthatfa
iled mi
serably(1),hadsom eredeem ingfe a
tures(2),p a
ssedwith
m
inorerror
s( 3
),andp a
ssed( 4
)a l
ongw i
thth ep ercentageofe achr a
ting
.

1
50
 L
esionSegment
ation B
iom a
rker
Neuro
radio
log
ist N euro
log
ist N
euro
radio
log
ist N euro
log
ist
N
eur
orad
iolog
ist 0.92
;(0.
76,0
.99) 0. 2
9;(0.
18,0.
41 .
) 092
;(0.
76,0.99
) 0. 2
4;(0.
11,0.
39)

1
N
eur
olog
ist 0
. 7
5;(0.
62,0.
86) 0
. 7
2;(0.
51,0.
86)

51
Tab
le5.1
: Thetabl
eonth ele
ftshowstheκc oeffic
ientsfo
rtheles
ionse
gm ent
ation
,andthetab
leontheri
ghtsh
ows
thesameforthebiom a
rker
. Thebe
tw e
en-ra
teragr
e emen
tisrepor
tedusingal
lles
ion
s. Thewi
thin
-ra
teragr
eemen
t
isrepo
rtedusin
gon lythefor
ty-
sev
enr ep
eatedl
esions
.
5
.3.1
.3 Reg
res
sion mode
l

PCAReg
ress
ionCoe
ff
ic
ien
ts
SPMS D
istancetoBounda
ry Age Sp
lineAge>4
5

5
*
*
−15 −5

−15 −5

−15 −5

−15 −5
* *

S
tero
ids Ma
le T
rea
tmen
t

* * * *
5

5
Un
ivar
iate
−15 −5

−15 −5

−15 −5
Mu
lt
iva
riate

F
igure5.6: Th
isfi guresh owsbarplot
softhecoeffi c
ien test
im a
tesfromth euni
-
va
riateandmu l
tivar
iatem ixed
-effectsmode
lswithth ebiom ark
erasanou tcome
.
Theresu
ltsfromth eun ivar
iat
em ode
lareshowninb lue,andth eresu
ltsfrom
the mul
tivar
iatem od e
la reshowning re
en. Asteri
sk sindica
tesignificanc
ea t
the5%l eve
l.Inbo thth euniv
ariateandmult
ivari
atem ode
ls,dis
e a
se-modi
fying
ther
ap y
,stero
ids,anda g
ew erefoundtobesignificant.

W
efitbo
thun
iva
ria
teand mu
lt
iva
ria
tem
ixed
-eff
ect
smod
elst
oin
ves
tig
ate

th
ere
lat
ion
shipb
etw
eenth
eco
var
iat
esandth
ebi
oma
rke
r. Th
ees
tim
ate
sof

th
eco
effic
ien
tsf
rombo
th m
ode
lsa
resh
owninth
eba
rpl
otsin F
igu
re5
.6,

w
itha
ste
risk
sind
ica
tin
gst
ati
sti
cals
ign
ific
anc
eatth
e5%l
eve
lus
ingth
eboo
t-

s
trapp
ed9
5%c
onfid
enc
ein
terv
als
.Tab
lesc
ont
ain
ingth
eco
effic
ien
tes
tim
ate
s,

s
tand
arde
rro
rs,t
-st
ati
sti
cs,p
-va
lue
sus
ingth
eno
rma
lapp
rox
ima
tion
,and9
5%

boo
tst
rapp
edc
onfid
enc
ein
terv
alsc
anb
efoundinth
e App
end
ixf
orbo
thth
e

un
iva
ria
teandth
e mu
lt
iva
ria
tem
ode
ls
. Th
erea
ren
odiff
eren
cesinth
econ
-

c
lus
ion
sde
term
inedb
yth
eno
rma
lapp
rox
ima
tionandth
eboo
tst
rapp
ed9
5%

c
onfid
enc
ein
terv
als
.Fo
rcon
tinu
ousc
ova
ria
tes
,su
cha
sag
e,th
eco
effic
ien
tis

1
52
in
terp
ret
eda
sth
eexp
ect
edch
ang
einth
ebi
oma
rke
rfo
raon
eun
itin
cre
asein
th
eco
var
iat
e.F
orb
ina
ryv
ari
abl
es,su
cha
sdi
sea
sesub
typ
e,th
eco
effic
ien
tis

in
terp
ret
eda
sth
ediff
eren
ceinth
eexp
ect
edch
ang
einth
ebi
oma
rke
rinth
e

sp
ecifi
edg
roup
. Th
ere
for
e,po
sit
ivec
oeffi
cien
tsa
reind
ica
tiv
eofth
evo
xelr
e-
tu
rnin
gtoin
ten
sit
yva
lue
scl
ose
rton
orm
al-
app
ear
ingt
issu
ewi
thanin
cre
ase

inth
eco
var
iat
e, wh
il
ene
gat
ivec
oeffi
cien
tsa
reind
ica
tiv
eofth
evo
xelm
ain
-
t
ain
ingth
ein
ten
sit
iesa
tle
sionin
cid
enc
ewi
thanin
cre
aseinth
eco
var
iat
e(o
r

ins
omer
arec
ase
sha
vin
gin
ten
sit
iesth
ath
aveanin
cre
asin
gdep
artu
ref
rom

th
oseo
fno
rma
l-app
ear
ingt
issu
eov
ert
imew
ithanin
cre
aseinth
eco
var
iat
e).

Th
ere
sul
tsind
ica
teth
atv
oxe
lsth
ata
ref
arth
eraw
ayf
romth
ebound
aryh
ave

in
cre
asedr
iskf
orm
ain
tain
ingabn
orm
als
ign
alin
ten
sit
y.Inth
ism
ode
l,th
eco
-

effi
cien
tfo
rdi
stan
cet
oth
ebound
aryh
asav
alu
eof-
9.4(
95%C
I:[
-9.
6,-
9.3
]),

ind
ica
tin
gth
atf
oraon
evo
xel(
or1mm)in
cre
aseind
ist
anc
eaw
ayf
romth
e

bound
ary(
tow
ardth
ecen
tero
fth
ele
sion
)th
eav
era
gev
alu
eofth
ebi
oma
rke
r
d
ecr
eas
esb
y9.
4,ad
jus
tin
gfo
rth
eoth
erc
oeffi
cien
tsandth
erand
omeff
ect
s.In

th
ela
str
owo
fFi
gur
e5.
2,w
ese
eth
issp
ati
alr
ela
tion
shipb
etw
eenth
ebi
oma
rke
r

andth
edi
stan
cet
oth
ele
sionbound
ary
,wi
thpo
sit
ives
cor
esn
earth
ebound
ary

andn
ega
tiv
esc
ore
sne
arth
ecen
tero
fth
ele
sion
.Inbo
th m
ode
ls
,wef
oundth
e

u
seo
fdi
sea
se-m
odi
fyin
gtr
eatm
entands
ter
oid
stob
eas
soc
iat
edw
ithr
etu
rno
f

av
oxe
ltoth
eva
lueo
fno
rma
l-app
ear
ingt
issu
e. Th
eco
effic
ien
tfo
rtr
eatm
ent
h
asav
alu
eof5
.4(
95% C
I:[
4.7
,6.
1])
,ind
ica
tin
gth
at wh
ensub
jec
tsa
reon

t
rea
tmen
tth
eav
era
gev
alu
eofth
ebi
oma
rke
rin
cre
ase
sby5
.4,ad
jus
tin
gfo
r

th
eoth
erc
oeffi
cien
tsandth
erand
omeff
ect
s. Th
eus
eofs
ter
oid
sha
sas
imi
lar
in
terp
ret
ati
on,w
ithac
oeffi
cien
tva
lueo
f4.
3(9
5%C
I:[
2.7
,5.
9])
.

1
53
5
.3.2 Func
tion
-on
-sca
larreg
res
sion

Th
ere
sul
tin
gco
effic
ien
tfun
cti
onsf
romth
efun
cti
on-
on-
sca
larr
egr
ess
ionw
ith
boo
tst
rapp
ed,po
int
-wi
se9
5%c
onfid
enc
ein
terv
alsw
ithth
eFLA
IRp
rofi
lea
s

th
eou
tcom
ear
esh
owninF
igu
re5
.7.S
imi
larfi
gur
esf
orm
ode
lsw
ithth
eT2
,

PD
,and T
1pr
ofil
esa
rep
rov
idedinth
e App
end
ix. Th
eco
effic
ien
tfun
cti
ons
f
orc
ont
inu
ousv
ari
abl
esinth
efun
cti
on-
on-
sca
larr
egr
ess
ion m
ode
lar
ein
ter
-

p
ret
eda
sth
ech
ang
einth
eexp
ect
edp
rofi
lea
tea
cht
imepo
intf
oraon
eun
it

in
cre
aseinth
eco
var
iat
e.S
imi
lar
ly
,fo
rbin
aryv
ari
abl
es,th
eco
effic
ien
tfun
cti
on

i
sin
terp
ret
eda
sth
ech
ang
einth
eexp
ect
edp
rofi
lef
orth
esp
ecifi
edg
roup
.Fo
r
th
eFLA
IRp
rofi
les
,th
eco
effic
ien
tfun
cti
onsc
orr
espond
ingt
odi
stan
cet
oth
e

bound
aryanda
geh
aveboo
tst
rapp
ed9
5%c
onfid
enc
ein
terv
alsth
atd
ono
tov
er-

l
apw
ith0a
cro
ssan
yofth
etim
epo
int
s,anda
reth
ere
for
est
ati
sti
cal
lys
ign
ific
ant

a e.
tth 0
5lev
el
. Th
eco
effic
ien
tfun
cti
onf
ord
ist
anc
etoth
ebound
aryi
sgr
eat
er

th
an0th
rou
ghou
tth
een
tir
etr
aje
cto
ry,ind
ica
tin
gth
atth
efa
rth
eraw
ayf
rom

th
ebound
aryth
evo
xeli
s,th
emo
reth
eFLA
IRh
ype
rin
ten
sit
yism
ain
tain
ed
w
ith
inth
evo
xel
.Fo
raon
evo
xel(
or1mm)in
cre
aseind
ist
anc
eaw
ayf
romth
e

bound
ary(
tow
ardth
ecen
tero
fth
ele
sion
)th
eav
era
gen
orm
ali
zedin
ten
sit
yof
th
etr
aje
cto
ryin
cre
ase
sbya
r .
ound05a
tal
ltim
epo
int
s,ad
jus
tin
gfo
rth
eoth
er

c
oeffi
cien
tsandth
erand
omeff
ect
s. Th
ere
sul
tfo
rdi
stan
cef
romth
ebound
ary

a
gre
esw
ithth
ere
sul
tsf
romth
ePCAr
egr
ess
ion m
ode
l.

1
54
 FLA
IRFunc
t
ion−on−Sca
larCoe
ff
ic
ien
ts
In
tercep
t SPMS D
istancef
romBounda
ry

.5

.5
5

1
4

.5

.5
t

t
ien

ien

ien
0

0
3
ic

ic

ic
f

f
f

f
coe

coe

coe
2

.5

.5
−0

−0
1

.5

.5
0

−1

−1
0 50 100 150 200 0 50 100 150 200 0 50 100 150 200
t
ime(
inda
ys) t
ime(
inda
ys) t
ime(
inda
ys)

Age Sp
lineAge>40 S
tero
ids
.5

.5

.5
1

1
.5

.5

.5
t

t
ien

ien

ien
0

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ic

ic

ic
f

f
f

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coe

coe

coe
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−1

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0 50 100 150 200 0 50 100 150 200 0 50 100 150 200
t
ime(
inda
ys) t
ime(
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ime(
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Ma
le T
rea
tmen
t
.5

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t

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ien

ien
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ic

ic
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0 50 100 150 200 0 50 100 150 200

t
ime(
inda
ys) t
ime(
inda
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F
i gur
e5.7:E achda
rkliner epre
sent
sthec oefficien
tfuncti
on,andth esh aded
arearep
resent
saboo t
strapped,point
-wi
se9 5%c onfidenc
einterva
l.A l
on gthe
x-ax
isofe a
chp l
oti
sth etim eindaysfromles
ionin c
idence
.A longthey -axi
s
isthev a
lueofthecoeffi c
ientfunct
ionate a
cht imepoint
. Onlyd i
stancefrom
thebound a
ryanda gew er
ef oundtob ediffer
entfor0a tan ypointalongth e
profil
e.

5
.4 D
iscu
ssion

W
ein
trodu
cetw
omod
elst
ore
lat
ecl
ini
calin
form
ati
ont
oth
elon
gitud
ina
lin
ten
-

s
ityp
rofi
lesinl
esi
ont
issu
efr
omc
onv
ent
ion
al MR
Isequ
enc
es. Th
efir
stm
ode
lis

1
55
th
ePCAr
egr
ess
ion m
ode
l,wh
erew
eco
llap
seth
elon
gitud
ina
l, mu
lt
i-
sequ
enc
e
MR
Iin
form
ati
onin
toab
iom
ark
ero
fsl
ow,l
ong
-te
rmin
ten
sit
ych
ang
esw
ith
in

th
ele
siona
tth
evo
xel
-lev
elandth
enr
ela
teth
ist
ocl
ini
calin
form
ati
on. W
e

v
al
ida
teth
eab
il
ityo
fth
ebi
oma
rke
rtod
ete
ctth
esein
ten
sit
ych
ang
esu
sin
gan
exp
ertr
ate
rtr
ial
. Th
ese
cond m
ode
listh
efun
cti
on-
on-
sca
larr
egr
ess
ion m
ode
l,

wh
ichr
ela
tese
achl
ong
itud
ina
lin
ten
sit
ypr
ofil
ess
epa
rat
elyt
oth
ecl
ini
calin
-
f
orm
ati
onanda
llow
sfo
ras
ses
smen
tofth
etim
epo
int
sin wh
ichth
ecl
ini
cal

in
form
ati
oni
simp
act
ingth
epr
ofil
es. Th
eme
thod
olo
gyp
res
ent
edh
eresh
ows

p
rom
isef
orbo
thund
ers
tand
ingth
etim
ecou
rseo
fti
ssu
edam
agein MSand

f
orev
alu
atin
gth
eimp
acto
fneu
rop
rot
ect
iveo
rrep
ara
tiv
etr
eatm
ent
sfo
rth
e

d
ise
ase
. Th
ebi
oma
rke
rma
ybep
art
icu
lar
lyu
sefu
linc
lin
ica
ltr
ials
ett
ing
s,a
s

i
tiss
ens
it
ivet
oth
eeff
ect
sofd
ise
ase
-mod
ify
ingth
erap
iesandsh
owsimp
res
-

s
ivep
erf
orm
anc
einexp
ertv
isu
alv
al
ida
tion
.Re
liab
lem
eth
odst
oev
alu
atesu
ch

t
rea
tmen
ts,wh
icha
recu
rren
tlyund
erd
eve
lopm
ent
,ar
ela
ckin
gatp
res
ent
.In

c
ont
ras
ttop
rio
rstud
ieso
fch
ang
einl
esi
onin
ten
sit
yinc
lin
ica
ltr
ial
s,ou
rwo
rk

i
sfo
cus
edonv
oxe
l-
lev
elan
aly
sis
,andth
ere
for
eitc
anp
rov
idesp
ati
alin
form
a-

t
ionabou
tin
ten
sit
yre
cov
eryandd
oesn
ota
rtifi
cia
llyr
edu
ceth
esi
zeo
fth
eda
ta

s
et. Th
ism
ayh
aveimp
li
cat
ion
sonth
esamp
les
izec
alcu
lat
ion
sfo
rcl
ini
calt
ri
-

a
ls
. Th
esem
eth
odsa
rea
lsob
road
lyapp
li
cab
let
ooth
erim
agin
gmod
ali
tie
sand

d
ise
asea
rea
s,inwh
ichl
ong
itud
ina
lin
ten
sit
ypr
ofil
esm
ayl
eadt
omo
res
ens
it
ive

andsp
ecifi
cbi
oma
rke
rs.
Inth
ePCAandr
egr
ess
ion m
ode
l,w
eob
serv
eas
tat
ist
ica
llys
ign
ific
antr
ela
-

t
ion
shipb
etw
eenth
ebi
oma
rke
randth
eus
eofd
ise
ase
-mod
ify
ingth
erap
yand

s
ter
oid
s.B
otht
rea
tmen
tands
ter
oid
swe
rea
sso
cia
tedw
ithar
etu
rno
fav
oxe
l

t
oin
ten
sit
yva
lue
scl
ose
rtoth
ato
fno
rma
l-app
ear
ingt
issu
e. Th
ein
fer
enc
efr
om

1
56
bo
th m
ode
lsinr
ega
rdst
odi
sea
se-m
odi
fyin
gtr
eatm
entsh
ouldon
lyb
etak
ena
s
ap
roo
f-o
f-c
onc
eptf
orth
ere
lat
ion
shipb
etw
eenth
eim
agin
gandth
ecl
ini
calc
o-

v
ari
ate
s. Th
emod
elsm
aysuff
erf
romc
onf
ound
ingb
yind
ica
tion
,wh
icha
ris
es

wh
enind
ividu
alswh
oar
eonat
rea
tmen
tar
ediff
eren
tfr
omth
osewh
odon
ot
r
ece
ivet
rea
tmen
t,du
etoun
obs
erv
edc
ons
ide
rat
ion
s.Inth
emu
lt
iva
ria
tem
ode
l,

w
ead
jus
tfo
rag
e,s
ex,andd
ise
asesub
typ
e,bu
tun
obs
erv
abl
ediff
eren
cesr
ela
ted
t
otr
eatm
entch
oic
ema
ycau
seb
ias
edc
onc
lus
ion
s.H
owev
er,b
iasint
erm
sof

t
rea
tmen
teff
ectw
ould m
ostp
lau
sib
lyr
esu
ltinund
ere
stim
ati
ono
fimp
rov
e-

m
ent
s,a
smo
rea
ggr
ess
iveth
erap
iesa
rec
omm
onlyg
ivent
osub
jec
tsw
ith m
ore

a
ggr
ess
iveo
rre
fra
cto
ryd
ise
ase
. Thu
s,ou
rfind
ing
smi
ghtund
ere
stim
atewh
at

w
ouldb
eob
serv
edinar
and
omi
zedt
ria
lofd
ise
ase
-mod
ify
ingth
erap
y.

