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I
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I
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15
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2
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Ap
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20
25
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2
4
2
7
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2
4
3
5
2428
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b
e
tu
m
o
r
h
ete
r
o
g
en
eity
with
m
o
r
e
d
e
p
th
a
n
d
ac
cu
r
ac
y
t
h
an
e
v
er
b
ef
o
r
e.
B
y
u
tili
zin
g
t
h
e
an
aly
tical
p
o
wer
o
f
th
ese
r
ev
o
lu
tio
n
ar
y
tech
n
o
lo
g
ies,
o
n
co
lo
g
is
ts
m
ay
ad
a
p
t
th
er
a
p
ies
t
o
s
p
ec
if
ic
p
atien
ts
,
en
h
an
cin
g
th
er
ap
e
u
tic
s
u
cc
ess
wh
ile
r
ed
u
cin
g
ad
v
e
r
s
e
ef
f
ec
t
s
[
4
]
.
I
n
n
o
v
ativ
e
m
eth
o
d
s
f
o
r
tr
ac
k
i
n
g
th
er
a
p
eu
tic
ef
f
icac
y
an
d
an
ticip
atin
g
illn
ess
r
elap
s
e
h
av
e
b
ee
n
m
ad
e
p
o
s
s
ib
le
b
y
th
e
c
o
m
b
in
atio
n
o
f
g
e
n
o
m
ic
im
a
g
in
g
an
d
cl
o
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
ith
m
s
.
C
lin
ician
s
m
ay
m
ain
tain
a
d
y
n
am
ic
an
d
i
n
d
iv
id
u
alize
d
ap
p
r
o
ac
h
t
o
p
atie
n
t
ca
r
e
b
y
r
o
u
tin
ely
m
o
n
ito
r
in
g
tu
m
o
r
g
en
etic
p
r
o
f
iles
an
d
s
p
atial
ch
an
g
es
o
v
er
th
e
co
u
r
s
e
o
f
th
e
r
ap
y
[
5
]
.
T
h
e
d
ev
el
o
p
m
e
n
t
o
f
s
in
g
le
-
ce
ll
g
en
o
m
ic
s
eq
u
en
cin
g
tec
h
n
o
lo
g
y
h
as
led
to
a
d
ee
p
er
co
m
p
r
eh
en
s
io
n
o
f
ce
llu
lar
-
lev
el
tu
m
o
r
h
et
er
o
g
en
eity
.
C
an
ce
r
d
ev
elo
p
m
e
n
t
an
d
m
etastas
is
m
ay
b
e
b
etter
u
n
d
er
s
to
o
d
wh
e
n
tu
m
o
r
ce
lls
ar
e
s
tu
d
ied
o
n
a
ce
llu
lar
lev
el,
s
in
ce
th
is
r
ev
ea
ls
th
e
in
tr
icate
d
eta
ils
o
f
clo
n
al
ev
o
lu
tio
n
an
d
i
n
tr
a
-
tu
m
o
r
al
h
eter
o
g
e
n
eity
[
6
]
.
B
ey
o
n
d
p
r
im
a
r
y
tu
m
o
r
an
al
y
s
is
,
g
en
o
m
ic
-
im
a
g
in
g
m
eth
o
d
s
an
d
clo
u
d
-
b
as
ed
g
en
o
m
ic
alg
o
r
ith
m
s
h
av
e
a
wid
e
r
an
g
e
o
f
p
o
ten
tial
ap
p
licatio
n
s
.
T
h
eir
p
o
ten
tial
u
s
e
in
th
e
in
v
esti
g
atio
n
o
f
m
in
im
al
r
esid
u
al
d
i
s
ea
s
e
(
M
R
D)
an
d
cir
cu
latin
g
tu
m
o
r
ce
lls
(
C
T
C
)
is
cu
r
r
en
tly
b
ein
g
in
v
esti
g
ated
[
7
]
.
Diag
n
o
s
tics
,
th
er
ap
y
o
p
tim
izatio
n
,
e
ar
ly
d
etec
tio
n
,
an
d
co
n
tin
u
o
u
s
m
o
n
ito
r
in
g
ar
e
ju
s
t
s
o
m
e
o
f
th
e
m
an
y
u
s
es
f
o
r
g
en
o
m
ic
-
im
ag
in
g
m
eth
o
d
s
an
d
clo
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
it
h
m
s
in
ca
n
ce
r
.
T
h
ese
to
o
ls
n
o
t
o
n
l
y
im
p
r
o
v
e
o
u
r
k
n
o
wled
g
e
o
f
tu
m
o
r
h
eter
o
g
en
eity
b
u
t
also
p
r
o
v
id
e
d
o
cto
r
s
t
h
e
in
f
o
r
m
atio
n
th
ey
n
ee
d
to
p
er
f
o
r
m
s
u
cc
ess
f
u
l,
in
d
iv
id
u
alize
d
ca
n
ce
r
tr
ea
tm
en
t
[
8
]
.
Un
r
av
elin
g
th
e
co
m
p
lex
ity
o
f
ca
n
ce
r
im
m
u
n
o
th
er
a
p
y
is
a
f
ield
wh
er
e
th
e
co
m
b
in
atio
n
o
f
g
en
o
m
ic
-
im
a
g
in
g
m
eth
o
d
s
an
d
clo
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
ith
m
s
h
as
en
o
r
m
o
u
s
p
r
o
m
i
s
e
b
ey
o
n
d
clin
ical
ap
p
licatio
n
s
.