On
elim
ita
tiono
fth
iss
tudy w
asth
ere
lat
ive
lysm
allnumb
ero
fsub
jec
ts.

F
utu
rew
ork w
il
lin
volv
edep
loy
ingth
eme
thod
olo
gyand m
ode
lsonal
arg
er

numb
ero
fsub
jec
ts(n =3
4),inbo
thob
serv
ati
ona
lstud
iesandr
and
omi
zed

c
lin
ica
ltr
ial
s. Wh
il
eman
yofth
eco
effic
ien
tfun
cti
onsf
romth
efun
cti
on-
on-

s
cal
arr
egr
ess
iona
ren
otf
oundt
obes
tat
ist
ica
llyd
iffe
ren
tfr
om0
,th
ism
ode
l

m
ayh
avem
orepow
erw
ith m
oresub
jec
ts. F
orth
eboo
tst
rapp
roc
edu
rew
e

on
lyh
ave3
4sub
jec
ts,r
esu
lt
inginw
idec
onfid
enc
ein
terv
alsf
orth
ees
tim
ated

c
oeffi
cien
tfun
cti
ons
.Inc
ont
ras
t,th
ere
gre
ssi
onu
sin
gsc
oreou
tcom
esid
ent
ifie
s

s
tron
gas
soc
iat
ion
sbe
twe
ensp
ecifi
cco
var
iat
esand mu
lt
isequ
enc
elon
gitud
ina
l

p
att
ern
sofl
ong
itud
ina
lin
ten
sit
ies
.
Th
etw
omod
elsp
res
ent
edinth
isw
orka
refi
tvo
xel
-wi
seandth
ere
for
ema
y

b
esen
sit
ivet
oma
jorm
isr
egi
str
ati
onw
ith
inas
tudyandb
etw
eenl
ong
itud
ina
l

s
tud
iesf
orth
esam
esub
jec
t. Th
emod
elsa
rea
lsos
ens
it
ivet
olo
cald
isp
lac
emen
t

o
fti
ssu
edu
etot
ran
sien
tsw
el
lin
ginanda
roundl
esi
onso
rre
sorp
tiono
fle
sion

1
57
t
issu
e. W
eth
ere
for
edon
otc
allth
esl
owch
ang
esinin
ten
sit
ywi
thinth
evo
xel
s
th
ata
reob
serv
ed“
tis
suer
epa
ir
,”a
swec
ann
otb
ece
rta
inth
atth
ech
ang
eis

n
otdu
etom
isr
egi
str
ati
ono
rdi
spl
acem
ento
fti
ssu
efr
omth
ele
sion
sth
ems
elv
es.

W
edoob
serv
ear
ela
tion
shipb
etw
eenth
ere
turno
fvo
xel
stoth
ein
ten
sit
yof
n
orm
al-
app
ear
ingt
issu
eandbo
thd
ise
ase
-mod
ify
ingt
rea
tmen
tandt
rea
tmen
t

w
iths
ter
oid
s,andth
ere
for
efindth
ism
easu
reu
sefu
landd
ese
rvin
goffu
rth
er
s
tudy
. W
eal
sos
eeana
sso
cia
tion w
ithth
edi
stan
cet
oth
ebound
aryo
fth
e

l
esi
onands
low
,lon
g-t
ermin
ten
sit
ych
ang
es–w
ithv
oxe
lsn
earth
ebound
aryo
f

th
ele
sionr
etu
rnin
gtob
ase
lin
ein
ten
sit
yandv
oxe
lsn
earth
ecen
tero
fth
ele
sion

m
ain
tain
ingabn
orm
als
ign
alin
ten
sit
y.F
utu
rew
orkt
oas
ses
sti
ssu
erep
airm
ay

in
volv
ein
ves
tig
atin
gan
onl
ine
arr
egi
str
ati
onw
ith
inind
ividu
all
esi
ons
.

Th
eme
thod
sde
scr
ibedh
ereu
seon
lyc
onv
ent
ion
alc
lin
ica
lim
agin
gfo
rpa
-

t
ien
tsw
ith MS
,nam
elyFLA
IR,T
2,PD
,andT
1. Wh
il
eth
isi
sben
efic
ialf
or

u
sin
gth
eme
thod
olo
gyinac
lin
ica
ltr
ials
ett
ingo
rfo
ran
aly
siso
fre
tro
spe
c-

t
iveim
agin
gstud
ies
,on
ecou
lda
lsoin
corpo
rat
eadv
anc
edim
agin
gin
toth
e

m
eth
od. F
orex
amp
le
,ma
gne
tiz
ati
ont
ran
sfe
rra
tioim
agin
g[1
60]
,qu
ant
ita
-

t
iveT
1-w
eigh
tedim
agin
g[1
61]
,andd
iffu
siont
ens
orim
agin
g[1
62]h
aveb
een

s
tud
iedin MSl
esi
ons
. Th
elon
gitud
ina
ldyn
ami
cso
fle
sion
sonth
eseim
age
s

c
ouldb
ein
corpo
rat
edin
toou
rfr
amew
orkt
obe
tte
rund
ers
tandth
ebeh
avi
oro
f

l
esi
onso
vert
imeandth
eimp
acto
fdi
sea
se-m
odi
fyin
gth
erap
iesonth
isb
eha
vio
r.

F
orth
isan
aly
sis
,al
l MR
Istud
iesa
rea
cqu
iredonas
ing
le1
.5T MR
Isc
an-
n
era
ton
eim
agin
gcen
ter
.Sim
ila
ran
aly
sisc
ouldb
epe
rfo
rmeda
thi
ghe
rfie
ld

s
tren
gth
,bu
tfo
rth
isan
aly
sisw
eus
ea1
.5Td
ata
setf
orth
eav
ai
lab
il
ityo
fth
e

l
arg
ere
tro
spe
ctiv
ecoh
orts
tudyo
veral
ongp
eri
odo
ftim
e. A
lth
oughd
iffe
r-

en
tsc
ann
ingp
aram
ete
rsw
ereu
sedf
orth
eacqu
is
it
ion
s,fu
rth
erin
ves
tig
ati
oni
s

1
58
w
arr
ant
edin
toth
erobu
stn
esso
fth
eme
thod
stoch
ang
esins
cann
er,ch
ang
esin
m
agn
eti
cfie
lds
tren
gth
,asw
el
lch
ang
esinth
eim
agin
gcen
ter
.

1
59
Append
ice
s

1
60
Append
ix A

Append
ixto“OAS
ISi
s
Au
toma
tedS
tat
ist
ica
lIn
ference
fo
rSegmen
tat
ion
,wi
th
app
lica
tion
sto mu
ltip
lesc
lero
sis
le
sionsegmen
tat
ionin MR
I

A
.1 OAS
IScoeffi
cien
ts

T
abl
e1andT
abl
e2d
isp
layth
eco
effic
ien
tsf
romth
etw
ofit
softh
eOAS
ISm
ode
l.

Th
eco
effic
ien
tsf
ore
ach m
oda
li
tya
reth
elo
godd
sra
tio
sofl
esi
onin
cid
enc
efo
r

v
oxe
lsc
orr
espond
ingt
oanin
cre
asedin
ten
sit
yofon
eno
rma
li
zedun
it
,fix
inga
ll

o
the
rpr
edi
cto
rs.L
esi
onsa
rech
ara
cte
riz
edb
yhyp
erin
ten
sit
iesinth
eFLA
IR,

PD
,and T
2-w
eigh
tedim
age
sandh
ypo
int
ens
it
iesinth
eT1
-we
igh
tedim
age
,

1
61
a
lth
oughn
ota
lll
esi
onsw
il
lapp
earonth
eT1
-we
igh
tedim
age
. A
sexp
ect
ed,
th
esi
gnso
fco
effic
ien
tsf
orth
eFLA
IRandT
2-w
eigh
tedin
ten
sit
iesa
repo
sit
ive
.

Th
eco
effic
ien
tofn
ega
tiv
esi
gnf
orth
ePDandpo
sit
ives
ignf
orth
eT1
-we
igh
ted

a
rein
terp
ret
edinth
econ
tex
twh
erea
llo
the
rpr
edi
cto
rsa
refix
ed. Du
etoth
e
s
tron
gco
rre
lat
ionam
ongth
eim
agin
gmod
ali
tie
s,i
tisd
ifficu
ltt
ovi
sua
li
zeth
e

imp
actth
ataon
est
and
ardd
evi
ati
onin
cre
aseinth
eno
rma
li
zedin
ten
sit
yinan
im
ageh
asonth
elo
godd
sra
tio wh
ena
llo
the
rmod
ali
tie
sar
ekep
tcon
stan
t.

Th
eco
effic
ien
tsf
orth
esm
ooth
edv
olum
esa
rem
ored
ifficu
ltt
oin
terp
ret
. Th
ey

a
rea
gainth
elo
godd
sra
tio
sofl
esi
onin
cid
enc
efo
rvo
xel
sco
rre
spond
ingt
oan

in
cre
asedin
ten
sit
yofon
eno
rma
li
zedun
it
,fix
inga
llo
the
rpr
edi
cto
rs. Bu
t,i
tis

v
eryd
ifficu
ltt
ocon
cep
tua
li
zewh
ataon
eun
itin
cre
aseinth
esm
ooth
edFLA
IR

w
ithk
ern
elw
ind
ows
izeo
f10
,fix
ingth
eFLA
IRandth
esm
ooth
edFLA
IRw
ith

k
ern
elw
ind
ows
izeo
f20
. Th
ein
ten
sit
iesinth
eseth
reeim
age
sar
ehi
ghlyc
orr
e-

l
atedandth
ism
ayexp
lain
,fo
rex
amp
le
,wh
yth
esi
gnsf
orth
esm
ooth
edFLA
IR

im
agea
reoppo
sit
e,wh
enin
tui
tiv
elyy
ouw
ouldexp
ectbo
tht
obepo
sit
ive
.Al
so,

th
esi
gnsonth
eco
effic
ien
tsf
rome
ach m
oda
li
tyf
romth
efir
stands
econdfi
t

a
rea
llth
esam
e,ex
cep
tfo
rth
eco
effic
ien
tfo
rth
esm
ooth
edT
2-w
eigh
tedw
ith

k
ern
elw
ind
ows
izeo
f10
,th
esm
ooth
edT
2-w
eigh
tedw
ithk
ern
elw
ind
ows
izeo
f

2
0andth
ein
ter
act
ionb
etw
eenth
eT2
-we
igh
tedim
ageandth
esm
ooth
edT
2-

w
eigh
tedw
ithk
ern
elw
ind
ows
izeo
f20
.Ag
ain
,th
ism
ayb
eexp
lain
edb
yth
e

c
orr
ela
tionam
ongth
eim
age
s. W
eal
soa
sse
ssedth
eva
ria
tioninth
eco
effic
ien
ts
b
ynonp
aram
etr
ica
llyboo
tst
rapp
ingth
esub
jec
tsw
ithr
epl
acem
ent
. Th
eboo
t-

s
trapp
ed9
5%c
onfid
enc
ein
terv
alsf
orth
eco
effic
ien
tsa
rea
lsop
rov
idedinT
abl
e

1
. Th
eva
rian
ceo
fth
esec
oeffi
cien
tsi
sla
rgeinc
omp
ari
sont
oth
ees
tim
ate
sof

th
eco
effic
ien
ts. Th
ism
ayb
eexp
lain
edb
yth
est
ron
gco
rre
lat
ionam
ongth
e

1
62
im
agin
gmod
ali
tie
sandth
esm
ooth
edim
age
s. Bu
t,th
ein
stab
il
ityinth
eco
effi-
c
ien
tsd
oesn
otimp
actth
epe
rfo
rman
ceo
fOAS
IS,a
sil
lus
tra
tedinth
est
abi
li
ty

o
fth
epa
rti
alROCcu
rve
.

1
63
 Tab
leA.1
:R egr
ess
ioncoeffici
ent
sfr
omfi r
stands e
condfito
fth el
ogis
ticre
gress
ion modelona llofth
e MR
Istud
ies
inval
ida
tionse
t1
Fi
t1 C
oeffi c
ient Stand
ardE rr
or B oots
trapped Me an(95%C I)
Inte
rcep
t -6
.44 0.01 -6.68(-
7.86
,- 5.84
)
FLAIR 1
.98 0.0
0 2.06(1
.61,2 .45
)
GFLA IR(10) 7
.73 0.0
3 6
.62(1.53
,1 1
.83)
GFLA IR(20) -6
.87 0.06 -4
.87(-14.4
7,5 .70)
PD -0
.46 0.00 -0.50(-0
.87,-0.09)
GPD( 10) -2
.18 0.02 -1.91(-5
.10,1 .27)
GPD( 20) 2
.00 0.0
3 1
.69(-3.88
,7 .11)
T2 0
.64 0.0
0 0.65(0
.38,0 .98
)
GT2(10) 0
.53 0.0
2 0
.41(-2.80
,3 .50)
GT2(20) -0
.03 0.04 -0
.45(-5
.16,4 .0
5)

1
T1 1
.52 0.0
0 1.56(1
.27,1 .89
)

64
GT1(10) 8
.68 0.0
2 8
.84(6.19
,1 1
.66)
GT1(20) -15.44 0.03 -15
.52(-20.2
0,- 10
.72)
FLA IR∗GFLA IR(10) 0.10 0.01 0
.50(-1.12
,2 .50)
FLA IR∗GFLA IR(20) -
5.02 0.03 -5.75(-9
.34,-2.53)
PD∗GPD( 10) -1
.76 0.01 -2.01(-3
.29,-0.67)
PD∗GPD( 20) 1
.80 0.0
2 2.16(0
.30,4 .30
)
T2∗GT2 (10
) -0
.10 0.01 -0
.06(-1
.41,1 .1
3)
T2∗GT2 (20
) -1
.47 0.02 -1
.45(-3
.29,0 .5
0)
T1∗GT1 (10
) -0
.64 0.01 -0
.72(-1
.62,0 .2
5)
T1∗GT1 (20
) 0
.41 0.0
2 0
.46(-1.70
,2 .25)
 T
abl
eA .2
:R eg
res
sioncoeffici
entsf
romthesecondfi
tofthelogi
sti
cr e
gre
ssi
on m ode
lona l
lo fthe MRIs
tud
iesin
v
al
idat
ionse
t1
Fi
t2 C
o effici
ent Stand
ardE rro
r B oot
strapped Me an(95%C I)
Inte
rcept -5.66 0.01 -5.
98(-7.09
,- 5.1
2)
FLAIR 1
.87 0.0
0 1.96(1
.52,2 .48
)
2
G FLA IR(10) 3
.96 0.0
4 2
.82(-2.8
1,1 0
.31)
G2FLA IR(20) -3.19 0.06 -1.44(-15
.18,1 0.
2 5
)
PD -0.78 0.00 -0.80(-
1.21,-0.29)
G2PD( 10) -1.20 0.03 -0
.97(-4.71
,- 0.2
9)
G2PD( 20) 3
.16 0.0
4 2
.83(-2.96
,7 .97)
T2 0
.91 0.0
0 0.91(0
.56,1 .28
)
G2T2(10) -2.63 0.03 -2
.51(-6.33,1
.47)
2
G T2(20) 0
.10 0.0
4 -0.37(-8
.44,6 .0
5)

1
T1 1
.90 0.0
0 1.92(1
.49,2 .40
)

65
G2T1(10) 5
.38 0.0
2 5.83(2
.61,9 .20
)
2
G T1(20) -11
.57 0.03 -12.11(-
17.91,-6.78)
FLA IR∗G2FLA IR(10
) 0
.10 0.02 0
.58(-1.27
,2 .40)
FLA IR∗G2FLA IR(20
) -4.9
7 0.03 -5.71(-
9.81,-1.98)
2
PD∗GPD( 10) -2.26 0.01 -2.36(-
2.36,-1.00)
PD∗G2PD( 20) 2
.73 0.0
2 2.95(0
.36,5 .26
)
T2∗G2T2 (10
) 1
.59 0.0
2 1.55(0
.15,2 .68
)
T2∗G2T2 (20
) -4.52 0.02 -4.43(-
7.04,-2.37)
2
T1∗GT1 (10
) -0.82 0.01 -0.86(-1
.70,0 .0
7)
2
T1∗GT1 (20
) 0
.33 0.0
2 0
.28(-1.63
,2 .01)
A
.2 Repea
tedsub
jec
tsfo
rva
lida
tions
tudy1

T
abl
e3d
isp
lay
sth
epr
efe
rred m
eth
odam
ong
stth
eOAS
ISemp
ir
ica
llyad
jus
ted

th
resh
oldandL
esi
onTOADSs
egm
ent
ati
onf
romth
eneu
ror
adi
olo
gis
t,n
eur
olo
-
g
ist
,andr
adi
olo
gis
tfo
rth
efiv
esub
jec
tsw
ithr
epe
ateds
tud
iesf
romv
al
ida
tion

s
et2
. Th
erew
asat
ieb
etw
eenth
etw
ome
thod
sfo
rth
eRad
iol
ogi
st’
sse
cond

r
ank
ingo
fSub
jec
t5.

T
ableA.3:Pref
erredme
thodfromn eu
rorad
iol
ogi
st,neu
rol
ogis
t,andr
adiol
o g
ist
f
o rthe5repeat
edsubj
ectsinval
idat
ionset2
Neurorad
iologi
s t Fi
rstR ank
ing S ec
ondR ank
ing R ank
ingPres
erved
Study1 OAS
IS OAS
IS Ye
s
Study2 L
eso
inTOADS L
esi
onTOADS Yes
Study3 OAS
IS OAS
IS Ye
s
Study4 OAS
IS OAS
IS Ye
s
Study5 L
esi
onTOADS OASIS No
Neurolog
ist
Study1 OAS
IS OASIS Y
es
Study2 L
esi
onTOADS Le
sionTOADS Y
es
Study3 OAS
IS OASIS Y
es
Study4 OAS
IS OASIS Y
es
Study5 OAS
IS L
esi
onTOADS No
Radio
log
ist
S
tudy1 OAS
IS OAS
IS Ye
s
S
tudy2 OAS
IS L
esi
onTOADS No
S
tudy3 OAS
IS OAS
IS Ye
s
S
tudy4 OAS
IS L
esi
onTOADS No
S
tudy5 L
esi
onTOADS t
ie No

1
66
Append
ix B

Append
ixto“Acompa
risono
f
supe
rvi
sed mach
inelea
rning
a
lgo
rithm
sandfea
turev
ecto
rs
fo
r MSle
sionsegmen
tat
ionu
sing
mu
ltimoda
lst
ruc
tura
l MR
I”

B
.1 C
las
sifica
tiona
lgo
rithm
s

V
oxe
l-
lev
ell
esi
ons
egm
ent
ati
oni
sab
ina
ryc
las
sifi
cat
ionp
rob
lemw
ithtw
ocl
ass
es,

v
oxe
lse
ith
erc
ont
ainl
esi
ono
rdon
otc
ont
ainl
esi
on. W
eus
eth
eno
tat
ion

y
v ∈{0,
1}t
obeac
las
slab
elind
ica
tin
g wh
eth
ero
rno
tvo
xelvo
fab
rain

im
agef
rom MR
Istudyc
ont
ain
sal
esi
on.H
erew
epr
ovid
eab
rie
fsumm
aryo
f

e
achc
las
sifi
cat
iona
lgo
rithmu
sedinou
ran
aly
sisandth
etun
ingp
aram
ete
rs

1
67
a
sso
cia
ted w
ithth
eal
gor
ithm
. Ac
omp
let
eov
erv
iewo
fth
esea
lgo
rithm
scan
b
efoundinTh
eEl
emen
tso
fSt
ati
sti
calL
earn
ing
:Da
taM
inin
g,In
fer
enc
eand

P
red
ict
ion[
163
].F
ore
achc
las
sifi
cat
iona
lgo
rithm
,Tab
le4
.1inth
eMe
thod
s

s
ect
ionsh
owsth
e Rp
ack
ageu
sedt
ofitth
eal
gor
ithmandth
eva
lue
sfo
rth
e
tun
ingp
aram
ete
rs.Infi
ttin
gea
cho
fth
eal
gor
ithm
sonth
etr
ain
ings
et,1
0-f
old

c
ros
sva
lid
ati
onw
asu
sedt
oop
tim
izea
lltun
ingp
aram
ete
rs.

B
.1.1 Log
ist
icreg
res
sion

L
ogi
sti
cre
gre
ssi
oni
sasp
eci
alc
aseo
fth
egen
era
li
zedl
ine
arm
ode
l,w
itha

l
ogi
sti
clinkfun
cti
on. Th
egen
era
li
zedl
ine
arm
ode
lwi
thl
ogi
sti
clinkfun
cti
on,
s
t
,ist
{P(
yv =1| }= β0+βTx, wh
X = x) eret
(s) =l
og(
1−s
). Th
ere
sul
tin
g

d
eci
sionbound
aryf
orl
ogi
sti
cre
gre
ssi
oni
slin
ear
.

B
.1.2 L
inea
rdi
scr
iminan
tana
lys
is

L
ine
ard
isc
rim
inan
tan
aly
sism
ode
lse
achc
las
sasa mu
lt
iva
ria
teG
aus
sianw
ith

p
rob
abi
li
tyd
ist
ribu
tionfun
cti
onsf
0(v)andf
1(v)w
ith m
ean
sµ0andµ1r
esp
ec-

t
ive
ly
.Lin
eard
isc
rim
inan
tan
aly
sism
ake
sth
eas
sump
tionth
atbo
thc
las
sesh
ave

ac
omm
onc
ova
rian
cem
atr
ixΣ
.Pr
iorp
rob
abi
li
tie
sofb
elon
gin
gtoac
las
sar
e

c
alcu
lat
edf
romth
etr
ain
ingd
ataanda
red
eno
teda
sπ0andπ1. Th
en,th
epr
ob-
f1(
x)π1
ab
il
ityo
fvo
xelb
ein
gpa
rto
fal
esi
oni
sdefin
eda
sP(
yv =1|
X =x)=f0(
x)π0
.

Th
ere
sul
tin
gde
cis
ionbound
aryi
slin
ear
.

1
68
B
.1.3 Quad
rat
icd
isc
rim
inan
tana
lys
is

Qu
adr
ati
cdi
scr
imin
antan
aly
sisi
ssim
ila
rtol
ine
ard
isc
rim
inan
tan
aly
sis
,bu
t
a
llow
sfo
rth
etw
ocl
ass
est
oha
ved
iffe
ren
tco
var
ian
cem
atr
ice
s,Σ
0andΣ
1. Th
e
r
esu
lt
ingd
eci
sionbound
aryi
saqu
adr
ati
csu
rfa
ce.

B
.1.4 Gau
ssian m
ixtu
re mode
l

Ina G
aus
sian m
ixtu
rem
ode
l,e
achc
las
ski
smod
eleda
sa m
ixtu
reo
fno
rma
l
Rk
d
ist
ribu
tion
swi
thd
ens
ityP(
X = x|
yv=k)= r=1 ψkrφ(
X;µkr,
Σ),k=0,
1.

Th
emix
ingp
ropo
rti
onsf
ore
achc
las
s, ψkr, mu
stsumt
oon
e. Th
en,P(
yv=

1
|X =x)=P(X=x|yP(
v=
X=x|
1
yv=1
)π1+P(
)π1
X=x|yv=0
)π0
,wh
ereπ0andπ1a
reth
epr
iorp
rob
abi
l-

i
tie
sofb
elon
gin
gtoe
achc
las
s,c
alcu
lat
edf
romth
etr
ain
ingd
ata
. Th
ede
cis
ion

bound
aryf
orth
eGau
ssi
an m
ixtu
rem
ode
lis mu
lt
i-m
oda
l

B
.1.5 Suppo
rtv
ecto
r mach
ine w
ithl
inea
rke
rne
l

Inasuppo
rtv
ect
orm
ach
inew
ithl
ine
ark
ern
el
,wea
imt
ofindth
ehyp
erp
lan
e

th
ats
epa
rat
esth
etw
ocl
ass
esw
ithth
ela
rge
stm
arg
in. Th
ehyp
erp
lan
eth
at

s
epa
rat
esth
etw
ocl
assi
sdefin
eda
s x) =β0 +βtx}
,{x:f( . Ac
ost Ci
s

a
ssi
gnedt
ovo
xel
svth
ata
rec
las
sifi
edin
cor
rec
tly
,and ψi≤ C,wh
ereψii
s

th
eam
oun
twh
ichth
evo
xeli
sonth
ein
cor
rec
tsid
eofth
ema
rgin
. W
ese
arch

o
verth
eC =1
/8,1
/4,1
/2,1
,2,4
,and8
. Th
ede
cis
ionbound
aryf
orth
e

suppo
rtv
ect
orm
ach
inei
slin
earinth
eimp
li
citk
ern
elsp
ace
,bu
tnon
lin
earin

th
eor
igin
alsp
ace
.

1
69
B
.1.6 Randomfo
res
t

Ar
and
omf
ore
stc
omb
ine
s mu
lt
ipl
ecl
ass
ific
ati
ont
ree
sandth
esec
las
sifi
cat
ion
t
ree
svo
teonwh
ichc
las
san
ewv
oxe
lsh
ouldb
ecl
ass
ifieda
s.Inth
eimp
lem
en-

t
ati
ono
fth
erand
omf
ore
st,w
eus
e50
0cl
ass
ific
ati
ont
ree
s. Th
epa
ram
ete
rwe

tun
eth
eal
gor
ithmo
veri
sth
emt
ryp
aram
ete
r,th
enumb
ero
fva
riab
less
amp
led
a
tea
chsp
li
tofth
ede
cis
iont
ree
. W
ese
archo
verm
try=1t
oth
edim
ens
iono
f

th
efe
atu
resp
ace
. Th
ede
cis
ionbound
aryf
ore
acht
reei
spi
ecew
isel
ine
ar.

B
.1.7 k
-nea
res
tne
ighbo
rs

Ink
-ne
are
stn
eighbo
rst
ocl
ass
ifyan
ewv
oxe
l,v, w
ithf
eatu
resX = x, w
e

c
alcu
lat
eth
edi
stan
ceo
fit
sfe
atu
resf
romth
efe
atu
reso
fth
evo
xel
sinth
e
l
abe
ledt
rain
ings
et,u
sin
gEu
cl
ide
and
ist
anc
e. Th
ekv
oxe
lsinth
etr
ain
ings
et

w
ithth
esm
all
estd
ist
anc
etoth
enewv
oxe
lvo
teonth
ecl
asso
fth
enewv
oxe
l.

Th
etun
ingp
aram
ete
rfo
rth
ek-n
ear
estn
eighbo
ral
gor
ithmi
sth
enumb
ero
f
v
oxe
lst
obeu
sed
. W
ese
archo
verk=
1,1
0,and1
00n
eighbo
rs.

B
.1.8 Neu
ralne
two
rk

Inas
ing
leh
idd
enl
aye
rneu
raln
etw
ork
,de
riv
edf
eatu
res
,Z,a
rec
rea
tedf
rom
T
l
ine
arc
omb
ina
tion
softh
einpu
tfe
atu
re,X :Zp=σ(
s αop+αpX)
,p∈{1
,..
.,P
}.

Th
esed
eriv
edf
eatu
resZa
rec
all
edh
idd
enun
its
. W
eel
ect
edt
ous
eas
igm
oid

a
ctiv
ati
onfun
cti
onσ,σ(
s) =(1+ex1
p(−s
))
,a
sth
isi
styp
ica
l. Th
eou
tcom
e,y
v,

i
sth
en m
ode
leda
safun
cti
ono
fth
ehidd
enun
its
:yv=t
(β0+βTz
).W
eus
e

as
ing
leh
idd
enl
aye
rneu
raln
etw
orkw
iths
igm
oida
ctiv
ati
onfun
cti
on;1
0-f
old

c
ros
sva
lid
ati
oni
sus
edt
ose
lec
tth
enumb
ero
fhidd
enun
itsinth
eal
gor
ithm

1
70
ands
ear
cho
verP=1
,5,and1
0.

B
.1.9 Supe
rlea
rne
r

Th
esup
erl
earn
eri
sa m
eth
odf
orc
omb
inin
gcl
asse
stim
ati
onsf
romd
iffe
ren
t
c
las
sifi
cat
iona
lgo
rithm
s,b
ywe
igh
tin
gth
ecl
ass
ifie
rsa
cco
rdin
gtoth
eirp
red
ict
ion

p
erf
orm
anc
eus
ingac
ros
s-v
al
ida
tionl
ossfun
cti
on. W
eus
eth
esup
erl
ean
er

a
lgo
rithmw
ith1
0-f
oldc
ros
sva
lid
ati
onw
ith m
eansqu
arede
rro
rlo
ss,bu
tan
y

o
the
rcr
ossv
al
ida
tiono
rlo
ssfun
cti
on m
ayb
eus
ed. Th
esup
erl
earn
err
equ
ire
s

al
ibr
aryo
f Ksup
erv
isedc
las
sifi
cat
iona
lgo
rithm
s.T
otr
ainth
esup
erl
earn
er

w
ith1
0-f
oldc
ros
sva
lid
ati
on,th
etr
ain
ings
et,T,o
fsi
zenv
oxe
lsi
spa
rti
tion
ed

in
to1
0equ
als
amp
les
. F
ore
acho
fth
ese1
0samp
les
,th
e Ka
lgo
rithm
sar
e

t
rain
edonth
erem
ain
ingd
atainth
etr
ain
ings
et. Ap
red
ict
ionf
ore
achv
oxe
l
vinth
ere
serv
eds
amp
lei
sth
en m
adef
o ekthc
rth las
sifi
cat
iona
lgo
rithm
,hk,

d
eno
teda
sϕk(
v),k∈{1
,..
.,K
}. A
fte
rth
isi
spe
rfo
rmedf
ora
ll1
0samp
les
,

ac
oeffi
cien
tαk f
ore
achc
las
sifi
cat
iona
lgo
rithmi
sse
lec
ted
,tom
inim
izeth
e
1 2
m
eansqu
aree
rro
r: n v∈T[
yv− kαkϕk(
v)],und
erth
econ
str
ain
t kαk =1
.

Th
efit
tedc
las
sifi
ersw
ithth
eco
effic
ien
tsαk c
anth
enu
sedt
omak
epr
edi
cti
ons

f
orn
ews
amp
les
. W
eus
eth
eSup
erL
earn
erRp
ack
ageb
asedona
llo
fth
eoth
er

sup
erv
isedc
las
sifi
cat
iona
lgo
rithm
sandtun
ingp
aram
ete
rsu
sedinth
isan
aly
sis
.

T
ode
cre
asep
red
ict
iont
imef
orn
ewd
ata
,al
gor
ithm
swi
thαk c
oeffi
cien
tsc
los
e

t
oze
roa
red
ropp
eddu
rin
gth
epr
edi
cti
onph
ase(
theon
lySLp
aram
ete
riss
et

t
oTRUEwh
en m
akin
gpr
edi
cti
ons
;th
ede
fau
ltf
orth
isp
aram
ete
risFALSE
).

1
71
Append
ix C

Append
ixto“Re
lat
ing
mu
lti
-sequencelong
itud
ina
l
in
ten
sityp
rofi
lesandc
lin
ica
l
cov
aria
tesininc
iden
t mu
ltip
le
sc
lero
sisle
sion
s”

C
.1 Long
itud
ina
lprofi
lep
ipe
line

H
erew
epr
ovid
ea m
orec
omp
let
ede
scr
ipt
iono
fth
epr
ocedu
ref
orex
tra
ctin
g

th
elon
gitud
ina
lvo
xel
-lev
ell
esi
onp
rofi
les
,wh
ichi
sdiv
idedin
tof
ours
tep
s:(
1)

id
ent
ify
ingv
oxe
lsw
ithn
ewl
esi
onf
orm
ati
on,(
2)in
ten
sit
yno
rma
li
zat
ion
,(3
)

t
empo
rala
lignm
ent
,and(
4)t
empo
ralin
terpo
lat
ion
.Al
lvo
xel
sinth
isan
aly
sis

a
rep
arto
fin
cid
ento
ren
lar
gin
gle
sion
sde
tec
teddu
rin
gth
esub
jec
t’sf
oll
ow-up

1
72
p
eri
od.A
llv
oxe
lsth
ata
rep
arto
fle
sion
sth
atex
ist
eda
tba
sel
inea
reex
clud
ed
f
romth
ean
aly
sis
.

C
.1.1 Iden
tify
ingvoxe
lsw
ithnewle
sionfo
rma
tion

Wh
enid
ent
ify
ingv
oxe
lsw
ithn
ewl
esi
onf
orm
ati
on,w
edi
stin
gui
shb
etw
eena
r-

e
asth
atc
ont
ainv
aso
gen
iced
ema(wh
ichw
ewi
llr
efe
rtos
imp
lya
s“ed
ema
”)
anda
ctu
all
esi
on, wh
ichbo
th m
ani
fes
tasa
rea
sofabn
orm
als
ign
alin
ten
sit
y,

e
spe
cia
llyonth
eT2
-we
igh
teds
equ
enc
es.F
orth
isan
aly
sis
,wea
rein
ter
est
ed

ina
rea
swi
tht
issu
edam
age
,asoppo
sedt
oed
ema
.Toid
ent
ifya
rea
swi
thn
ew

l
esi
onf
orm
ati
on,w
efir
stfinda
rea
sinth
e MR
Iwi
thn
ewabn
orm
als
ign
alin
-

t
ens
ity
, wh
ichin
clud
esbo
thed
emaandl
esi
on. W
eth
ens
egm
entl
esi
onsb
y
an
aly
zin
gsub
sequ
entv
is
itd
ata
.

SuBL
IMEs
egm
ent
ati
ono
fvo
xel
-lev
ell
esi
onin
cid
enc
eanden
lar
gem
enti
sa

m
eth
odf
ord
ete
ctin
gvo
xel
sth
ata
rep
arto
fana
reao
fnewabn
orm
als
ign
al

in
ten
sit
ybe
twe
entw
o MR
Istud
ies[
9].F
ore
achsub
jec
t,w
epr
odu
ceSuBL
IME

m
apsb
etw
eenth
ere
spe
ctiv
ese
tso
fcon
secu
tiv
e MR
Istud
ies
. W
eex
clud
eal
l

abn
orm
als
ign
alin
ten
sit
yar
easth
atc
ont
ain
edf
ewe
rth
an2
7vo
xel
s,a
sth
ese

a
rea
scou
ldb
ear
ti
fac
torn
ois
e. W
eth
enp
rodu
cec
ros
s-s
ect
ion
all
esi
ons
egm
en-

t
ati
onsu
sin
gOAS
ISs
egm
ent
ati
ono
fabn
orm
als
ign
alp
res
enc
e[7
].A
sth
esi
gna
l

f
romed
emad
isapp
ear
srap
idlyf
romth
e MR
Iaf
terl
esi
onf
orm
ati
on,w
elo
cat
e

th
ein
cid
entabn
orm
als
ign
alv
oxe
lsu
sin
gSuBL
IME
,bu
ton
lyin
clud
eth
evo
xel
s

th
ata
red
ete
ctedb
yOAS
ISa
tth
efo
llow
ings
tudyv
is
it
,asth
esev
oxe
lssh
ould

n
otc
ont
ained
ema
. Th
ere
for
e,on
lyv
oxe
lsth
ath
avean MR
Istudyw
ith
in4
0

d
aysa
fte
rSuBL
IMEd
ete
ctsth
ear
eao
fabn
orm
als
ign
alin
ten
sit
y, wh
ereth
e

1
73
in
ten
sit
yrem
ain
sinth
e OAS
IS m
aps
,ar
econ
sid
ereda
sle
siont
issu
eandu
sed
inth
isan
aly
sis
,asb
yth
ist
imeed
emaw
ouldsub
sid
e. W
eus
eexp
ertv
al
ida
tion

b
yan
eur
orad
iol
ogi
standan
eur
olo
gis
t,bo
thw
ithexp
eri
enc
ein MSim
agin
g,t
o

c
onfi
rmth
atth
ism
eth
odi
sid
ent
ify
ingl
esi
ont
issu
e,wh
ichw
ede
scr
ibeind
eta
il
inth
ese
cti
onE
xpe
rtV
al
ida
tion. Th
efigu
reb
elowsh
owsth
eSuBL
IMEs
egm
en-

t
ati
onf
ore
achs
tudyandth
eOAS
ISs
egm
ent
ati
onf
ore
achs
tudy
,co
rre
spond
ing
t
oFi
gur
e5.
2. Th
erowc
orr
espond
ingt
oth
eSuBL
IMEs
egm
ent
ati
oni
sfu
rth
er

d
ivid
edin
toed
emaandl
esi
onv
oxe
lsu
sin
gth
eme
thodd
esc
rib
edabo
ve. On
ly

v
oxe
lsth
ata
rep
arto
fle
siont
issu
ear
eus
edinth
ean
aly
sis
.