I
n
ce
r
tain
ca
s
es
o
f
ca
n
ce
r
,
im
m
u
n
o
t
h
er
ap
ie
s
in
clu
d
in
g
im
m
u
n
e
ch
ec
k
p
o
in
t
in
h
ib
ito
r
s
an
d
ch
im
er
ic
an
tig
e
n
r
ec
e
p
to
r
(
C
AR
-
T
)
ce
ll
tr
ea
tm
en
ts
h
av
e
s
h
o
wn
t
o
b
e
q
u
ite
ef
f
ec
ti
v
e.
Du
e
to
tu
m
o
r
h
eter
o
g
en
eity
,
th
eir
ef
f
icac
y
v
ar
ies
s
u
b
s
tan
tially
ac
r
o
s
s
p
atien
ts
.
B
y
s
tu
d
y
in
g
th
e
tu
m
o
r
'
s
g
en
etic
an
d
g
eo
g
r
a
p
h
ical
p
r
o
p
er
ties
,
r
esea
r
ch
er
s
m
ay
f
in
d
p
ar
ticu
lar
im
m
u
n
e
e
v
asio
n
m
eth
o
d
s
ex
p
lo
i
ted
b
y
ca
n
ce
r
ce
lls
[
9
]
.
C
o
llab
o
r
atio
n
s
b
etwe
en
r
esear
ch
er
s
f
r
o
m
d
if
f
e
r
en
t
f
ield
s
h
av
e
p
r
o
life
r
ated
s
in
c
e
g
en
o
m
ic
-
im
ag
i
n
g
m
eth
o
d
s
wer
e
in
teg
r
ated
with
clo
u
d
-
b
ased
p
latf
o
r
m
s
.
T
o
u
n
d
er
s
tan
d
th
e
co
m
p
lex
r
el
atio
n
s
h
ip
b
etwe
en
g
en
etic
m
u
tatio
n
s
,
p
h
y
s
ical
s
p
ac
e,
an
d
p
atien
t
o
u
tco
m
es,
r
esear
ch
er
s
f
r
o
m
s
ev
er
al
d
is
cip
lin
es,
in
clu
d
in
g
g
en
o
m
ics,
r
ad
io
m
ics,
b
io
in
f
o
r
m
atics,
an
d
d
ata
s
cien
ce
,
m
u
s
t
wo
r
k
to
g
eth
er
[
1
0
]
.
C
an
ce
r
r
e
s
ea
r
ch
an
d
th
er
ap
y
h
av
e
b
ec
o
m
e
m
o
r
e
ac
ce
s
s
ib
le
th
an
k
s
to
th
e
wid
esp
r
ea
d
av
a
ilab
ilit
y
o
f
g
e
n
etic
d
ata
v
ia
clo
u
d
-
b
ased
s
y
s
tem
s
.
B
y
r
em
o
v
in
g
p
h
y
s
ical
b
o
u
n
d
ar
ies
an
d
cr
ea
tin
g
a
wo
r
ld
wi
d
e
n
etwo
r
k
o
f
r
esear
ch
er
s
,
l
ar
g
e
g
en
o
m
ic
an
d
im
ag
in
g
d
atasets
ar
e
n
o
w
ac
c
ess
ib
le
to
s
cien
tis
t
s
ev
er
y
wh
er
e
[
1
1
]
.
T
h
e
r
e
h
as
b
ee
n
a
s
ig
n
i
f
ican
t
ad
v
a
n
ce
m
en
t
in
th
e
f
ield
o
f
ca
n
ce
r
th
an
k
s
to
th
e
c
o
m
b
in
atio
n
o
f
g
e
n
o
m
ic
im
ag
in
g
m
eth
o
d
s
an
d
g
en
o
m
i
c
alg
o
r
ith
m
s
h
o
s
ted
o
n
th
e
clo
u
d
.
T
h
ese
to
o
ls
n
o
t
o
n
ly
s
h
ed
lig
h
t
o
n
th
e
co
m
p
lex
ter
r
ain
o
f
tu
m
o
r
h
ete
r
o
g
e
n
eity
,
b
u
t
also
d
r
iv
e
n
o
v
el
in
s
ig
h
ts
,
in
d
iv
id
u
alize
d
th
er
ap
ies,
an
d
team
-
b
ased
r
esear
ch
.
B
y
in
co
r
p
o
r
atin
g
th
ese
in
n
o
v
ativ
e
s
tr
ateg
ies,
th
e
o
n
co
lo
g
y
co
m
m
u
n
ity
m
ay
m
a
k
e
ca
n
ce
r
m
o
r
e
o
f
a
m
an
ag
ea
b
le
illn
ess
f
o
r
p
atien
ts
an
d
ch
an
g
e
th
e
co
u
r
s
e
o
f
ca
n
ce
r
tr
ea
tm
en
t
f
o
r
th
e
b
etter
[
1
2
]
.
C
an
ce
r
p
r
e
v
en
tio
n
an
d
p
u
b
lic
h
ea
lth
p
r
o
g
r
a
m
s
ar
e
also
b
e
n
e
f
itin
g
f
r
o
m
th
e
a
d
v
an
ce
s
m
ad
e
p
o
s
s
ib
le
b
y
g
en
o
m
ic
-
im
ag
in
g
m
eth
o
d
s
an
d
clo
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
ith
m
s
.
R
esear
ch
er
s
m
ay
lear
n
m
o
r
e
ab
o
u
t
th
e
g
en
etic
p
r
ed
is
p
o
s
itio
n
s
an
d
r
is
k
f
ac
to
r
s
lin
k
ed
with
d
if
f
er
en
t
f
o
r
m
s
o
f
ca
n
ce
r
b
y
ex
a
m
in
in
g
lar
g
e
-
s
ca
le
g
en
o
m
ic
d
ata
f
r
o
m
v
ar
ied
p
o
p
u
latio
n
s
.
T
h
r
o
u
g
h
th
is
ev
i
d
en
c
e
-
b
ased
s
tr
ateg
y
,
p
o
licy
m
ak
er
s
ar
e
b
etter
a
b
le
to
r
ed
u
ce
th
e
ca
n
ce
r
b
u
r
d
en
o
n
s
o
ciety
b
y
allo
ca
tin
g
r
eso
u
r
ce
s
ef
f
ec
tiv
ely
,
im
p
lem
e
n
tin
g
f
o
c
u
s
ed
in
ter
v
en
tio
n
s
,
an
d
in
cr
ea
s
in
g
awa
r
en
ess
o
f
p
r
ev
en
tativ
e
m
ea
s
u
r
es
[
1
3
]
.
B
y
id
en
tify
in
g
th
o
s
e
at
g
r
ea
test
r
is
k
,
we
m
ay
cr
ea
te
in
d
iv
id
u
alize
d
s
cr
ee
n
in
g
p
r
o
g
r
am
s
an
d
life
s
ty
le
tr
ea
tm
en
ts
to
r
ed
u
ce
th
eir
lik
elih
o
o
d
o
f
d
e
v
elo
p
in
g
th
e
d
is
ea
s
e.
T
h
e
in
co
r
p
o
r
atio
n
o
f
clo
u
d
-
b
ased
an
aly
tics
in
to
p
u
b
lic
h
ea
lth
s
y
s
tem
s
also
p
er
m
its
co
n
tin
u
o
u
s
tr
ac
k
in
g
o
f
ca
n
ce
r
r
ates
a
n
d
ten
d
en
cies.
T
h
ese
m
eth
o
d
s
ar
e
also
h
el
p
in
g
r
esear
ch
er
s
u
n
d
er
s
tan
d
h
o
w
ca
n
ce
r
p
atien
ts
d
ev
elo
p
r
esis
tan
ce
t
o
tr
ea
tm
en
t
[
1
4
]
.
T
o
cr
ea
te
n
o
v
el
tr
ea
tm
en
t
s
tr
ateg
ies,
s
u
ch
as
co
m
b
in
atio
n
th
er
ap
ies
th
at
s
id
estep
d
r
u
g
r
esis
tan
ce
p
ath
way
s
,
a
m
o
lecu
lar
u
n
d
e
r
s
tan
d
in
g
o
f
th
ese
p
r
o
ce
s
s
es
is
es
s
en
tial.
C
lo
u
d
-
b
ased
g
en
o
m
ic
s
y
s
tem
s
s
er
v
e
a
v
ital
r
o
le
in
g
ath
er
in
g
an
d
p
r
o
ce
s
s
in
g
v
ast
in
f
o
r
m
atio
n
f
r
o
m
clin
ical
tr
ials
an
d
p
atien
t
co
h
o
r
ts
,
allo
win
g
th
e
d
ev
elo
p
m
en
t
o
f
p
r
ed
ictiv
e
b
io
m
ar
k
e
r
s
o
f
tr
ea
tm
en
t
r
esp
o
n
s
e
an
d
r
esis
tan
ce
[
1
5
]
.
On
co
lo
g
y
is
alwa
y
s
ch
an
g
in
g
,
m
ak
in
g
tu
m
o
r
h
eter
o
g
en
eity
a
m
ajo
r
co
n
ce
r
n
.
T
u
m
o
r
h
ete
r
o
g
en
eity
—
th
e
v
ar
iatio
n
in
g
e
n
etic
an
d
p
h
en
o
ty
p
ic
tr
aits
with
in
a
tu
m
o
r
—
m
ak
es
th
er
ap
y
d
if
f
icu
lt.
R
ec
en
tly
d
ev
elo
p
ed
g
en
o
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I
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2429
d
r
iv
e
ca
n
ce
r
g
r
o
wth
.
Nex
t
-
g
e
n
er
atio
n
s
eq
u
en
cin
g
(
NGS)
an
d
h
ig
h
-
r
eso
lu
tio
n
im
ag
in
g
m
o
d
alities
r
ev
ea
l
th
e
tu
m
o
r
'
s
g
en
o
m
ic
la
n
d
s
ca
p
e
a
n
d
s
p
atial
s
tr
u
ctu
r
e
.
R
esear
ch
er
s
m
ay
u
n
co
v
er
g
en
etic
m
u
tatio
n
s
,
ep
ig
e
n
etic
alter
atio
n
s
,
an
d
m
icr
o
en
v
ir
o
n
m
en
tal
v
ar
iab
les
u
s
in
g
th
ese
m
eth
o
d
s
,
r
ev
ea
lin
g
th
e
tu
m
o
r
'
s
co
m
p
lex
ity
.