C
.1.2 In
ten
sityno
rma
liza
tion

S
tru
ctu
ral MR
Iisa
cqu
iredina
rbi
tra
ryun
its
. Th
ere
for
e,inadd
it
iont
opu
lse

s
equ
enc
esim
ila
rit
y,in
ten
sit
yno
rma
li
zat
ioni
spa
ram
oun
tfo
rcomp
arin
gin
ten
-

s
it
iesinav
oxe
lov
ert
imew
ith
insub
jec
tandf
orc
omp
arin
gvo
xelin
ten
sit
ies
b
etw
eensub
jec
ts. W
eno
rma
li
zee
achs
equ
enc
esep
ara
telyone
achs
canb
yca
l-

cu
lat
ingth
eme
anands
tand
ardd
evi
ati
ono
vera m
asko
fth
eno
rma
l-app
ear
ing

wh
item
att
er(NAWM
)fr
omth
ebr
ains
egm
ent
ati
ond
esc
rib
edinth
ese
cti
on

Ima
geA
cqu
isi
tionand P
rep
roc
ess
ing[
66]
. W
eth
ensub
tra
ctth
eme
anf
rom

th
ein
ten
sit
yine
achv
oxe
landd
ivid
ebyth
est
and
ardd
evi
ati
on[
93,1
55]
.Le
t

Silv(
t)b
eth
eob
serv
edin
ten
sit
yfr
omim
agin
gsequ
enc
eSinv
oxe
lvf
orsub
jec
t

iinl
esi
onla
tstudyt
imet
,wi
thS=FLA
IR,T
1,T
2,andPD
.Le
tµSi(
t)and
σSi(
t)b
eth
eme
anands
tand
ardd
evi
ati
on,r
esp
ect
ive
ly
,ov
erth
eNAWM m
ask

f
ors
equ
enc
eSa
tsc
ant
imetf
orsub
jec
ti. Th
enth
eno
rma
li
zedin
ten
sit
yin

v
oxlvinl
e esi
onlf
orsub
jec
tia
tsc
ant
imeti
s:

1
74
 F
LAIR T2 PD T1

T
ime 98 119 175 210 238 266 280 343

F
LAIR

T2

PD

T1

Edema
SuB
LIM
E Les
ion

OA
SIS

D
is
tan
ce 6vo
xel
s

F
i gureC.1:E ach0
c o
vl
o
xum
es no
l fthefigu r
er epr
esentsadiffe
rent MRIstudy,star
ting
at9 8d
PC1aysafterb
35aselineinth efarlef
tc olumnandg oin
gun ti
l3 43d aysaft
er
basel
i
S
con
e
r.
e
s A l
esion
0isfi rs
t iden
tifiedin thi
sa re
aa t175days
. Thefirs
t fourrows
sh owthel ongi
tu-
di
54nalb ehavi
orofth eFLA IR
,T 2,PD,andT 1sequences
. The
nextr owssh owth eSuBL IMEs egm en
t a
tionofles
ioninc
idencefore achstudy
andth e OAS ISse gm entationoflesionp r
esenceineachstudy
. Th eSuBL IME
segm entat
ionh asb eenfurtherdiv
id edintoareasofedemaandl es
ion.

N Silv(
t)−µSi(
t)
Si
lv(t
)=
σSi(
t)

Thu
s,a
llim
agein
ten
sit
iesa
reexp
res
seda
sad
epa
rtu
re,inmu
lt
ipl
eso
fst
and
ard

d
evi
ati
ono
fwh
item
att
erin
ten
sit
ies
,fr
omth
esub
jec
t’sm
eann
orm
al-
app
ear
ing
wh
item
att
er(NAWM
)ine
achim
agin
gsequ
enc
e.

1
75
C
.1.3 T
empo
rala
lignmen
t

Th
eda
teo
fth
estudyv
is
ita
t wh
ichSuBL
IMEd
ete
ctsth
ele
sionv
oxe
lsi
s
c
ons
ide
redth
etim
eofin
cid
enc
efo
rth
isv
oxe
l.I
fav
oxe
lisd
ete
rmin
edt
o

b
ean
ewo
ren
lar
gin
gle
sionb
ySuBL
IME m
oreth
anon
ceo
verth
efo
llow
-up

t
ime
,th
efir
sto
ccu
rren
cei
scon
sid
eredt
obeth
etim
eofl
esi
onin
cid
enc
efo
r
th
atv
oxe
l. V
oxe
lpr
ofil
esf
romin
cid
entl
esi
onsdu
rin
gth
efo
llow
-upo
fea
ch

sub
jec
tar
eal
ign
edint
ime
,us
ingth
etim
eofin
cid
enc
east
ime0
,th
ere
for
ean
y

ob
serv
ati
onsb
efo
rein
cid
enc
eha
vean
ega
tiv
etim
eanda
fte
rle
sionin
cid
enc
e

h
aveapo
sit
ivet
ime
. L
e en
ttd o
teth
isa
lign
edt
imes
cal
e. Th
en w
eha
ve
N N
Si
lv(t)
,wh
ereSi
lv(0
)ind
ica
testh
ein
ten
sit
yins
equ
enc
eSa
tth
etim
eofl
esi
on

in
cid
enc
e.

C
.1.4 T
empo
ralin
terpo
lat
ion

N
extw
epe
rfo
rmat
empo
rall
ine
arin
terpo
lat
ions
oth
ata
llv
oxe
lsa
reob
serv
ed

onth
esam
etim
egr
id.Inth
isw
ork
,wea
rein
ter
est
edinth
ele
siondyn
ami
cs

on
lya
fte
rle
sionin
cid
enc
e,th
ere
for
ewep
erf
ormth
elin
earin
terpo
lat
ionw
ith
in

th
ewind
owa
fte
rle
sionin
cid
enc
eandupt
o20
0da
yspo
st-
inc
iden
ce. Th
eend

po
into
f20
0da
ysi
sse
lec
teda
sith
asb
eenp
rev
iou
slyf
oundth
atn
ewT
2le
sion
s

sh
owth
emo
std
ram
ati
cch
ang
esinin
ten
sit
yfo
rth
reet
ofou
rmon
ths[
146
],and

w
eop
ttob
econ
serv
ativ
eandin
clud
eda
tab
eyondth
isr
epo
rteds
tab
il
iza
tion
po
int
.Vo
xel
sar
ese
lec
tedf
orth
ean
aly
sisi
fth
esub
jec
tha
satl
eas
ton
evi
sit

2
00d
ayso
rmo
rea
fte
rle
sionin
cid
enc
e. O
fth
e60sub
jec
tsinth
isan
aly
sis
,

3
4ha
vev
oxe
lpr
ofil
esm
eet
ingth
isin
clu
sionc
rit
eri
a,a
fte
rrem
ovin
gth
eth
ree

sub
jec
tsf
orpoo
rlon
gitud
ina
lre
gis
tra
tion
. W
elin
ear
lyin
terpo
lat
eov
erag
rid

1
76
o
f0t
o20
0da
ysb
yin
crem
ent
sof5d
ayss
oth
ata
llp
rofi
lesa
reob
serv
edonth
e
s
amet
imeg
rid
. W
eden
oteth
eve
cto
rofob
serv
ati
onsf
romav
oxe
lov
erth
is
N N
t
imeg
ridf
ors
equ
enc
eSa
sSi
lv,wh
ereSi
lvi
sa1
×41v
ect
or.

C
.2 Pa
rame
tricboo
tst
rapp
ingp
rocedu
re

L
etB b
eth
enumb
ero
fboo
tst
raps
amp
lest
obep
erf
orm
edandl
etbind
ex

th
eseB s
amp
les
.Le
tYilv b
eth
eou
tcom
efo
ranob
serv
ati
onind
exedb
yi,l
,

andv.L
etX b
eth
ede
sign m
atr
ixandβb
eth
eve
cto
rofth
eco
effic
ien
ts.F
or

th
isan
aly
sisw
eha
vea m
ode
lofth
efo
rm:

Yilv=Xβ +b
i+b
l+ i
lv

2 2
wh
ereb
i ∼ N(
0,σ
i)andb
l ∼ N(
0,σ
l)a
rer
and
omin
ter
cep
ts,and ilv ∼
2
N(
0,σ)i
sane
rro
rte
rm.F
orth
epa
ram
etr
icm
ode
l,w
efitth
eabo
vem
ixed
-

eff
ectm
ode
ltog
etane
stim
at fβ, wh
eo ich w
eden
otea
sβ̂. W
eth
enfix
2 2
th
ise
stim
ate
,andk
eepXβ̂. U
sin
gth
efit
tedv
ari
anc
es,σ̂i,σ̂l andσ̂2, w
e
2
g
ene
rat
ear
and
omin
ter
cep
tfo
rea
chl
esi
onf
romaN(
0,σ̂i)d
ist
ribu
tion
,a
2
r
and
omin
ter
cep
tfo
rea
chsub
jec
tfr
omaN(
0,σ̂l),andr
and
omn
ois
efo
rea
ch

v
oxe
lfomaN(
r 0,σ̂2)
. W
eth
enaddth
erand
omin
ter
cep
tsandn
ois
etoXβ̂f
or

th
eco
rre
spond
ingob
serv
ati
onandu
seth
isa
sou
rou
tcom
etor
efitth
emod
el
∗
andg
etou
tboo
tst
rapp
edc
oeffi
cien
tve
cto
rβb.T
oob
tainth
eboo
tst
raps
amp
le
,

w
erep
eatth
isp
roc
edu
reB t
ime
s.

1
77
C
.3 Expe
rtv
alida
tion

Ex
amp
leso
fth
ese
tofev
alu
ati
onim
age
spr
esen
tedt
oth
eexp
ert
sfo
rea
chl
esi
on

a
resh
owninF
igu
resC
.2,C
.3,C
.4,andC
.5. Th
efir
str
owo
fth
efigu
ressh
ows
th
efu
llax
ials
li
cef
orth
eFLA
IR,T
2,PD
,andT
1vo
lum
esth
atc
ont
ain
sth
e

l
arg
estnumb
ero
fvo
xel
swi
thabn
orm
als
ign
alin
ten
sit
y. Th
ese
condth
rou
gh

f
our
thr
owssh
owth
een
tir
eco
ll
ect
iono
flon
gitud
ina
lsc
ansf
orabo
xcon
tain
ing

th
eabn
orm
als
ign
alin
ten
sit
yinth
eFLA
IR,T
2,PD
,andT
1we
igh
tedv
olum
es

a
tth
eba
sel
inet
imepo
intf
orth
isax
ials
li
ce. Th
esc
ansa
red
isp
lay
edinch
ron
o-

l
ogi
calo
rde
r,f
romfi
rstt
imepo
intt
ola
stt
imepo
int
,fr
oml
eftt
ori
ght
. Th
e

fi
fthr
owsh
owsth
ese
gmen
tat
iono
fth
ele
sionanded
emat
issu
ewi
thinth
isbo
x

a
tea
cht
imepo
int
. Th
esix
thr
owsh
owsth
esc
oreonth
efir
stPCf
orth
evo
xel
s

s
egm
ent
eda
sle
siont
issu
e,d
isp
lay
eda
tth
etim
eofl
esi
onin
cid
enc
efo
rea
ch

v
oxe
l. Th
esev
enthth
rou
ght
enthr
owsh
owth
een
tir
eco
ll
ect
iono
flon
gitud
ina
l

s
can
sfo
rth
eFLA
IR,T
2,PD
,andT
1we
igh
tedv
olum
esw
ith
inth
isbo
x,w
ith

th
esc
oref
orth
efir
stPCo
ver
laidonth
eim
age
sfo
rea
chs
cana
fte
rle
sionin
ci-

d
enc
e. Th
ela
str
owsh
owsth
esc
alef
orth
esc
oreonth
efir
stPC
.Th
efigu
res

sh
owex
amp
leso
fth
efou
rdiff
eren
tra
tin
gsf
orth
esc
oreonth
efir
stPC
.Bo
th

r
ate
rsr
ateth
esc
ansa
sei
the
r(1
)fa
il
ed m
ise
rab
ly
,(2
)som
ered
eem
ingf
eatu
res
,

(
3)p
ass
edw
ith m
ino
rer
ror
s,o
r(4
)pa
ssed
.

1
78
C
.4 P
rinc
ipa
lcomponen
tana
lys
isandreg
res
-

s
ion

T
abl
eC.
1sh
owsth
eco
effic
ien
tes
tim
ate
s,s
tand
arde
rro
rs,t
-st
ati
sti
cs,th
ep-

v
alu
esu
sin
gth
eno
rma
lapp
rox
ima
tion
,andth
e95%boo
tst
rapp
edc
onfid
enc
e
in
terv
alsf
orth
e mu
lt
iva
ria
tePCAr
egr
ess
ion m
ode
l.T
abl
eC.
2sh
owsth
esam
e

f
orth
eind
ividu
alun
iva
ria
tePCAr
egr
ess
ion m
ode
ls
.

1
79
 PC1Sco
res
33
.1

2
.5

−28
.1

Fi
gureC.
2: Th
issc
anrec
eivedara
tin
go f4fo
rthes
c o
reonthefi
rstPCfrom
bothr
ate
rs.Bothr
ate
rsal
sog a
vearat
ingof4fo
rtheles
ions
egmen
tat
ion
.

1
80
 PC1Sco
res
20
.4

−0
.7

−21
.7

Fi
gu r
eC .3
: Th
iss canrec
eivedaratingof3f orthescor
eonth efirstPCfrom
bothr a
ters
. Bothr a
ter
sa lsogavear atin
go f3f orthele
sionse
gm en
tat
ion.
Notethatatth
e2 3rdtimepointnewlesionvoxel
sa r
esegmented
,butthesco
re
forthefi r
stPCi sn o
tprodu c
edforthistimepoint,asthevoxe
lsdidnotm e
et
thescanningc
rite
riaforbeingin
cludedinth eanalys
is
.

1
81
 PC1Sco
res
14

Figu
reC .4
: Thisscanrec
eiv edaratingo f2forthesc
oreonth efi rs
tPCf rom
bothrate
rs.B o
thr a
ter
sals ogavear a
tingof2f o
rtheles
ionsegm enta
tion
. Th
e
neuro
radio
loig
stc ommentedth a
tthiss canre
ceivedalowrat
in gb e
causeitwa
s
notcle
arth a
tth esegmen
t edporti
onf ortimepoint3w asle
sion.

1
82
 PC1Sco
res
19
.9

−4
.1

−28
.1

Fi
gureC.5: Thi
sscanrece
ivedaratin
go f1forth
es co
reonthefi r
stPCfrom
bothrat
ers. Bothrat
ersalsoga
vear at
ingof1fortheles
ionsegmen
tat
ion.
Bothra
terscomm en
tedthatthelowratingwasbecau
sethele
sionhadex
ist
ed
inallt
im epoin
tsandw asnotan ewlesi
on.

1
83
 E
stimat
e St
and
ardE
rror t
-va
lue p
-va
lue 9
5%B
ootst
rappedCI
SPMS 2.15 4
.41 0
.49 0
.63 (
-6.19
,10.
93)
D
ist
anc
etoBoundary -9
.39 0
.08-123
.74 0
.00 (
-9.56
,-9.
25)
Age -0
.21 0
.18 - 1
.16 0
.25 (
-0.57
,0.13
)
(Age− 4)+ -0
.10 0
.23 - 0
.42 0
.68 (
-0.54
,0.35
)
S
ter
oids 4.26 0
.79 5
.42 0
.00 (2.67
,5.85
)
Male 1
.16 2
.55 0
.45 0
.65 (
-3.94
,6.61
)
T
reatment 5
.39 0
.36 1 5
.03 0
.00 (4.67
,6.08
)
In
tercept 8
.89 1
.92 4
.64 0
.00 (5.17
,12.
85)

T
abl
eC.1:C o
effi c
iente
stim
ates
,stand
arderr
ors
,t-
sta
tis
tic
s,p
-va
lue
s,andboo
tst
rapp
ed9
5%c
onfid
enc
ein
terv
als
f
orthe mu
lt
ivar
iat
ePCAr egr
ess
ion mod
el
.

1
84
 E
stimat
e St
and
ardE
rror t
-va
lue p
-va
lue 9
5%B
ootst
rappedCI
SPMS 0.65 4
.11 0
.16 0
.88 (-7.7
1,9.
18)
D
ist
anc
etoBoundary -9
.37 0
.08-123
.18 0
.00 (-
9.52
,-9.
22)
Age 0
.89 0
.19 4
.58 0
.00 (0.51
,1.23
)
(Age− 4)+ -1
.55 0
.24 - 6
.40 0
.00 (
-1.95
,-1.
14)
S
ter
oids 6.03 0
.78 7
.77 0
.00 (4.55
,7.59
)
Male 0
.43 2
.43 0
.18 0
.86 (
-4.32
,4.97
)
T
reatment 4
.48 0
.38 1 1
.76 0
.00 (3.67
,5.25
)

T
abl
eC.2:Coeffici
ente
stima
tes
,standarder
ror
s,t
-st
ati
sti
cs,p
-va
lue
s,andboo
tst
rapp
ed9
5%c
onfid
enc
ein
terv
als
f
ortheun
iva
ria
tePCAr eg
res
sion mod
el.

1
85
C
.5 Func
tion
-on
-sca
larreg
res
sion

Th
eco
effic
ien
tfun
cti
onsf
romth
efun
cti
on-
on-
sca
larr
egr
ess
ionw
ithboo
tst
rapp
ed

9
5%c
onfid
enc
ein
terv
alsw
ithth
eT2
,PD
,andT
1pr
ofil
easth
eou
tcom
ear
e
sh
ownb
elow
.Sim
ila
rtou
sin
gth
eFLA
IRp
rofi
lea
sth
eou
tcom
e,on
lyth
edi
s-

t
anc
etoth
ebound
aryanda
gew
eref
oundt
obed
iffe
ren
tfr
om0a
tan
ypo
int

a
lon
gth
epr
ofil
e.