C
lo
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
ith
m
s
ar
e
ess
en
tial
f
o
r
p
r
o
ce
s
s
in
g
th
ese
m
eth
o
d
s
'
m
ass
iv
e
d
ata
s
ets.
T
h
ese
m
eth
o
d
s
u
s
e
clo
u
d
co
m
p
u
tin
g
to
q
u
ick
ly
a
n
d
co
r
r
ec
tly
h
a
n
d
le
lar
g
e
d
ata
s
ets.
T
h
ese
ad
v
an
ce
s
h
av
e
p
r
o
m
is
e,
b
u
t
o
b
s
tacle
s
r
em
ain
.
Stan
d
ar
d
izin
g
g
en
o
m
ic
-
im
ag
in
g
m
et
h
o
d
o
lo
g
ies,
cl
o
u
d
d
ata
p
r
i
v
ac
y
an
d
s
ec
u
r
it
y
,
an
d
in
ter
p
r
etab
le
alg
o
r
ith
m
s
ar
e
u
r
g
e
n
t
is
s
u
es.
I
n
teg
r
atin
g
g
en
o
m
es,
p
r
o
teo
m
ics,
an
d
m
etab
o
lo
m
ics
d
ata
r
eq
u
ir
es
n
ew
s
o
lu
tio
n
s
.
T
u
m
o
r
h
eter
o
g
en
eity
h
as
p
r
o
m
p
ted
o
n
co
l
o
g
y
r
esear
ch
e
r
s
to
u
s
e
cu
ttin
g
-
ed
g
e
tech
n
o
lo
g
y
.
NGS
an
d
h
ig
h
-
r
eso
lu
tio
n
im
ag
i
n
g
h
av
e
tr
an
s
f
o
r
m
e
d
ca
n
ce
r
b
i
o
lo
g
y
.
T
h
ese
m
eth
o
d
s
r
ev
ea
l
th
e
m
u
tatio
n
s
,
ep
ig
en
etic
ch
an
g
es,
an
d
m
icr
o
en
v
ir
o
n
m
e
n
tal
v
ar
iab
les
th
at
ca
u
s
e
tu
m
o
r
h
eter
o
g
e
n
eity
b
y
d
iv
in
g
i
n
to
tu
m
o
r
g
e
n
etics.
I
n
p
ar
allel,
clo
u
d
-
b
ased
g
e
n
o
m
ic
alg
o
r
ith
m
s
en
ab
le
r
ap
i
d
a
n
aly
s
is
o
f
lar
g
e
an
d
c
o
m
p
licated
g
en
o
m
ic
d
atasets
.
T
h
ese
m
eth
o
d
s
in
teg
r
ate
m
u
lti
-
o
m
ics
d
ata
u
s
in
g
clo
u
d
c
o
m
p
u
tin
g
,
h
elp
i
n
g
r
esear
ch
e
r
s
f
in
d
p
r
ev
i
o
u
s
ly
u
n
d
is
co
v
er
e
d
p
atter
n
s
an
d
r
el
atio
n
s
h
ip
s
.
R
esear
ch
er
s
m
ay
d
is
co
v
er
n
ew
b
io
m
ar
k
er
s
an
d
th
er
ap
eu
tic
tar
g
ets
b
y
co
m
b
in
in
g
r
eso
u
r
ce
s
an
d
ab
ilit
y
to
d
ec
ip
h
er
t
h
ese
co
m
p
lex
d
atasets
.
Stan
d
ar
d
izin
g
g
en
o
m
ic
-
im
ag
in
g
p
r
o
ce
d
u
r
es
is
a
m
ajo
r
a
d
v
an
ce
.
C
lin
ician
s
m
ay
c
r
ea
te
tai
lo
r
ed
tr
ea
tm
e
n
t
p
la
n
s
b
y
d
ec
ip
h
er
in
g
co
m
p
lex
g
en
etic
p
atter
n
s
.
I
n
ter
p
r
etab
le
alg
o
r
ith
m
s
let
h
ea
lth
ca
r
e
p
r
a
ctitio
n
er
s
m
ak
e
ed
u
ca
te
d
ch
o
i
ce
s
f
o
r
p
atien
ts
b
y
co
n
n
ec
tin
g
r
aw
d
ata
to
cli
n
ical
ap
p
licatio
n
.
A
n
ew
er
a
o
f
p
atien
t
in
v
o
lv
e
m
en
t
an
d
ag
e
n
cy
ar
e
u
s
h
er
ed
b
y
th
e
co
m
b
in
atio
n
o
f
g
e
n
o
m
ic
im
ag
in
g
an
d
clo
u
d
c
o
m
p
u
tin
g
.
Patien
ts
m
ay
n
o
w
ac
ce
s
s
th
eir
g
en
etic
an
d
im
a
g
in
g
d
ata
in
way
s
n
e
v
er
b
e
f
o
r
e
p
o
s
s
ib
le,
g
iv
in
g
th
em
a
v
o
ice
in
t
h
eir
c
ar
e
d
ec
is
io
n
s
.
Mo
r
e
in
d
iv
id
u
a
lized
an
d
p
atien
t
-
ce
n
ter
ed
ca
n
ce
r
tr
ea
tm
en
t
is
th
e
r
esu
lt
o
f
a
n
o
p
en
a
p
p
r
o
ac
h
,
wh
ich
im
p
r
o
v
es
co
m
m
u
n
icati
o
n
b
etwe
en
p
atien
ts
an
d
d
o
ct
o
r
s
,
in
cr
ea
s
es
tr
u
s
t,
an
d
en
co
u
r
ag
es
co
llab
o
r
ativ
e
d
ec
is
io
n
-
m
ak
in
g
[
1
6
]
.
T
h
e
in
f
o
r
m
atio
n
ac
ce
s
s
ib
le
to
r
esear
ch
er
s
an
d
clin
ician
s
m
ay
b
e
im
p
r
o
v
ed
b
y
th
e
ad
d
itio
n
o
f
p
atien
t
-
g
en
e
r
ated
d
ata
s
u
ch
as lif
esty
le
ch
o
ices a
n
d
tr
ea
tm
en
t p
r
ef
er
e
n
ce
s
to
g
en
etic
d
atab
ases
.
An
all
-
e
n
co
m
p
ass
in
g
ap
p
r
o
ac
h
to
ca
n
ce
r
tr
ea
tm
en
t
a
n
d
s
u
r
v
iv
al
is
e
n
s
u
r
ed
b
y
g
ai
n
in
g
a
m
o
r
e
t
h
o
r
o
u
g
h
u
n
d
er
s
tan
d
i
n
g
o
f
th
e
d
is
ea
s
e
th
r
o
u
g
h
t
h
e
e
y
e
s
o
f
p
atien
ts
an
d
u
s
in
g
th
at
k
n
o
wled
g
e
to
s
h
a
p
e
th
e
d
esig
n
o
f
s
u
p
p
o
r
tiv
e
ca
r
e
i
n
ter
v
en
tio
n
s
[
1
7
]
.
T
h
e
f
ield
o
f
o
n
c
o
lo
g
y
is
u
n
d
er
g
o
in
g
a
r
ad
ical
tr
an
s
f
o
r
m
atio
n
as
cu
ttin
g
-
ed
g
e
g
e
n
o
m
ic
-
im
a
g
in
g
m
eth
o
d
s
an
d
clo
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
ith
m
s
ar
e
b
r
o
u
g
h
t
to
g
eth
er
.
T
h
ese
tech
n
o
lo
g
ies
h
a
v
e
f
ar
-
r
ea
ch
in
g
im
p
licatio
n
s
th
r
o
u
g
h
o
u
t
th
e
wh
o
le
ca
n
ce
r
ca
r
e
co
n
tin
u
u
m
,
f
r
o
m
ex
p
a
n
d
in
g
p
r
ec
is
io
n
m
ed
icin
e
an
d
co
ll
ab
o
r
ativ
e
r
esear
ch
to
im
p
r
o
v
in
g
ca
n
ce
r
p
r
e
v
en
tio
n
m
ea
s
u
r
es
an
d
p
atien
t
in
v
o
lv
em
e
n
t
[
1
8
]
.
C
an
ce
r
clin
ical
tr
ials
an
d
d
r
u
g
d
ev
elo
p
m
en
t
ar
e
u
n
d
e
r
g
o
i
n
g
a
s
ea
ch
an
g
e
with
t
h
e
co
m
b
in
atio
n
o
f
g
en
o
m
ic
-
im
a
g
in
g
m
eth
o
d
s
a
n
d
clo
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
ith
m
s
.
T
h
e
co
m
p
lex
ities
o
f
t
u
m
o
r
h
eter
o
g
e
n
eity
ar
e
ty
p
ically
o
v
er
lo
o
k
ed
in
c
o
n
v
en
tio
n
al
clin
ical
tr
ial
d
esig
n
s
,
r
esu
ltin
g
to
in
f
er
io
r
r
esu
lt
s
in
p
atien
t
co
h
o
r
ts
.
C
o
m
p
r
eh
en
s
iv
e
g
en
o
m
ic
s
eq
u
en
cin
g
an
d
h
ig
h
-
r
eso
lu
tio
n
im
ag
in
g
h
av
e
allo
wed
f
o
r
t
h
e
s
tr
atif
icatio
n
o
f
tr
ea
tm
en
t
tr
ials
ac
co
r
d
in
g
to
th
e
p
r
esen
ce
o
r
ab
s
en
ce
o
f
ce
r
tain
g
en
etic
ch
an
g
es
an
d
s
p
a
tial
p
atter
n
s
in
s
id
e
m
alig
n
an
cies
[
1
9
]
.
Patien
ts
ar
e
m
o
r
e
lik
ely
t
o
b
en
e
f
it
f
r
o
m
ex
p
er
im
e
n
tal
th
er
ap
ies
if
t
h
ey
ar
e
in
clu
d
ed
in
s
tu
d
ies
aim
ed
at
th
ei
r
s
p
ec
if
ic
g
en
etic
r
is
k
f
ac
to
r
s
.
Ad
ap
tiv
e
tr
ial
d
esig
n
s
th
at
m
ay
f
ast
m
o
d
if
y
d
ep
e
n
d
in
g
o
n
n
ew
g
en
etic
d
is
co
v
er
ies
ar
e
m
ad
e
p
o
s
s
ib
le
b
y
cl
o
u
d
-
b
a
s
ed
to
o
ls
th
at
p
er
m
it
r
ea
l
-
ti
m
e
d
ata
p
r
o
ce
s
s
in
g
.