1
86
 T2Func
tion−on−Sca
larCoe
ff
ic
ien
ts
In
tercep
t SPMS D
istancef
romBounda
ry

.5

.5
5

1
4

.5

.5
t

t
ien

ien

ien
0

0
3
ic

ic

ic
f

f
f

f
coe

coe

coe
2

.5

.5
−0

−0
1

.5

.5
0

−1

−1
0 50 100 150 200 0 50 100 150 200 0 50 100 150 200
t
ime(
inda
ys) t
ime(
inda
ys) t
ime(
inda
ys)

Age Sp
lineAge>40 S
tero
ids
.5

.5

.5
1

1
.5

.5

.5
t

t
ien

ien

ien
0

0
c

c
i

i
f

f
f

f
coe

coe

coe
.5

.5

.5
−0

−0

−0
.5

.5

.5
−1

−1

−1
0 50 100 150 200 0 50 100 150 200 0 50 100 150 200
t
ime(
inda
ys) t
ime(
inda
ys) t
ime(
inda
ys)

Ma
le T
rea
tmen
t
.5

.5
1

1
.5

.5
t

t
ien

ien
0

0
c

c
i

i
f

f
f

f
coe

coe
.5

.5
−0

−0
.5

.5
−1

−1

0 50 100 150 200 0 50 100 150 200

t
ime(
inda
ys) t
ime(
inda
ys)

F
igu r
eC .6
:E achda
rklinerep
resent
sthecoeffic
ientfunction,andthesh aded
ar
e arepre
sent
saboots
trapped
,po in
t-w
ise95%confid enc
ein terv
al
.A longthe
y-
axisisthevalu
eofthecoefficien
tfunc
tionateachtimepo int
. Onlydist
an c
e
fromth ebounda
ryandagew e
refoundtobediff
erentfrom0a tanypointalong
thep rofi
le
.

1
87
 PDFunc
tion−on−Sca
larCoe
ff
ic
ien
ts
In
tercep
t SPMS D
istancef
romBounda
ry

.5

.5
5

1
4

.5

.5
t

t
ien

ien

ien
0

0
3
ic

ic

ic
f

f
f

f
coe

coe

coe
2

.5

.5
−0

−0
1

.5

.5
0

−1

−1
0 50 100 150 200 0 50 100 150 200 0 50 100 150 200
t
ime(
inda
ys) t
ime(
inda
ys) t
ime(
inda
ys)

Age Sp
lineAge>40 S
tero
ids
.5

.5

.5
1

1
.5

.5

.5
t

t
ien

ien

ien
0

0
c

c
i

i
f

f
f

f
coe

coe

coe
.5

.5

.5
−0

−0

−0
.5

.5

.5
−1

−1

0 50 100 150 200 0 50 100 150 200 −1 0 50 100 150 200

t
ime(
inda
ys) t
ime(
inda
ys) t
ime(
inda
ys)

Ma
le T
rea
tmen
t
.5

.5
1

1
.5

.5
t

t
ien

ien
0

0
c

c
i

i
f

f
f

f
coe

coe
.5

.5
−0

−0
.5

.5
−1

−1

0 50 100 150 200 0 50 100 150 200

t
ime(
inda
ys) t
ime(
inda
ys)

F
i gur
eC .7
:E achdarkliner
epresentsth
ecoeffi c
ientfun c
tion
,andth esh aded
arearep
resent
saboo ts
trapped
,po int
-wi
se95%c onfiden cein
terva
l.A l
on gthe
x-ax
isofe a
chp l
oti
sth etimeind aysfr
oml e
sioninc
id ence
.A longthey -axi
s
isthev a
lueofthecoeffi c
ien
tfunc t
ionateachtimepo int
. Onlydistancefrom
thebound a
ryanda gew e
refoundt obediff
erentfr
om0a tanypointalongth e
profil
e.

1
88
 T1Func
tion−on−Sca
larCoe
ff
ic
ien
ts
In
tercep
t SPMS D
istancef
romBounda
ry

.5

.5
−5 −4 −3 −2 −1 0

1
.5

.5
t

t
ien

ien

ien
0

0
ic

ic

ic
f

f
f

f
coe

coe

coe
.5

.5
−0

−0
.5

.5
−1

−1
0 50 100 150 200 0 50 100 150 200 0 50 100 150 200
t
ime(
inda
ys) t
ime(
inda
ys) t
ime(
inda
ys)

Age Sp
lineAge>40 S
tero
ids
.5

.5

.5
1

1
.5

.5

.5
t

t
ien

ien

ien
0

0
c

c
i

i
f

f
f

f
coe

coe

coe
.5

.5

.5
−0

−0

−0
.5

.5

.5
−1

−1

0 50 100 150 200 0 50 100 150 200 −1 0 50 100 150 200

t
ime(
inda
ys) t
ime(
inda
ys) t
ime(
inda
ys)

Ma
le T
rea
tmen
t
.5

.5
1

1
.5

.5
t

t
ien

ien
0

0
c

c
i

i
f

f
f

f
coe

coe
.5

.5
−0

−0
.5

.5
−1

−1

0 50 100 150 200 0 50 100 150 200

t
ime(
inda
ys) t
ime(
inda
ys)

F
i gur
eC .8
:E achdarkliner
epresentsth
ecoeffi c
ientfun c
tion
,andth esh aded
arearep
resent
saboo ts
trapped
,po int
-wi
se95%c onfiden cein
terva
l.A l
on gthe
x-ax
isofe a
chp l
oti
sth etimeind aysfr
oml e
sioninc
id ence
.A longthey -axi
s
isthev a
lueofthecoeffi c
ien
tfunc t
ionateachtimepo int
. Onlydistancefrom
thebound a
ryanda gew e
refoundt obediff
erentfr
om0a tanypointalongth e
profil
e.

1
89
B
ibl
iog
raphy

[
1]M
.A.S
ahr
aianandE
.-W
.Radu
e,MR
Iat
laso
f MSl
esion
s. Sp
rin
ger

S
cien
ce&Bu
sin
essM
edi
a,2
007
.

[
2]À
.Ro
vir
aandA
.Le
ón
,“M
rinth
edi
agn
osi
sand m
oni
tor
ingo
f mu
lt
ipl
e

s
cle
ros
is
:ano
verv
iew
,”Eu
rop
eanjou
rna
lofr
adio
log
y,v
ol.6
7,n
o.3
,pp
.

4
09–
414
,20
08.

[
3]À
.Ro
vir
a,J
.Sw
ant
on,M
.Tin
tor
é
,E.Hu
erg
a,F
.Ba
rkh
of,M
.Fi
lipp
i,J
.L.

F
red
erik
sen
,A.L
angk
ild
e,K
.Mi
szk
ie
l,C
.Po
lmane
tal
.,“As
ing
le
,ea
rly

m
agn
eti
cre
son
anc
eim
agin
gstudyinth
edi
agn
osi
sof mu
lt
ipl
esc
ler
osi
s,”

A
rch
ive
sofN
eur
olo
gy,v
ol.6
6,n
o.5
,pp
.58
7–5
92,2
009
.

[
4]C
.H.P
olm
an,S
.C.R
ein
gold
,B.B
anw
el
l,M
.Cl
ane
t,J
.A.C
ohen
,M.F
il
-

ipp
i,K
.Fu
jih
ara
,E.H
avrd
ova
,M. Hu
tch
ins
on,L
.Kappo
seta
l.,“D
i-

a
gno
sti
ccr
ite
riaf
or mu
lt
ipl
esc
ler
osi
s:2
010r
evi
sion
stoth
emcd
ona
ld

c
rit
eri
a,”Anna
lso
fneu
rolo
gy,v
ol.6
9,n
o.2
,pp
.29
2–3
02,2
011
.

[
5]F
.Ba
rkh
of,“Th
ecl
ini
co-
rad
iol
ogi
calp
arad
oxin mu
lt
ipl
esc
ler
osi
srev
is
-

i
ted
,”Cu
rren
top
inioninn
eur
olo
gy,v
ol.1
5,n
o.3
,pp
.23
9–2
45,2
002
.

1
90
[
6]E
.M.Sw
een
ey,A
.El
oyan
,R.T
.Sh
inoh
ara
,andC
.M.C
rain
ice
anu
,“A
tu
tor
ialf
or mu
lt
isequ
enc
ecl
ini
cals
tru
ctu
ralb
rain MR
I,”inHand
boo
kof

Mo
dernS
tat
ist
ica
lMe
tho
ds:N
eur
oima
gin
gDa
taAna
lys
is,t
oapp
ear
.

[
7]E
.M.Sw
een
ey,R
.T.Sh
inoh
ara
,N.Sh
iee
,F.J
.Ma
teen
,A.A
.Chud
gar
,

J
.L. Cu
zzo
cre
o,P
.A.C
alab
res
i,D
.L.Ph
am,D
.S.R
eich
,and C
.M.
C
rain
ice
anu
,“OAS
ISi
sau
tom
ateds
tat
ist
ica
lin
fer
enc
efo
rse
gmen
tat
ion
,

w
ithapp
li
cat
ion
sto mu
lt
ipl
esc
ler
osi
sle
sions
egm
ent
ati
onin MR
I,”N
eu-

r
oIma
ge:c
lin
ica
l,v
ol.2
,pp
.40
2–4
13,2
013
.

[
8]E
.M.Sw
een
ey,J
.T.V
oge
lst
ein
,J.L
.Cu
zzo
cre
o,P
.A.C
alab
res
i,D
.S.
R
eich
,C.M
.Cr
ain
ice
anu
,and R
.T.Sh
inoh
ara
,“Ac
omp
ari
sono
fsu
-

p
erv
ised m
ach
inel
earn
inga
lgo
rithm
sandf
eatu
rev
ect
orsf
or MSl
esi
on

s
egm
ent
ati
onu
sin
g mu
lt
imod
als
tru
ctu
ralm
ri
,”P
loSon
e,v
ol.9
,no
.4,

p
.e9
575
3,2
014
.

[
9]E
.Sw
een
ey,R
.Sh
inoh
ara
,C.Sh
ea,D
.Re
ich
,andC
.Cr
ain
ice
anu
,“Au
-

t
oma
ticl
esi
onin
cid
enc
ees
tim
ati
onandd
ete
cti
onin mu
lt
ipl
esc
ler
osi
sus
-

in
gmu
lt
isequ
enc
elon
gitud
ina
lmr
i,”Am
eri
canJou
rna
lofN
eur
orad
iolo
gy,

v
ol.3
4,n
o.1
,pp
.68
–73
,20
13.

[
10]E
. M
. Sw
een
ey, R
.T. Sh
inoh
ara
, B
.E. D
ewey
, M
. K
.Sch
ind
ler
,

J
. Mu
sch
el
li
,D.S
.Re
ich
,C.M
.Cr
ain
ice
anu
,and A
.El
oyan
,“R
ela
t-

in
g mu
lt
i-
sequ
enc
elon
gitud
ina
lin
ten
sit
ypr
ofil
esandc
lin
ica
lco
var
iat
es

inin
cid
ent mu
lt
ipl
esc
ler
osi
sle
sion
s,”N
eur
oIma
ge:C
lin
ica
l,v
ol.1
0,pp
.

1
–17
,20
16.

1
91
[
11]S
.W.A
tla
s,Ma
gne
ticr
esonan
ceima
gin
gofth
ebr
ainandsp
ine. L
ip-
p
inc
ottW
il
liam
s& W
ilk
ins
,20
09,v
ol.1
.

[
12]B
.Kev
les
,Na
kedtoth
ebon
e:M
edi
calima
gin
ginth
etw
ent
iethc
entu
ry.

Ru
tge
rsUn
ive
rsi
tyP
res
s,1
997
.

[
13]M
.A.L
indqu
iste
tal
.,“Th
est
ati
sti
calan
aly
siso
ffm
rid
ata
,”S
tat
ist
ica
l
S
cien
ce,v
ol.2
3,n
o.4
,pp
.43
9–4
64,2
008
.

[
14] RC
oreT
eam
,R:AL
angua
geandEn
vir
onm
entfo
rSta
tis
tic
alCompu
tin
g,

RF
ound
ati
onf
orS
tat
ist
ica
lCompu
tin
g,V
ienn
a,Au
str
ia,2
014
.[On
lin
e]
.

Av
ai
lab
le
:ht
tp:
//www
.R-p
roj
ect
.or
g/

[
15]B
. Wh
itch
er, V
.J.S
chm
id, and A
. Th
orn
ton
, “W
ork
ingw
ithth
e

D
ICOM and N
IfT
Ida
tas
tand
ard
sin R
,” Jou
rna
lofS
tat
ist
ica
l

So
ftwa
re, v
ol.4
4, n
o.6
, pp
.1–
28, 2
011
. [On
lin
e]
. Av
ai
lab
le
:

h
ttp
://www
.j
sta
tso
ft
.or
g/v
44/
i06
/

[
16]R
. Sh
inoh
ara
, C
.Cr
ain
ice
anu
, B
.Caff
o, M
. G
aitn
, and D
.Re
ich
,

“P
opu
lat
ion
-wid
epr
inc
ipa
lcompon
ent
-ba
sed qu
ant
ific
ati
on o
fbl
ood
-

b
rain
-ba
rri
erdyn
ami
csin mu
lt
ipl
esc
ler
osi
s,”N
eur
oima
ge,v
ol.5
7,n
o.4
,

pp
.14
30–
144
6,2
011
.

[
17]R
.Sh
inoh
ara
,A.G
old
smi
th,F
.Ma
teen
,C.C
rain
ice
anu
,and D
.Re
ich
,

“P
red
ict
ingb
reakd
owno
fth
ebl
ood
-br
ainb
arr
ierin mu
lt
ipl
esc
ler
osi
s

w
ith
outc
ont
ras
tag
ent
s,” Am
eri
canJou
rna
lofN
eur
orad
iolo
gy,v
ol.3
3,

n
o.8
,pp
.15
86–
159
0,2
012
.

1
92
[
18]G
.vanR
ossumandJ
.deB
oer
,“In
ter
act
ive
lyt
est
ingr
emo
tes
erv
ersu
sin
g
th
epy
thonp
rog
ramm
ingl
angu
age
,”CW
I Qua
rte
rly,v
ol.4
,no
.4,pp
.

2
83–
303
,19
91.[On
lin
e]
.Av
ai
lab
le
:ht
tp:
//www
.j
sta
tso
ft
.or
g/v
44/
i06
/

[
19]J
.G.S
led
,A.P
.Zi
jdenbo
s,andA
.C.Ev
ans
,“An
onp
aram
etr
icm
eth
od

f
orau
tom
ati
cco
rre
cti
ono
fin
ten
sit
ynonun
ifo
rmi
tyin m
rid
ata
,”M
edi
cal
Ima
gin
g,IEEET
ran
sac
tion
son
,vo
l.1
7,n
o.1
,pp
.87
–97
,19
98.

[
20]N
.J.T
ust
ison
,B.B
. Av
ant
s,P
.A.C
ook
,Y.Zh
eng
,A.E
gan
,P.A
.

Y
ushk
evi
ch,andJ
.C.G
ee,“N
4itk
:Imp
rov
edn
3bi
asc
orr
ect
ion
,”M
edi
cal

Ima
gin
g,IEEET
ran
sac
tion
son
,vo
l.2
9,n
o.6
,pp
.13
10–
132
0,2
010
.

[
21]S
.Gr
even
,C.M
.Cr
ain
ice
anu
,B.C
affo
,and D
.Re
ich
,“L
ong
itud
ina
l

fun
cti
ona
lpr
inc
ipa
lcompon
entan
aly
sis
,”E
lec
tron
icJou
rna
lofS
tat
ist
ics,

v
ol.4
,pp
.10
22–
105
4,2
010
.

[
22]M
.A.B
ern
ste
in,K
.F.K
ing
,and X
.J.Zh
ou,Hand
boo
kof MR
Ipu
lse

s
equ
enc
es. E
lsev
ier
,20
04.

[
23]E
.L.G
edamu
,D.C
oll
ins
,andD
.L.A
rno
ld,“Au
tom
atedqu
ali
tyc
ont
rol

o
fbr
ain m
rim
age
s,”Jou
rna
lof Ma
gne
ticR
esonan
ceIma
gin
g,v
ol.2
8,

n
o.2
,pp
.30
8–3
19,2
008
.

[
24]T
.Ih
ala
inen
,O.S
ipi
lä
,andS
.Sa
vol
ain
en,“M
riqu
ali
tyc
ont
rol
:sixim
-

a
ger
sstud
iedu
sin
gel
evenun
ifiedim
agequ
ali
typ
aram
ete
rs”Eu
, rop
ean

r
adio
log
y,v
ol.1
4,n
o.1
0,pp
.18
59–
186
5,2
004
.

[
25]D
.E.R
ex,J
.Q.M
a,and A
. W
.To
ga,“Th
elon
ipip
elin
epr
oce
ssin
g

en
vir
onm
ent
,”N
eur
oima
ge,v
ol.1
9,n
o.3
,pp
.10
33–
104
8,2
003
.

1
93
[
26]M
.Jenk
ins
on,C
.F.B
eckm
ann
,T.E
.Beh
ren
s,M
.W.W
ool
rich
,andS
.M.
Sm
ith
,“F
sl
,”N
eur
oima
ge,v
ol.6
2,n
o.2
,pp
.78
2–7
90,2
012
.

[
27]B
.C.Lu
cas
,J.A
.Bo
gov
ic
,A.C
ara
ss,P
.-L
.Ba
zin
,J.L
.Pr
inc
e,D
.L.
Ph
am,andB
.A.L
andm
an,“Th
eja
vaim
ages
cien
cet
oolk
it(
ji
st)f
orr
apid

p
rot
otyp
ingandpub
li
shin
gofn
eur
oim
agin
gso
ftw
are
,”N
eur
oin
forma
tic
s,
v
ol.8
,no
.1,pp
.5–
17,2
010
.

[
28]M
.J.M
cAu
liff
e,F
.M.L
alond
e,D
.McG
arry
, W
.Gand
ler
,K.C
saky
,

and B
.L.T
rus
,“M
edi
calim
agep
roc
ess
ing
,an
aly
sisandv
isu
ali
zat
ion

inc
lin
ica
lre
sea
rch
,”inCompu
ter
-Ba
sedM
edi
calS
yst
ems
,2001
. CBMS

2001
.Pr
oce
edin
gs.14
thIEEES
ymp
osiumon. IEEE
,20
01,pp
.38
1–3
86.

[
29]Z
.Hou
,“Ar
evi
ewon m
rim
agein
ten
sit
yinh
omo
gen
eit
yco
rre
cti
on,
”In
-

t
erna
tiona
lJou
rna
lofB
iom
edi
calIma
gin
g,v
ol.2
006
,20
06.