I
m
p
r
o
v
ed
p
atien
t
ac
ce
s
s
to
cu
ttin
g
-
ed
g
e
m
ed
icatio
n
s
is
a
d
i
r
ec
t
r
esu
lt
o
f
th
is
ad
ap
tab
ilit
y
,
wh
ich
b
o
o
s
ts
th
e
ef
f
icac
y
o
f
clin
ical
tr
ials
b
y
s
p
ee
d
in
g
u
p
th
e
tr
a
n
s
latio
n
o
f
p
r
o
m
is
in
g
th
er
ap
ies f
r
o
m
th
e
la
b
to
th
e
clin
ic
[
2
0
]
.
Data
in
teg
r
ity
an
d
s
ec
u
r
ity
in
ca
n
ce
r
r
esear
ch
ar
e
b
ein
g
c
o
m
p
letely
tr
an
s
f
o
r
m
ed
b
y
th
e
c
o
m
b
in
atio
n
o
f
b
lo
c
k
ch
ain
tec
h
n
o
lo
g
y
,
g
e
n
o
m
ic
-
im
ag
in
g
to
o
ls
,
an
d
clo
u
d
-
b
ased
p
latf
o
r
m
s
.
B
lo
ck
c
h
a
in
'
s
d
is
tr
ib
u
ted
an
d
tam
p
er
-
p
r
o
o
f
n
atu
r
e
ass
u
r
es
g
en
etic
an
d
im
ag
in
g
d
ata
is
im
m
u
tab
le,
s
h
ield
in
g
it
f
r
o
m
p
r
y
in
g
e
y
es.
T
h
is
p
r
o
tecte
d
s
ettin
g
p
r
o
m
o
tes
co
n
f
id
en
ce
am
o
n
g
p
ar
ticip
an
ts
,
wh
ich
in
tu
r
n
f
u
els
u
n
p
r
ec
e
d
e
n
ted
lev
els
o
f
d
ata
ex
ch
an
g
e
an
d
co
o
p
er
atio
n
[
2
1
]
.
Scien
tis
ts
m
ay
wo
r
k
t
o
g
e
th
er
with
o
u
t
wo
r
r
y
in
g
ab
o
u
t
co
m
p
r
o
m
is
in
g
th
e
s
ec
u
r
ity
o
f
th
eir
d
ata
s
in
ce
th
e
y
ca
n
tr
u
s
t
th
at
it
will
b
e
s
af
e.
Sm
ar
t
co
n
tr
ac
ts
m
ad
e
p
o
s
s
ib
le
b
y
th
e
b
lo
ck
c
h
ain
m
ig
h
t
d
r
am
atica
lly
alter
t
h
e
m
an
n
er
in
wh
ich
in
s
titu
tio
n
s
an
d
in
d
i
v
id
u
al
r
esear
c
h
er
s
wo
r
k
to
g
et
h
er
,
p
o
o
l
r
eso
u
r
ce
s
,
an
d
co
n
tr
ib
u
te
to
lar
g
e
-
s
ca
le
in
ter
n
atio
n
al
g
en
o
m
ic
ef
f
o
r
ts
.
T
h
is
n
o
v
el
m
eth
o
d
n
o
t
o
n
ly
p
r
o
tects
p
atien
ts
'
p
r
iv
ac
y
b
u
t
also
lay
s
a
s
o
lid
g
r
o
u
n
d
wo
r
k
f
o
r
m
o
r
e
s
ec
u
r
e
an
d
eth
ical
d
ata
-
d
r
iv
e
n
ca
n
ce
r
r
esear
ch
in
th
e
f
u
tu
r
e
[
2
2
]
.
E
d
u
ca
tio
n
a
n
d
tr
ain
in
g
in
th
e
m
ed
ical
f
ield
ar
e
ev
o
lv
in
g
as
ao
r
tic
r
eg
u
r
g
itatio
n
(
AR
)
an
d
th
er
ap
eu
tic
v
ir
tu
al
r
ea
lity
(
VR
)
tech
n
o
lo
g
y
ar
e
co
m
b
in
ed
with
g
en
o
m
ic
im
ag
in
g
m
et
h
o
d
s
.
No
w,
d
o
ct
o
r
s
ca
n
d
iv
e
d
ee
p
in
to
3
D
tu
m
o
r
m
o
d
els
an
d
ex
p
lo
r
e
th
eir
g
e
n
etic
an
d
s
p
atial
co
m
p
lex
ities
with
o
u
t
le
av
in
g
th
eir
d
esk
s
.
Mu
ltid
is
cip
lin
ar
y
tu
m
o
r
b
o
ar
d
s
an
d
g
lo
b
al
co
llab
o
r
atio
n
a
r
e
m
ad
e
ea
s
ier
b
y
au
g
m
en
ted
an
d
v
ir
tu
al
r
ea
lity
tech
n
o
lo
g
y
[
2
3
]
.
E
x
p
e
r
ts
f
r
o
m
all
ac
r
o
s
s
th
e
wo
r
ld
,
in
cl
u
d
in
g
o
n
co
l
o
g
is
ts
,
g
en
eticist
s
,
r
ad
io
lo
g
is
ts
,
an
d
r
esear
ch
er
s
,
m
ay
wo
r
k
to
g
et
h
er
o
n
v
i
r
tu
al
p
latf
o
r
m
s
to
ev
alu
ate
co
m
p
licated
g
e
n
o
m
ic
an
d
im
ag
in
g
d
ata.