[
30]U
.Vo
vk,F
.Pe
rnu
s,andB
.Lik
ar,“Ar
evi
ewo
fme
thod
sfo
rco
rre
cti
on

o
fin
ten
sit
yinh
omo
gen
eit
yin m
ri
,”M
edi
calIma
gin
g,IEEET
ran
sac
tion
s

on
,vo
l.2
6,n
o.3
,pp
.40
5–4
21,2
007
.

[
31]S
.M.Sm
ith
,“F
astr
obu
stau
tom
atedb
rainex
tra
cti
on,
”Humanb
rain

mapp
ing,v
ol.1
7,n
o.3
,pp
.14
3–1
55,2
002
.

[
32]C
.Fenn
ema
-No
tes
tin
e,I
.B.O
zyu
rt,C
.P.C
lark
,S.M
orr
is
,A.B
isch
off-

G
reth
e,M
.W.B
ond
i,T
.L.J
ern
igan
,B.F
isch
l,F
.Se
gonn
e,D
.W.Sh
at-

tu
cke
tal
.,“Qu
ant
ita
tiv
eev
alu
ati
ono
fau
tom
atedsku
ll
-st
ripp
ingm
eth
-

od
sapp
li
edt
ocon
tempo
raryandl
ega
cyim
age
s:Eff
ect
sofd
iagn
osi
s,b
ias
c
orr
ect
ion
,ands
li
cel
oca
tion
,”Humanb
rain mapp
ing,v
ol.2
7,n
o.2
,pp
.

9
9–1
13,2
006
.

1
94
[
33]J
.-M
.Le
e,U
.Yoon
,S.H
.Nam
,J.
-H.K
im,I
.-Y
.Kim
,andS
.I.K
im,
“Ev
alu
ati
ono
fau
tom
atedands
emi
-au
tom
atedsku
ll
-st
ripp
inga
lgo
rithm
s

u
sin
gsim
ila
rit
yind
exands
egm
ent
ati
one
rro
r,”Compu
ter
sinb
iolo
gyand
m
edi
cin
e,v
ol.3
3,n
o.6
,pp
.49
5–5
07,2
003
.

[
34]A
.Ca
ras
s,J
.Cu
zzo
cre
o,M
.B. Wh
eel
er,P
.-L
.Ba
zin
,S.M
.Re
sni
ck,and

J
.L.P
rin
ce,“S
imp
lep
arad
igmf
orex
tra
-ce
reb
ralt
issu
erem
ova
l:a
lgo
-

r
ithmandan
aly
sis
,”N
eur
oIma
ge,v
ol.5
6,n
o.4
,pp
.19
82–
199
2,2
011
.

[
35]J
.E.I
gle
sia
s,C
.-Y
.Liu
,P.M
.Th
omp
son
,andZ
.Tu
,“R
obu
stb
rainex
-

t
rac
tiona
cro
ssd
ata
set
sandc
omp
ari
sonw
ithpub
li
clya
vai
lab
lem
eth
ods
,”

M
edi
calIma
gin
g,IEEE T
ran
sac
tion
son,v
ol.3
0,n
o.9
,pp
.16
17–
163
4,

2
011
.

[
36]R
.A.H
eck
emann
,J.V
.Ha
jna
l,P
.Al
jab
ar,D
.Ru
eck
ert
,andA
.Hamm
ers
,

“Au
tom
ati
can
atom
ica
lbr
ain m
ris
egm
ent
ati
onc
omb
inin
glab
elp
rop
aga
-

t
ionandd
eci
sionfu
sion
,”N
eur
oIma
ge,v
ol.3
3,n
o.1
,pp
.11
5–1
26,2
006
.

[
37]S
.K. W
arfi
eld
,K.H
.Zou
,and W
.M. W
el
ls
,“S
imu
ltan
eou
stru
thand

p
erf
orm
anc
elev
ele
stim
ati
on(
stap
le)
:ana
lgo
rithmf
orth
eva
lid
ati
ono
f

im
ages
egm
ent
ati
on,
”Me
dic
alIma
gin
g,IEEE T
ran
sac
tion
son,v
ol.2
3,

n
o.7
,pp
.90
3–9
21,2
004
.

[
38]K
.K.L
eun
g,J
.Ba
rne
s,M
.Mod
at,G
.R.R
idgw
ay,J
.W.B
art
let
t,N
.C.

F
ox,andS
. Ou
rse
lin
,“B
rain m
aps
:anau
tom
ated
,ac
cur
ateandr
obu
st

b
rainex
tra
cti
ont
echn
iqu
eus
ingat
emp
lat
elib
rary
,”N
eur
oima
ge,v
ol.5
5,

n
o.3
,pp
.10
91–
110
8,2
011
.

1
95
[
39]J
.Do
shi
,G.E
rus
,Y. Ou
,B.G
aonk
ar,andC
.Da
vat
zik
os,“Mu
lt
i-a
tla
s
sku
ll
-st
ripp
ing
,”A
cad
emi
crad
iolo
gy,v
ol.2
0,n
o.1
2,pp
.15
66–
157
6,2
013
.

[
40]S
.F.E
ski
lds
en,P
.Coup
é
,V.F
ono
v,J
.V. M
anj
ón
, K
.K.L
eun
g,

N
. Gu
iza
rd,S
.N.W
ass
ef,L
.R.Ø
ste
rga
ard
,and D
.L.C
oll
ins
,“B
eas
t:

B
rainex
tra
cti
onb
asedonn
onl
oca
lse
gmen
tat
iont
echn
iqu
e,”N
eur
oIma
ge,
v
ol.5
9,n
o.3
,pp
.23
62–
237
3,2
012
.

[
41]D
.W.Sh
attu
ck,G
.Pr
asad
,M.M
irz
a,K
.L.N
arr
,andA
.W.T
oga
,“On
-

l
iner
esou
rcef
orv
al
ida
tiono
fbr
ains
egm
ent
ati
on m
eth
ods
,”N
eur
oIma
ge,

v
ol.4
5,n
o.2
,pp
.43
1–4
39,2
009
.

[
42]S
.M.Sm
ith
,M.J
enk
ins
on,M
. W
. W
ool
rich
,C.F
.Be
ckm
ann
,T.E
.

B
ehr
ens
,H.J
ohan
sen
-Be
rg,P
.R.B
ann
ist
er,M
.DeLu
ca,I
.Dr
obn
jak
,

D
.E.F
li
tney e
tal
.,“Adv
anc
esinfun
cti
ona
lands
tru
ctu
ralm
rim
age

an
aly
sisandimp
lem
ent
ati
ona
sfs
l,”N
eur
oima
ge,v
ol.2
3,pp
.S2
08–S
219
,

2
004
.

[
43]B
.C.Lu
cas
,J.A
.Bo
gov
ic
,A.C
ara
ss,P
.-L
.Ba
zin
,J.L
.Pr
inc
e,D
.L.

Ph
am,andB
.A.L
andm
an,“Th
eja
vaim
ages
cien
cet
oolk
it(
ji
st)f
orr
apid

p
rot
otyp
ingandpub
li
shin
gofn
eur
oim
agin
gso
ftw
are
, eu
”N r
oin
forma
tic
s,

v
ol.8
,no
.1,pp
.5–
17,2
010
.

[
44]T
.M.L
ehm
ann
,C.G
onn
er,andK
.Sp
itz
er,“Su
rvey
:In
terpo
lat
ionm
eth
-

od
sin m
edi
calim
agep
roc
ess
ing
,”M
edi
calIma
gin
g,IEEE T
ran
sac
tion
s

on
,vo
l.1
8,n
o.1
1,pp
.10
49–
107
5,1
999
.

1
96
[
45]K
.J.F
ri
ston
,J.T
.Ashbu
rne
r,S
.J.K
ieb
el,T
.E.N
ich
ols
,and W
.D.
P
enn
y,S
tat
ist
ica
lpa
ram
etr
ic mapp
ing
: Th
eana
lys
iso
ffun
ctiona
lbr
ain

ima
ges
: Th
eana
lys
iso
ffun
ctiona
lbr
ainima
ges
. A
cad
emi
cPr
ess
,20
05.

[
46]J
.V.H
ajn
alandD
.L.H
il
l,M
edi
calima
ger
egi
str
ation. CRCp
res
s,2
010
.

[
47]I
.Dryd
enandK
.Ma
rdi
a,S
tat
ist
ica
lshap
eana
lys
is. J
ohn W
il
ey&S
ons
,
Ch
ich
est
er,1
998
.

[
48]B
.B.Av
ant
s,N
.Tu
sti
son
,and G
.Son
g,“Adv
anc
edn
orm
ali
zat
iont
ool
s

(
ant
s),
”In
sigh
tJ,2
009
.

[
49]L
.G. Nyu
landJ
.K. Udup
a,“Ons
tand
ard
iz
ingth
emrim
agein
ten
sit
y

s
cal
e,”Ma
gne
ticR
esonan
cein M
edi
cin
e,v
ol.4
2,n
o.6
,pp
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72–
108
1,

1
999
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[
50]M
.Sh
ah,Y
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ao,N
.Subb
ann
a,S
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anc
is
,D.L
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old
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ll
ins
,

andT
.Arb
el,“Ev
alu
atin
gin
ten
sit
yno
rma
li
zat
iononm
riso
fhum
anb
rain

w
ith mu
lt
ipl
esc
ler
osi
s,”M
edi
calIma
geAna
lys
is,v
ol.1
5,n
o.2
,pp
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7–

2
82,2
011
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[
51]N
. W
eis
enf
eldandS
. W
arfi
eld
,“N
orm
ali
zat
iono
fjo
intim
age
-in
ten
sit
y
s
tat
ist
icsin m
riu
sin
gth
eku
llb
ack
-le
ibl
erd
ive
rgen
ce,
”inB
iom
edi
cal

Ima
gin
g: Nanoto Ma
cro
, 2004
.IEEEIn
terna
tiona
lSymp
osiumon
.

IEEE
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04,pp
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04.

[
52]R
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inoh
ara
, E
. Sw
een
ey, J
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old
smi
th, N
. Sh
iee
, F
. M
ate
en,
P
. C
alab
res
i,S
.Ja
rso
, D
. Ph
am, D
. R
eich
, and C
. C
rain
ice
anu
,

1
97
 “N
orm
ali
zat
ion t
echn
iqu
es f
or s
tat
ist
ica
l in
fer
enc
e f
rom m
ag-
n
eti
cre
son
anc
eim
agin
g,”in UP
enn B
ios
tat
ist
ics Wo
rkin
g Pap
ers.

h
ttp
://b
ios
tat
s.b
epr
ess
.com
/up
ennb
ios
tat
/ar
t36
,20
13,p
.Wo
rkin
gPap
er
3
6.

[
53]L
.G.Nyu
l,J
.K.Udup
a,andX
.Zh
ang
,“N
ewv
ari
ant
sofam
eth
odo
fmr
i

s
cal
est
and
ard
iza
tion
,”IEEE T
ran
sac
tion
son M
edi
calIma
gin
g,v
ol.1
9,
n
o.2
,pp
.14
3–1
50,2
000
.

[
54]R
.T.Sh
inoh
ara
,C. M
.Cr
ain
ice
anu
,B.S
.Caff
o, M
.I.G
ait
án
,and

D
.S.R
eich
,“P
opu
lat
ion
-wid
epr
inc
ipa
lcompon
ent
-ba
sedqu
ant
ific
ati
on

o
fbl
ood
-br
ain
-ba
rri
erdyn
ami
csin mu
lt
ipl
esc
ler
osi
s.”N
eur
oIma
ge,2
011
.

[
55]E
.M.Sw
een
ey,R
.T.Sh
inoh
ara
,C.D
.Sh
ea,D
.S.R
eich
,and C
.M.

C
rain
ice
anu
,“Au
tom
ati
cle
sion
inc
iden
cee
stim
ati
onandd
ete
cti
oninmu
l-

t
ipl
esc
ler
osi
sus
ingmu
lt
isequ
enc
elon
gitud
ina
lmr
i,”Am
eri
canJou
rna
lof

N
eur
orad
iolo
gy,2
012
.

[
56]D
.Rupp
ert
,M.P
.Wand
,andR
.J.C
arr
oll
,Sem
ipa
ram
etr
icR
egr
ess
ion.

C
amb
rid
geUn
ive
rsi
tyP
res
s,2
003
.

[
57]C
.E.P
rieb
e,M
.I.M
il
ler
,andJ
.Ti
lakR
atn
ana
the
r,“S
egm
ent
ingm
ag-

n
eti
cre
son
anc
eim
age
svi
ahi
era
rch
ica
lmix
tur
emod
el
lin
g,”Compu
ta-

t
iona
lsta
tis
tic
s&da
taana
lys
is,v
ol.5
0,n
o.2
,pp
.55
1–5
67,2
006
.

[
58]T
.P.B
ere
sfo
rd,D
.B.A
rcin
ieg
as,J
.Al
fer
s,L
.Cl
app
,B.M
art
in,Y
.Du
,

D
.Liu
,D.Sh
en,and C
.Da
vat
zik
os,“H
ippo
campu
svo
lum
elo
ssdu
eto

ch
ron
ich
eavyd
rink
ing
,”A
lcoho
li
sm:C
lin
ica
landE
xpe
rim
enta
lRe
sea
rch,

v
ol.3
0,n
o.1
1,pp
.18
66–
187
0,2
006
.

1
98
[
59]D
.L.Ph
am,C
.Xu
,andJ
.L.P
rin
ce,“Cu
rren
tme
thod
sinm
edi
calim
age
s
egm
ent
ati
on1
,”Annua
lre
viewo
fbiom
edi
calen
gin
eer
ing,v
ol.2
,no
.1,

pp
.31
5–3
37,2
000
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[
60]M
.A.B
ala
far
,A.R
.Ram
li
,M.I
.Sa
rip
an,andS
.Ma
shoh
or,“R
evi
ew

o
fbr
ainm
riim
ages
egm
ent
ati
on m
eth
ods
,”A
rtifi
cia
lIn
tel
lig
enc
eRe
view,
v
ol.3
3,n
o.3
,pp
.26
1–2
74,2
010
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[
61]M
.A.S
ahr
aian
,E.
-W.R
adu
e,and A
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ss,MR
Iat
laso
f MSl
esion
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Sp
rin
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[
62]J
.Sim
on,D
.Li
,A.T
rabou
lse
e,P
.Co
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,D.A
rno
ld,F
.Ba
rkh
of,J
.Fr
ank
,

R
.Gr
ossm
an,D
.Pa
ty,E
.Radu
eeta
l.,“S
tand
ard
izedm
rim
agin
gpr
oto
col

f
or mu
lt
ipl
esc
ler
osi
s:C
ons
ort
iumo
fmsc
ent
ersc
ons
ensu
sgu
ide
lin
es,
”

Am
eri
canJou
rna
lofN
eur
orad
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gy,v
ol.2
7,n
o.2
,pp
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5–4
61,2
006
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[
63]D
.Ga
rcı́
a-L
oren
zo,S
.Fr
anc
is
,S.N
ara
yan
an,D
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rno
ld,and D
.L.
C
oll
ins
,“R
evi
ewo
fau
tom
ati
cse
gmen
tat
ion m
eth
odso
f mu
lt
ipl
esc
ler
o-

s
is wh
item
att
erl
esi
onsonc
onv
ent
ion
alm
agn
eti
cre
son
anc
eim
agin
g,”

M
edi
calima
geana
lys
is,v
ol.1
7,n
o.1
,pp
.1–
18,2
013
.

[
64]X
.Ll
adó
,O.G
ani
ler
,A.O
liv
er,R
.Ma
rtı́
,J.F
reix
ene
t,L
.Va
ll
s,J
.C.

V
ilan
ova
,L.R
ami
ó
-To
rren
tà
,and À
.Ro
vir
a,“Au
tom
atedd
ete
cti
ono
f
mu
lt
ipl
esc
ler
osi
sle
sion
sins
eri
alb
rainm
ri
,”N
eur
orad
iolo
gy,v
ol.5
4,n
o.8
,

pp
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7–8
07,2
012
.

[
65]X
.ó
,A.O
liv
er, M
.Cab
eza
s,J
.Fr
eix
ene
t,J
.C.V
ilan
ova
,A. Qu
il
es,

L
.Va
ll
s,L
.Ram
ió
-To
rren
tà
,andÀ
.Ro
vir
a,“S
egm
ent
ati
ono
f mu
lt
ipl
e

1
99
 s
cle
ros
isl
esi
onsinb
rain m
ri
:ar
evi
ewo
fau
tom
atedapp
roa
che
s,”In
for
-
ma
tionS
cien
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ol.1
86,n
o.1
,pp
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4–1
85,2
012
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[
66]N
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iee
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azin
,A.O
ztu
rk,D
.S.R
eich
,P.A
.Ca
lab
res
i,andD
.L.

Ph
am,“At
opo
logy
-pr
ese
rvin
gapp
roa
cht
oth
ese
gmen
tat
iono
fbr
ainim
-

a
gesw
ithmu
lt
ipl
esc
ler
osi
sle
sion
s,”N
eur
oIma
ge,v
ol.4
9,n
o.2
,pp
.15
24–
1
535
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10.

[
67]M
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yne
r,J
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e, B
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S
.Ma
rko
vic
-Pl
ese
,V.J
ewe
ll
s,andS
.Wa
rfie
ld,“
3ds
egm
ent
ati
oninth
e

c
lin
ic
: Ag
randch
all
eng
eii
: M
sle
sions
egm
ent
ati
on,
”MIDASJou
rna
l,

v
ol.2
008
,pp
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6,2
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[
68]D
.Hand
,“C
las
sifi
ert
echn
olo
gyandth
eil
lus
iono
fpr
ogr
ess
,”S
tat
ist
ica
l

T
echno
log
y,v
ol.2
1,n
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15,2
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[
69]K
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an L
eempu
t,F
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aes
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and
erm
eul
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lch
est
er, and
P
.Su
eten
s,“Au
tom
ateds
egm
ent
ati
ono
f mu
lt
ipl
esc
ler
osi
sle
sion
sby

m
ode
lou
tl
ierd
ete
cti
on,
”Me
dic
alIma
gin
g,IEEET
ran
sac
tion
son,v
ol.2
0,

n
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88,2
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[
70]M
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orm
ani
,L.B
onz
ano
,L.R
occ
ata
gli
ata
,G.R
.Cu
tte
r,G
.L.M
an-

c
ard
i,andP
.Bru
zzi
,“M
agn
eti
cre
son
anc
eim
agin
gasapo
ten
tia
lsu
rro
gat
e

f
orr
elap
sesin mu
lt
ipl
esc
ler
osi
s: Am
eta
-an
aly
ticapp
roa
ch,
”Anna
lso
f

n
eur
olo
gy,v
ol.6
5,n
o.3
,pp
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8–2
75,2
009
.