Patien
ts
will
b
en
ef
it
f
r
o
m
im
p
r
o
v
ed
d
iag
n
o
s
tic
ac
cu
r
ac
y
an
d
in
d
iv
id
u
alize
d
tr
ea
tm
e
n
t
s
tr
ateg
ies
th
an
k
s
to
th
e
d
ig
ital
tr
an
s
f
o
r
m
atio
n
o
f
m
ed
i
ca
l
ed
u
ca
tio
n
th
at
is
p
r
o
v
id
in
g
h
ea
lth
ca
r
e
p
r
o
f
ess
io
n
als
with
th
e
k
n
o
wled
g
e
an
d
s
k
ills
n
ec
ess
ar
y
to
ef
f
ec
tiv
ely
lev
er
ag
e
g
e
n
o
m
ic
-
im
a
g
in
g
tec
h
n
iq
u
es
an
d
clo
u
d
-
b
ased
al
g
o
r
ith
m
s
[
2
4
]
.
C
an
ce
r
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
0
8
8
-
8
7
0
8
I
n
t J E
lec
&
C
o
m
p
E
n
g
,
Vo
l.
15
,
No
.
2
,
Ap
r
il
20
25
:
2
4
2
7
-
2
4
3
5
2430
r
esear
ch
,
d
iag
n
o
s
is
,
tr
ea
tm
en
t,
an
d
e
d
u
ca
tio
n
ar
e
all
b
ein
g
p
r
o
f
o
u
n
d
ly
alter
e
d
b
y
th
e
r
ev
o
lu
tio
n
ar
y
c
o
n
f
lu
e
n
ce
o
f
g
en
o
m
ic
-
im
ag
in
g
m
et
h
o
d
s
,
clo
u
d
-
b
ased
g
e
n
o
m
ic
alg
o
r
ith
m
s
,
b
lo
ck
ch
ain
tech
n
o
lo
g
y
,
an
d
au
g
m
en
te
d
o
r
v
ir
tu
al
r
ea
lity
b
r
ea
k
t
h
r
o
u
g
h
s
.
T
h
e
f
u
tu
r
e
is
u
n
q
u
esti
o
n
ab
l
y
b
etter
an
d
h
ea
lth
ier
f
o
r
ca
n
ce
r
p
atien
ts
an
d
th
eir
f
am
ilies
th
r
o
u
g
h
o
u
t
th
e
g
lo
b
e
if
we
em
b
r
ac
e
th
ese
d
e
v
elo
p
m
en
ts
with
ex
citem
en
t
an
d
a
c
o
llab
o
r
ativ
e
attitu
d
e
[
2
5
]
.
T
h
e
d
e
t
a
i
l
e
d
s
t
u
d
y
i
s
f
o
l
l
o
w
e
d
w
i
t
h
t
h
e
p
r
o
p
o
s
e
d
s
y
s
t
e
m
,
r
e
s
u
l
ts
a
n
d
d
i
s
c
u
s
s
i
o
n
,
c
o
n
c
l
u
s
i
o
n
.
K
-
m
e
a
n
c
l
u
s
t
e
r
i
n
g
e
x
a
m
i
n
e
t
h
e
i
n
f
l
u
e
n
c
e
o
f
d
i
f
f
e
r
e
n
t
i
m
a
g
e
c
l
u
s
t
e
r
s
a
n
d
e
a
c
h
c
l
u
s
te
r
i
s
s
e
p
a
r
a
te
l
e
f
t
a
n
d
r
i
g
h
t
p
o
r
t
i
o
n
s
.
M
o
r
e
o
v
e
r
,
t
h
e
m
u
t
u
a
l
s
y
m
m
e
t
r
y
m
e
a
s
u
r
e
i
s
u
s
e
f
u
l
t
o
e
v
a
l
u
at
e
t
h
e
c
l
u
s
t
e
r
w
h
i
c
h
c
o
n
t
a
i
n
s
th
e
t
u
m
o
r
[
2
6
]
.
A
n
a
u
t
o
m
a
t
i
c
b
r
a
i
n
t
u
m
o
r
d
e
t
e
c
ti
o
n
s
y
s
t
e
m
a
p
p
l
ie
s
t
h
e
b
o
d
y
a
c
t
io
n
s
o
f
t
h
e
b
r
a
i
n
t
o
d
i
s
t
i
n
g
u
i
s
h
b
r
a
i
n
t
u
m
o
r
s
[
2
7
]
.
I
n
c
o
r
p
o
r
a
t
i
n
g
i
n
t
e
r
n
e
t
o
f
t
h
i
n
g
s
(
I
oT
)
a
n
d
g
e
o
g
r
a
p
h
i
c
i
n
f
o
r
m
a
t
i
o
n
s
y
s
t
e
m
s
(
G
I
S
)
t
e
c
h
s
t
o
en
h
a
n
c
e
t
h
e
q
u
a
l
it
y
o
f
o
b
s
e
r
v
i
n
g
s
y
s
te
m
;
as
a
r
e
s
u
l
t
,
im
p
r
o
v
e
t
h
e
s
e
n
s
i
n
g
f
i
el
d
p
r
o
c
e
s
s
[
2
8
]
.