[
71]M
.Cab
eza
s,A
.Ol
ive
r,X
.Ll
adó
,J.F
reix
ene
t,and M
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adr
a,“A

r
evi
ewo
fat
las
-ba
seds
egm
ent
ati
onf
orm
agn
eti
cre
son
anc
ebr
ainim
age
s,”

2
00
 Compu
term
etho
dsandp
rog
ram
sinb
iom
edi
cin
e,v
ol.1
04,n
o.3
,pp
.e1
58–
e
177
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11.

[
72]D
.Go
ldb
erg
-Zim
rin
g,A
.Ach
iron
,S.M
iron
,M.F
aib
el,and H
.Azh
ari
,
“Au
tom
atedd
ete
cti
onandch
ara
cte
riz
ati
ono
fmu
lt
ipl
esc
ler
osi
sle
sion
sin

b
rain m
rim
age
s,”Ma
gne
ticr
esonan
ceima
gin
g,v
ol.1
6,n
o.3
,pp
.31
1–
3
18,1
998
.

[
73]B
.Al
fan
o,A
.Brun
ett
i,M
.La
rob
ina
,M.Qu
aran
tel
li
,E.T
ede
sch
i,A
.Ci
a-

rm
ie
llo
,E.M
.Co
vel
li
,and M
.Sa
lva
tor
e,“Au
tom
ateds
egm
ent
ati
onand

m
easu
rem
ento
fgl
oba
lwh
item
att
erl
esi
onv
olum
einp
ati
ent
swi
th mu
lt
i-

p
les
cle
ros
is
,”Jou
rna
lof Ma
gne
ticR
esonan
ceIma
gin
g,v
ol.1
2,n
o.6
,pp
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7
99–
807
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00.

[
74]P
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eek
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cken
,M.J
.vanO
sch
,R.H
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ssch
ops
,andJ
.vand
er

G
rond
,“P
rob
abi
li
sti
cse
gmen
tat
iono
fwh
item
att
erl
esi
onsin m
rim
ag-

in
g,”N
eur
oIma
ge,v
ol.2
1,n
o.3
,pp
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37–
104
4,2
004
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[
75]P
. Anb
eek
,K.L
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cken
,G.S
.Van B
och
ove
, M
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an O
sch
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J
.vand
erG
rond
,“P
rob
abi
li
sti
cse
gmen
tat
iono
fbr
aint
issu
ein m
rim
ag-

in
g,”N
eur
oima
ge,v
ol.2
7,n
o.4
,pp
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5–8
04,2
005
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[
76]P
. Anb
eek
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cken
,and M
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ier
gev
er,“Au
tom
ated m
s-
les
ion

s
egm
ent
ati
onb
yk-n
ear
estn
eighbo
rcl
ass
ific
ati
on,
”MIDASJ,2
008
.

[
77]B
.R.S
ajj
a,S
.Da
tta
,R.H
e,M
.Meh
ta,R
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ta,J
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ol
insky
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P
.A.N
ara
yan
a,“Un
ifiedapp
roa
chf
or mu
lt
ipl
esc
ler
osi
sle
sions
egm
ent
a-

t
iononb
rain m
ri
,”Anna
lso
fbiom
edi
calen
gin
eer
ing,v
ol.3
4,n
o.1
,pp
.

1
42–
151
,20
06.

2
01
[
78]S
.Da
tta
,B.R
.Sa
jja
,R.H
e,J
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ol
insky
,R.K
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ta,andP
.A.
N
ara
yan
a,“S
egm
ent
ati
onandqu
ant
ific
ati
ono
fbl
ackh
ole
sin mu
lt
ipl
e

s
cle
ros
is
,”N
eur
oima
ge,v
ol.2
9,n
o.2
,pp
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7–4
74,2
006
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[
79]M
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lly
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agn
ott
a,C
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spa
rov
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el
lig
rim
o,D
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is
, and

H
.Bo
ckh
olt
,“3ds
egm
ent
ati
oninth
ecl
ini
c:ag
randch
all
eng
eiia
tmi
cca
i
2
008
–msl
esi
ons
egm
ent
ati
on,
”inM
IDASJou
rna
l-M
ICCA
I2008 Wo
rk-

shop
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[
80]J
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rra
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u,A
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ga,andP
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son
,“Au
tom
ati
cse
gmen
tat
ion

o
fmsl
esi
onsu
sin
gac
ont
extu
alm
ode
lfo
rth
emi
cca
igr
andch
all
eng
e,”

G
rand Cha
llen
ge Wo
rk.
: Mu
lt
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ler
.Le
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egm
. Cha
ll
eng
e,pp
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[
81]N
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ann
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anc
is
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ld,

andT
.Arb
el,“M
sle
sions
egm
ent
ati
onu
sin
gma
rko
vrand
omfi
eld
s,”in
P
roc
eed
ing
sofIn
terna
tiona
lCon
fer
enc
eon M
edi
calIma
geCompu
tin
gan
d

Compu
terA
ssi
ste
dIn
ter
ven
tion
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[
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.Le
coeu
r,J
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rré
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ri
llo
t,“Op
tim
izedsup
erv
iseds
egm
en-

t
ati
ono
fmsl
esi
onsf
rom mu
lt
isp
ect
ralm
ris
,”inM
ICCA
Iwo
rkshopon

M
edi
calIma
geAna
lys
ison Mu
lt
ipl
eSc
ler
osi
s(va
lida
tionand m
etho
dolo
g-

i
cali
ssu
es)
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09.

[
83]E
.T.Bu
llm
ore
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ckl
ing
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erm
eye
r,S
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e-H
esk
eth
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ayl
or,

and M
.J.B
ramm
er,“G
lob
al,v
oxe
l,andc
lus
tert
est
s,b
yth
eoryand
p
ermu
tat
ion
,fo
rad
iffe
ren
ceb
etw
eentw
ogr
oup
sofs
tru
ctu
ralm
rim
age
s

2
02
 o
fth
ebr
ain
,”M
edi
calIma
gin
g,IEEET
ran
sac
tion
son,v
ol.1
8,n
o.1
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3
2–4
2,1
999
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[
84]T
.A.D
inh
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iland
er,C
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im,and T
.-Y
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ong
,“Anau
tom
ated

p
ath
olo
gic
alc
las
slev
elann
ota
tionsy
stemf
orv
olum
etr
icb
rainim
age
s,”

inAM
IAAnnua
lSymp
osiumP
roc
eed
ing
s,v
ol.2
012
. Am
eri
can M
edi
cal
In
form
ati
csA
sso
cia
tion
,20
12,p
.12
01.

[
85]C
.-H
.Le
e,M
.Schm
idt
,A. Mu
rth
a,A
.Bi
str
itz
,J.S
and
er,andR
.Gr
ein
er,

“S
egm
ent
ingb
raintum
orsw
ithc
ond
it
ion
alr
and
omfi
eld
sandsuppo
rt

v
ect
orm
ach
ine
s,”inCompu
terv
is
ionfo
rbiom
edi
calima
geapp
li
cat
ion
s.

Sp
rin
ger
,20
05,pp
.46
9–4
78.

[
86]Z
.Ka
rim
agh
aloo
,M.Sh
ah,S
.J.F
ran
cis
,D.L
.Arn
old
,D.L
.Co
ll
ins
,

and T
.Arb
el,“Au
tom
ati
cde
tec
tiono
fgad
olin
ium
-enh
anc
ing mu
lt
ipl
e

s
cle
ros
isl
esi
onsinb
rain m
riu
sin
gcond
it
ion
alr
and
omfi
eld
s,”M
edi
cal

Ima
gin
g,IEEET
ran
sac
tion ,v
son o
l.3
1,n
o.6
,pp
.11
81–
119
4,2
012
.

[
87]R
.Sh
inoh
ara
,J.G
old
smi
th,F
.Ma
teen
,C.C
rain
ice
anu
,and D
.Re
ich
,

“P
red
ict
ingb
reakd
owno
fth
ebl
ood
-br
ainb
arr
ierin mu
lt
ipl
esc
ler
osi
s

w
ith
outc
ont
ras
tag
ent
s,” Am
eri
canJou
rna
lofN
eur
orad
iolo
gy,v
ol.3
3,

n
o.8
,pp
.15
86–
159
0,2
012
.

[
88]A
.Ca
ras
s,J
.Cu
zzo
cre
o,M
.B. Wh
eel
er,P
.-L
.Ba
zin
,S.M
.Re
sni
ck,and

J
.L.P
rin
ce,“S
imp
lep
arad
igmf
orex
tra
-ce
reb
ralt
issu
erem
ova
l:A
lgo
-

r
ithmandan
aly
sis
,”N
eur
oIma
ge,v
ol.5
6,n
o.4
,pp
.19
82–
199
2,2
011
.

2
03
[
89]C
.Bo
rdi
er,M
.Do
jat
,andP
.L.D
eMi
che
aux
,“An
aly
zefm
ri
:anrp
ack
age
t
ope
rfo
rms
tat
ist
ica
lan
aly
sisonfm
rid
ata
set
s,”inu
seR
!2009
-Th
eRU
ser

Con
fer
enc
e,2
009
,p.2
5.

[
90]T
.Lum
ley
,“b
iglm
:bound
edm
emo
ryl
ine
arandg
ene
ral
izedl
ine
arm
ode
ls
.

rp
ack
agev
ers
ion0
.7,
”20
09.

[
91]D
.Ad
ler
,C.G
lae
ser
,O.N
enad
ic
,J.O
ehl
sch
lŠ
gel
,and W
.Zu
cch
ini
,“ff
:

m
emo
ryeffi
cien
tst
ora
geo
fla
rged
ataond
iskandf
asta
cce
ssfun
cti
ons
.r

p
ack
agev
ers
ion2
.2–
2,”2
011
.

[
92]T
.Sin
g,O
.Sand
er,N
.Be
erenw
ink
el
,T.L
eng
aue
r,T
.Sin
g,andO
.Sand
er,

“V
isu
ali
zin
gth
epe
rfo
rman
ceo
fsc
orin
gcl
ass
ifie
rs,
”Pa
cka
geROCRV
er-

s
ion1
.0,v
ol.4
,20
09.

[
93]R
.T.Sh
inoh
ara
,C. M
.Cr
ain
ice
anu
,B.S
.Caff
o, M
.I.G
ait
án
,and

D
.S.R
eich
, “P
opu
lat
ion
-wid
epr
inc
ipa
lcompon
ent
-ba
sed qu
ant
ific
a-

t
iono
fbl
ood
–br
ain
-ba
rri
erdyn
ami
csin mu
lt
ipl
esc
ler
osi
s,”N
eur
oIma
ge,

v
ol.5
7,n
o.4
,pp
.14
30–
144
6,2
011
.

[
94]N
.A.Obu
chow
ski
,“R
ece
ive
rop
era
tin
gch
ara
cte
ris
ticcu
rve
sandth
eiru
se

inr
adi
olo
gy1
,”R
adio
log
y,v
ol.2
29,n
o.1
,pp
.3–
8,2
003
.

[
95]N
.Sh
iee
,P.
-L.B
azin
,J.L
.Cu
zzo
cre
o,D
.S.R
eich
,P.A
.Ca
lab
res
i,and

D
.L.Ph
am,“T
opo
log
ica
llyc
ons
tra
ineds
egm
ent
ati
ono
fbr
ain
ima
gesw
ith
mu
lt
ipl
esc
ler
osi
sle
sion
s,”2
008
.

2
04
[
96]N
.Sh
iee
,P.B
azin
,andD
.Ph
am,“Mu
lt
ipl
esc
ler
osi
sle
sions
egm
ent
ati
on
u
sin
gst
ati
sti
calandt
opo
log
ica
lat
las
es,
”Gr
andCha
ll
eng
e Wo
rk.
: Mu
lt
.

S
cle
r.L
esionS
egm
.Cha
ll
eng
e,pp
.1–
10,2
008
.

[
97]L
.R.D
ice
,“M
easu
reso
fth
eam
oun
tofe
col
ogi
cas
soc
iat
ionb
etw
een

sp
eci
es,
”Ec
olo
gy,v
ol.2
6,n
o.3
,pp
.29
7–3
02,1
945
.

[
98]M
.S.P
epe
,Th
esta
tis
tic
ale
valua
tiono
fme
dic
alt
est
sfo
rcla
ssifi
cat
ion

andp
red
ict
ion. Ox
fordUn
ive
rsi
tyP
res
s,2
003
.

[
99]L
. Ax
el
,J.C
ost
ant
ini
,andJ
.Li
ste
rud
,“In
ten
sit
yco
rre
cti
oninsu
rfa
ce-

c
oilm
rim
agin
g,”Am
eri
canJou
rna
lofR
oen
tgeno
log
y,v
ol.1
48,n
o.2
,pp
.

4
18–
420
,19
87.

[
100
]E.M
jol
sne
ssandD
.DeC
ost
e,“M
ach
inel
earn
ingf
ors
cien
ce:s
tat
eofth
e

a
rtandfu
tur
epr
osp
ect
s,”S
cien
ce,v
ol.2
93,n
o.5
537
,pp
.20
51–
205
5,

2
001
.

[
101
]I.K
onon
enk
o,“M
ach
inel
earn
ingf
orm
edi
cald
iagn
osi
s:h
ist
ory
,st
ateo
f

th
ear
tandp
ersp
ect
ive
,”A
rtifi
cia
lIn
tel
lig
enc
ein m
edi
cin
e,v
ol.2
3,n
o.1
,

pp
.89
–10
9,2
001
.

[
102
]P.L
arr
añ
aga
,B.C
alv
o,R
.San
tan
a,C
.Bi
elz
a,J
.Ga
ldi
ano
,I.In
za,J
.A.

L
ozan
o,R
.Arm
añ
anz
as,G
.San
taf
é
,A.P
é
re ta
ze l
.,“M
ach
inel
earn
ing

inb
ioin
form
ati
cs,
”Br
iefin
gsinb
ioin
forma
tic
s,v
ol.7
,no
.1,pp
.86
–11
2,

2
006
.

2
05
[
103
]E.B
aue
randR
.Koh
avi
,“Anemp
ir
ica
lcomp
ari
sono
fvo
tin
gcl
ass
ific
ati
on
a
lgo
rithm
s:B
agg
ing
,boo
stin
g,andv
ari
ant
s,”Ma
chin
ele
arn
ing,v
ol.3
6,

n
o.1
-2,pp
.10
5–1
39,1
999
.

[
104
]N. W
il
liam
s,S
.Zand
er,and G
.Arm
ita
ge,“Ap
rel
imin
aryp
erf
orm
anc
e

c
omp
ari
sono
ffiv
ema
chin
ele
arn
inga
lgo
rithm
sfo
rpr
act
ica
lipt
raffi
c
fl
owc
las
sifi
cat
ion
,”ACMS
IGCOMMCompu
terCommun
ica
tionR
evi
ew,

v
ol.3
6,n
o.5
,pp
.5–
16,2
006
.

[
105
]R.C
aru
ana
,N.K
aramp
atz
iak
is
,andA
.Ye
ssen
alin
a,“Anemp
ir
ica
lev
alu
-

a
tiono
fsup
erv
isedl
earn
inginh
ighd
imen
sion
s,”inP
roc
eed
ing
softh
e25
th

in
terna
tiona
lcon
fer
enc
eon Ma
chin
ele
arn
ing
. ACM
,20
08,pp
.96
–10
3.

[
106
]D.G
arc
ı́
a-L
oren
zo,S
.Fr
anc
is
,S.N
ara
yan
an,D
.L.A
rno
ld,andL
.D.

C
oll
ins
,“R
evi
ewo
fau
tom
ati
cse
gmen
tat
ion m
eth
odso
f mu
lt
ipl
esc
ler
o-

s
is wh
item
att
erl
esi
onsonc
onv
ent
ion
alm
agn
eti
cre
son
anc
eim
agin
g,”
M
edi
calIma
geAna
lys
is,2
012
.

[
107
]D.J
.Hand
,“C
las
sifi
ert
echn
olo
gyandth
eil
lus
iono
fpr
ogr
ess
,”S
tat
ist
ica
l

S
cien
ce,v
ol.2
1,pp
.1–
14,2
006
.

[
108
]L.B
reim
an,“B
agg
ingp
red
ict
ors
,”Ma
chin
eLe
arn
ing,v
ol.2
4,n
o.2
,pp
.

1
23–
140
,19
96.

[
109
]M.L
eBl
ancand R
.Tib
shi
ran
i,“C
omb
inin
ges
tim
ate
sinr
egr
ess
ionand
c
las
sifi
cat
ion
,”Jou
rna
lofth
e Am
eri
canS
tat
ist
ica
lAs
soc
iat
ion,v
ol.9
1,

n
o.4
36,pp
.16
41–
165
0,1
996
.

2
06
[
110
]M.J
.vand
erL
aan
,E.C
.Po
ll
ey,and A
.E. Hubb
ard
,“Sup
erl
earn
er,
”
S
tat
ist
ica
l App
lic
ation
sin G
ene
tic
sand Mo
lecu
larB
iolo
gy,v
ol.6
,no
.1,

pp
.1–
21,2
007
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[
111
]D.H
.Wo
lpe
rt,“S
tac
kedg
ene
ral
iza
tion
,”N
eur
alN
etwo
rks,v
ol.5
,no
.2,
pp
.24
1–2
59,1
992
.

[
112
]C.B
ord
ier
,M.D
oja
t,and P
.L.d
eMi
che
aux
,“T
empo
ralandSp
ati
al
Ind
epend
entC
ompon
ent An
aly
sisf
orfMR
IDa
taS
etsEmb
edd
edinth
e

An
aly
zeFMR
IRP
ack
age
,”Jou
rna
lofS
tat
ist
ica
lSo
ftwa
re,v
ol.4
4,n
o.9
,

pp
.1–
24,2
011
.[On
lin
e]
.Av
ai
lab
le
:ht
tp:
//www
.j
sta
tso
ft
.or
g/v
44/
i09
/

[
113
]T.S
ing
, O
.Sand
er, N
. B
eer
enw
ink
el
, and T
.Len
gau
er, ROCR
:

V
isua
li
zin
gth
epe
rfo
rman
ceo
fsc
orin
gcla
ssifi
ers
.,2
009
,rp
ack
agev
ers
ion

1
.0-
4.[On
lin
e]
.Av
ai
lab
le
:ht
tp:
//CRAN
.R-p
roj
ect
.or
g/p
ack
age=ROCR

[
114
]C.F
ral
ey,A
.E.R
aft
ery
,T.B
. Mu
rph
y,andL
.Sc
ruc
ca,m
clu
stV
ers
ion4

fo
rR: No
rma
lMi
xtu
re Mo
del
ingfo
r Mo
del
-Ba
sedC
lus
ter
ing
,Cla
ssifi
ca-

t
ion
,andD
ens
ityE
stima
tion
,20
12.

[
115
]C.F
ral
eyandA
.E.R
aft
ery
,“M
ode
l-b
asedc
lus
ter
ing
,di
scr
imin
antan
al-

y
sisandd
ens
itye
stim
ati
on,
”Jou
rna
lofth
eAm
eri
canS
tat
ist
ica
lAs
soc
i-

a
tion
,vo
l.9
7,pp
.61
1–6
31,2
002
.

[
116
]D. M
eye
r,E
.Dim
itr
iad
ou,K
.Ho
rnik
,A. W
ein
ges
sel
,and F
.Le
isch
,

e1071
:Mi
scF
unc
tion
softh
eDep
artm
ento
fSta
tis
tic
s(e1071
),TU W
ien
,

2
012
,r p
ack
agev
ers
ion 1
.6-
1.[On
lin
e]
. Av
ai
lab
le
: h
ttp
://CRAN
.R-

p
roj
ect
.or
g/p
ack
age=
e10
71

2
07
[
117
]A.L
iawand M
.Wi
ene
r,“C
las
sifi
cat
ionandr
egr
ess
ionb
yrand
omf
ore
st,
”
R N
ews, v
ol.2
, n
o.3
, pp
.18
–22
, 2
002
. [On
lin
e]
. Av
ai
lab
le
:

h
ttp
://CRAN
.R-p
roj
ect
.or
g/d
oc/Rn
ews
/

[
118
]E.P
oll
eyand M
.vand
erL
aan
,Sup
erL
earn
er:Sup
erL
earn
erP
red
ict
ion,
2
012
,r p
ack
agev
ers
ion 2
.0-
9.[On
lin
e]
. Av
ai
lab
le
: h
ttp
://CRAN
.R-

p
roj
ect
.or
g/p
ack
age=Sup
erL
earn
er

[
119
]S.W
alt
er,“Th
epa
rti
ala
reaund
erth
esumm
aryr
occu
rve
,”S
tat
ist
icsin

m
edi
cin
e,v
ol.2
4,n
o.1
3,pp
.20
25–
204
0,2
005
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[
120
]V.N
.Vapn
ikand A
.Y.Ch
erv
onenk
is
,“Onth
eun
ifo
rmc
onv
erg
enc
eof
r
ela
tiv
efr
equ
enc
ieso
fev
ent
stoth
eirp
rob
abi
li
tie
s,”Th
eor
yofP
rob
abi
li
ty

&I
tsApp
lic
ation
s,v
ol.1
6,n
o.2
,pp
.26
4–2
80,1
971
.

[
121
]B.G
aonk
arand C
.Da
vat
zik
os,“D
eriv
ings
tat
ist
ica
lsi
gnifi
can
cem
aps

f
orsvmb
asedim
agec
las
sifi
cat
ionandg
roupc
omp
ari
son
s,”inM
edi
cal

Ima
ge Compu
tin
gand Compu
ter
-As
sis
tedIn
ter
ven
tion–M
ICCA
I2012
.

Sp
rin
ger
,20
12,pp
.72
3–7
30.

[
122
]G.T
runk
,“Ap
rob
lemo
fdim
ens
ion
ali
ty: As
imp
leex
amp
le
,”Pa
tte
rn

Ana
lys
isand Ma
chin
eIn
tel
lig
enc
e,IEEET
ran
sac
t son,v
ion ol.1
,no
.3,

pp
.30
6–3
07,1
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[
123
]J.C
.Ru
ss,Th
eima
gep
roc
ess
inghand
boo
k. CRCp
res
s,2
006
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[
124
]G.S
chohnand D
.Cohn
,“L
essi
smo
re: A
ctiv
ele
arn
ingw
ithsuppo
rt

v
ect
orm
ach
ine
s,”inICML
. C
ite
see
r,2
000
,pp
.83
9–8
46.

2
08
[
125
]M.T
.Ha
ganand M
.B.M
enh
aj,“T
rain
ingf
eed
forw
ardn
etw
ork
swi
thth
e
m
arqu
ard
tal
gor
ithm
,”N
eur
alN
etwo
rks
,IEEE T
ran
sac
tion
son,v
ol.5
,

n
o.6
,pp
.98
9–9
93,1
994
.

[
126
]E.D
.Ka
rnin
,“As
imp
lep
roc
edu
ref
orp
run
ingb
ack
-pr
opa
gat
iont
rain
ed

n
eur
aln
etw
ork
s,”N
eur
alN
etwo
rks
,IEEET
ran
sac
tion
son,v
ol.1
,no
.2,
pp
.23
9–2
42,1
990
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[
127
]V.G
arc
ia,E
.Deb
reuv
e,and M
.Ba
rlaud
,“F
astkn
ear
estn
eighbo
rse
arch

u
sin
ggpu
,”inCompu
terV
is
ionand Pa
tte
rn R
eco
gni
tion Wo
rkshop
s,

2008
.CVPRW
’08
.IEEECompu
terSo
cie
tyCon
fer
enc
eon. IEEE
,20
08,

pp
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6.

[
128
]F.P
edr
ego
sa, G
.Va
roqu
aux
, A
.Gr
amf
ort
, V
. M
ich
el
,B. Th
ir
ion
,

O
.Gr
ise
l, M
.Bl
ond
el
,P.P
ret
tenh
ofe
r,R
. W
eis
s,V
. Dubou
rge
tal
.,

“S
cik
it
-le
arn
: M
ach
inel
earn
inginp
yth
on,
”Th
eJou
rna
lof Ma
chin
e

L
earn
ingR
ese
arch,v
ol.1
2,pp
.28
25–
283
0,2
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[
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]H.H
eandE
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arc
ia,“L
earn
ingf
romimb
alan
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ata
,”Know
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Da
taEn
gin
eer
ing
,IEEET
ran
sac
tion
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.12
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128
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[
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]N.J
apk
owi
cze
tal
.,“L
earn
ingf
romimb
alan
cedd
atas
ets
:ac
omp
ari
sono
f

v
ari
ouss
tra
teg
ies
,”inAAA
Iwo
rkshoponl
earn
ingf
romim
balan
cedda
ta

s
ets
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l.6
8. M
enl
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rk,CA
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[
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]L.G
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a,“Ons
tand
ard
iz
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e MRim
agein
ten
sit
y

s
cal
e,”Ima
ge,v
ol.1
081
,19
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2
09
[
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]P.Anb
eek
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cken
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.vanO
sch
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ssch
ops
,andJ
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er
G
rond
,“Au
tom
ati
cse
gmen
tat
iono
fdiff
eren
t-s
ized wh
item
att
erl
esi
ons

b
yvo
xelp
rob
abi
li
tye
stim
ati
on,
”Me
dic
alIma
ge Ana
lys
is,v
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[
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]A.C
era
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lot
ta,A
. Au
gim
eri
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erub
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ito
,
P
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za,P
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len
tin
o,M
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ioi
a,andA
.Qu
att
ron
e,“Ac
el
lul
arn
eur
al

n
etw
orkm
eth
odo
logyf
orth
eau
tom
ateds
egm
ent
ati
ono
fmu
lt
ipl
esc
ler
osi
s

l
esi
ons
,”Jou
rna
lofN
eur
osc
ien
ceM
etho
ds,v
ol.2
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[
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]B.J
ohn
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egm
ent
a-

t
iono
f mu
lt
ipl
esc
ler
osi
sle
sion
sinin
ten
sit
yco
rre
cted mu
lt
isp
ect
ralm
ri
,”

M
edi
calIma
gin
g,IEEET
ran
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tion
son,v
ol.1
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o.2
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69,1
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[
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]D.
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.Oo
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.Slump
,“Mu
lt
ipl
esc
ler
osi
sde
tec
tionin
mu
lt
isp
ect
ralm
agn
eti
cre
son
anc
eim
age
swi
thp
rin
cip
alc
ompon
ent
san
al-

y
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,”2
008
.

[
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]M.W
els
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.Ho
rne
gge
r,“F
ullyau
tom
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egm
ent
ati
ono
f

mu
lt
ipl
esc
ler
osi
sle
sion
sin mu
lt
isp
ect
ral MR
I,” Pa
tte
rnR
eco
gni
tionan
d

Ima
geAna
lys
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[
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]E.G
erem
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,B.H
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.Konuk
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N
.Ay
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ati
ald
eci
sionf
ore
stsf
or MSl
esi
ons
egm
ent
ati
onin mu
lt
i-

ch
ann
elm
agn
eti
cre
son
anc
eim
age
s,”N
eur
oIma
ge,v
ol.5
7,n
o.2
,pp
.37
8–

3
90,2
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.

2
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[
138
]R.H
arm
ouch
e,L
.Co
ll
ins
,D.A
rno
ld,S
.Fr
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,andT
.Arb
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aye
sian
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esi
onc
las
sifi
cat
ion m
ode
lin
gre
gion
alandl
oca
lsp
ati
alin
form
ati
on,
”

inPa
tte
rnR
eco
gni
tion
,2006
.ICPR2006
.18
thIn
terna
tiona
lCon
fer
enc
e
on
,vo
l.3
. IEEE
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[
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]M.K
amb
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al,D
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,

“M
ode
l-b
ased3
-Ds
egm
ent
ati
ono
f mu
lt
ipl
esc
ler
osi
sle
sion
sin m
agn
eti
c

r
eson
anc
ebr
ainim
age
s,”M
edi
calIma
gin
g,IEEET
ran
sac
tion
son,v
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4,

n
o.3
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[
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]A.H
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ipr
ocop
isandP
.To
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,“Anau
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egm
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ati
onm
eth
od

f
orf
astsp
ine
chom
agn
eti
cre
son
anc
eim
age
sus
inganen
semb
leo
fneu
ral

n
etw
ork
s,”inN
eur
alN
etwo
rksfo
rSi
gna
lPr
oce
ssin
g,2003
. NNSP
’03
.

2003IEEE13
th Wo
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18.

[
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]A.P
.Zi
jdenbo
s,B
.M.D
awan
t,R
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,andA
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or-
ph
ome
tri
can
aly
siso
f wh
item
att
erl
esi
onsin MRim
age
s: m
eth
odand

v
al
ida
tion
,”M
edi
calIma
gin
g,IEEET
ran
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son,v
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,pp
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7
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724
,19
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[
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]A.P
.Zi
jdenbo
s,R
.Fo
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ani
,and A
.C.Ev
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,“Au
tom
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c”p
ipe
lin
e”
an
aly
siso
f3-d m
rid
ataf
orc
lin
ica
ltr
ial
s:app
li
cat
iont
o mu
lt
ipl
esc
ler
o-

s
is
,”M
edi
calIma
gin
g,IEEET
ran
sac
tion
son,v
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1,n
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0,pp
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1
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02.

[
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]S.V
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tsk
i,C
.F.G
onz
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z,R
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obl
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rew
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2
11
 M
.Cu
rti
s,“F
astt
issu
ese
gmen
tat
ionb
asedona4Df
eatu
rem
apinch
ar-
a
cte
riz
ati
ono
fin
tra
cran
iall
esi
ons
,”Jou
rna
lof Ma
gne
ticR
esonan
ceIma
g-

in
g,v
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[
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]D.S
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ttm
ann
,“T
ime
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rie
san
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siso
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iin
ten
sit
y

p
att
ern
sinmu
lt
ipl
esc
ler
osi
s,”N
eur
oIma
ge,v
ol.2
0,n
o.2
,pp
.11
93–
120
9,
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003
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[
145
] ——
,“M
rit
imes
eri
esm
ode
lin
gofm
sle
siond
eve
lopm
ent
,”N
eur
oima
ge,

v
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[
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]D.S
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.We
ine
r,andC
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ttm
ann
,“T
ime
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rie
smod
el
ingo
f

mu
lt
ipl
esc
ler
osi
sdi
sea
sea
ctiv
ity
:ap
rom
is
ingw
ind
owond
ise
asep
rog
res
-

s
ionandr
epa
irpo
ten
tia
l?”N
eur
oth
erap
eut
ics,v
ol.4
,no
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[
147
]R. Gh
ass
emi
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rown
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anw
el
l,S
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anan
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tal
.,

“Qu
ant
ita
tiv
eme
asu
rem
ento
fti
ssu
edam
ageandr
eco
veryw
ith
inn
ewt
2w

l
esi
onsinp
edi
atr
ic-
andadu
lt
-on
set mu
lt
ipl
esc
ler
osi
s,”Mu
lt
ipl
eSc
ler
osi
s

Jou
rna
l,p
.13
524
585
145
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[
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]D.S
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ich
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ite
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se,L
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C
oll
ins
,andJ
.Pe
tkau
,“S
amp
le-
siz
eca
lcu
lat
ion
sfo
rsh
ort
-te
rmp
roo
f-
o
f-c
onc
epts
tud
ieso
fti
ssu
epr
ote
cti
onandr
epa
irin mu
lt
ipl
esc
ler
osi
sle
-

s
ion
svi
acon
ven
tion
alc
lin
ica
lim
agin
g,”Mu
lt
ipl
eSc
ler
osi
sJou
rna
l,p
.

1
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458
515
569
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[
149
]H.M
cFa
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arkh
of,J
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tel
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ll
er,“Th
ero
leo
fmr
ias
asu
rro
gat
eou
tcom
eme
asu
rein mu
lt
ipl
esc
ler
osi
s,”Mu
lt
ipl
eSc
ler
osi
s,

v
ol.8
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.1,pp
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–51
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02.

[
150
]J.F
anandJ
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,“Tw
o-s
tepe
stim
ati
ono
ffun
cti
ona
llin
earm
ode
ls

w
ithapp
li
cat
ion
stol
ong
itud
ina
lda
ta,
” Jou
rna
lofth
eRo
yalS
tat
ist
ica
l
So
cie
ty:S
eri
es B(S
tat
ist
ica
lMe
tho
dolo
gy),v
ol.6
2,n
o.2
,pp
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[
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]R D
eve
lopm
entC
oreT
eam
,R: AL
angua
ge and En
vir
onm
entfo
r

S
tat
ist
ica
lCompu
tin
g, RF
ound
ati
onf
orS
tat
ist
ica
lCompu
tin
g,V
ienn
a,

Au
str
ia,2
008
,ISBN3
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005
1-0
7-0
.[On
lin
e]
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[
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]B. Wh
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ithth
e

D
ICOM and N
IfT
Ida
tas
tand
ard
sin R
,” Jou
rna
lofS
tat
ist
ica
l

So
ftwa
re, v
ol.4
4, n
o.6
, pp
.1–
28, 2
011
. [On
lin
e]
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ai
lab
le
:

h
ttp
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sta
tso
ft
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i06
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[
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ono
v,A
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cKin
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lml
i,and D
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ins
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ias
ed

n
onl
ine
ara
ver
agea
ge-
app
rop
ria
teb
raint
emp
lat
esf
romb
irtht
oadu
lt
-

h
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,”N
eur
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[
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ss,M
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tt,and

J
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ce,“Aj
oin
tre
gis
tra
tionands
egm
ent
ati
onapp
roa
cht
osku
ll

s
tripp
ing
,”inB
iom
edi
calIma
gin
g:F
rom Nanoto M
acr
o,2007
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i,S
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“S
tat
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ica
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rma
li
zat
iont
echn
iqu
esf
orm
agn
eti
cre
son
anc
eim
agin
g,”

N
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[
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]B.E
fronand R
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[
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[
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ruc
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tu
ref
orc
onfi
rma
toryh
ypo
the
sist
est
ing
:Ke
epi
tmax
ima
l,”Jou
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lof

m
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[
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r
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gre
ssionw
ithF
unc
tiona
lDa
ta,2
014
,rp
ack
agev
ers
ion0
.1-
11.

[On
lin
e]
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:ht
tp:
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[
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ijeh
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alk
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omp
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llo
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mu
lt
ipl
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ler
osi
sle
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s:m
agn
eti
cre
son
anc
eim
agin
gin
sigh
tsin
tosub
-

s
tra
teso
fdi
sab
il
ity
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iffu
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ipl
esc
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osi
s

2
14
 l
esi
onsandn
orm
al-
app
ear
ing wh
item
att
eru
sin
gech
o-p
lan
arim
agin
g,”
A
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iffu
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s
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orm
agn
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son
anc
eim
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gin mu
lt
ipl
esc
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s,”N
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Sp
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2
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 Curr
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El
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TheJ ohnsHopkinsUniver
sity Ema
il
:em
swe
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BloombergSchoolofPublicHeal
th
Departmento
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tati
sti
cs
615N orth Wo
lfeStre
et
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im o
re MD2 1205

Educa
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rofe
ssiona
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intm
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2
18
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2
19
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2
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2
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2
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2
23
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si
sR e s
earch,Jo intS tatis
tica
lM eeting2016 ,Ch icago
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2
015 PeerF aci
litator, John s Hopk ins Un iversity Data Science
Hacka thon,Ba ltimo re, MD.
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Schoo lofPub l
icH ealth,Baltimo re
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2
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rn No rth Am er
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Intern at
ionalB iom etr
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ting,M iami
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014-2105 Stud entJou rnalC lub Co-O rganizerw ithJohn Mu schel
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lo f Public
Health,Ba ltimo re, MD .
2
014 Vo
lun t e
er, Ea stern No rth Am e
rica R egiono fth eInterna-
tionalB iom etricSo ciety Meeting2014 ,Ba ltimore, MD.
2013 Sess
i on Cha ir, Jo intS tatis
tical M eeting 2013, Mon treal
,
Canad a
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