R
a
s
p
b
e
r
r
y
P
i
-
e
n
a
b
l
e
d
w
e
a
r
a
b
l
e
s
e
n
s
o
r
s
t
o
o
b
s
e
r
v
e
s
t
h
e
h
e
a
l
t
h
[
2
9
]
.
I
o
T
-
e
n
a
b
l
e
d
m
e
d
i
c
a
t
i
o
n
s
a
f
e
t
y
u
n
d
e
r
t
a
k
e
s
a
s
i
g
n
i
f
i
ca
n
t
i
s
s
u
e
in
t
h
e
h
e
a
l
t
h
c
a
r
e
b
y
t
a
k
i
n
g
j
o
i
n
t
l
y
t
h
e
t
e
c
h
n
i
c
al
g
r
o
w
t
h
s
,
a
n
d
p
a
ti
e
n
t
-
c
e
n
t
e
r
e
d
t
r
e
a
tm
e
n
t
[
3
0
]
.
2.
P
RO
P
O
SE
D
SYS
T
E
M
2
.
1
.
Unlo
ck
ing
t
he
po
t
ent
ia
l
o
f
g
eno
m
ic
-
ima
g
ing
t
ec
hn
iqu
es
a
nd
clo
ud
-
ba
s
e
d
g
eno
m
ic
a
lg
o
rit
hm
s
in
un
dersta
n
din
g
t
um
o
r
het
er
o
g
eneit
y
in o
nco
lo
g
y
Un
d
er
s
tan
d
in
g
th
e
in
tr
icate
la
n
d
s
ca
p
e
o
f
tu
m
o
r
h
eter
o
g
en
eit
y
is
cr
u
cial
in
th
e
f
ield
o
f
o
n
c
o
lo
g
y
,
as
it
p
av
es
th
e
way
f
o
r
p
er
s
o
n
aliz
ed
an
d
ef
f
ec
tiv
e
ca
n
ce
r
tr
ea
t
m
en
ts
.
Gen
o
m
ic
-
im
ag
in
g
tec
h
n
iq
u
es
an
d
cl
o
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
ith
m
s
h
a
v
e
em
er
g
ed
as
r
ev
o
l
u
tio
n
ar
y
to
o
ls
,
o
f
f
er
in
g
u
n
p
r
ec
e
d
en
te
d
in
s
ig
h
ts
in
to
th
e
co
m
p
lex
g
en
o
m
ic
v
a
r
iatio
n
s
with
in
tu
m
o
r
s
.
Gen
o
m
ic
-
im
a
g
in
g
tech
n
i
q
u
es,
s
u
ch
as
NGS
an
d
h
i
g
h
-
r
eso
l
u
tio
n
im
ag
in
g
,
p
la
y
a
p
iv
o
tal
r
o
le
in
u
n
r
a
v
elin
g
th
e
g
en
o
m
ic
d
i
v
er
s
ity
o
f
tu
m
o
r
s
.
Fig
u
r
e
1
i
n
d
icate
s
th
at
in
tr
a
-
tu
m
o
r
al
h
eter
o
g
e
n
eity
is
a
d
iv
er
s
e
p
o
p
u
latio
n
o
f
s
u
b
-
clo
n
es
with
v
ar
iab
le
g
en
etics,
ep
i
g
en
etics,
m
etab
o
lis
m
,
tu
m
o
r
b
eh
av
i
o
r
,
an
d
tr
ea
tm
en
t
r
esp
o
n
s
e.
Dis
tin
ct
tu
m
o
r
s
in
th
e
s
am
e
p
atien
t
h
av
e
d
is
tin
ct
g
en
etic
a
n
d
n
o
n
-
g
en
etic
alter
atio
n
s
(
in
d
icate
d
b
y
d
if
f
e
r
en
t
c
o
lo
r
s
)
,
wh
ich
im
p
ac
ts
th
er
a
p
y
r
esp
o
n
s
e.
Pre
cisi
o
n
m
ed
icin
e
r
eq
u
ir
es
in
ter
-
tu
m
o
r
al
h
eter
o
g
en
eity
.
Nex
t
-
g
en
er
atio
n
s
eq
u
e
n
cin
g
r
ev
ea
led
g
en
etic
a
n
d
f
u
n
ctio
n
al
d
if
f
er
en
ce
s
b
etwe
en
tu
m
o
r
p
o
p
u
latio
n
s
o
r
s
u
b
clo
n
es.
So
m
e
h
eter
o
g
en
o
u
s
tu
m
o
r
s
u
b
-
clo
n
es
b
ec
o
m
e
d
r
u
g
-
r
esis
tan
t
o
r
s
u
r
v
iv
e
b
etter
a
f
ter
tr
ea
tm
en
t,
ca
u
s
in
g
r
ec
u
r
r
en
ce
.
Fig
u
r
e
1
.
Mu
ltip
le
d
eg
r
ee
s
o
f
ca
n
ce
r
h
eter
o
g
en
eity
im
p
ac
t p
atien
t o
u
tco
m
es
2
.
2
.
Rev
o
lutio
nizin
g
o
nco
lo
g
y
:
e
x
plo
ring
t
he
im
pa
ct
,
a
pp
lica
t
io
ns
,
a
nd
a
dv
a
nta
g
es
o
f
ev
a
lua
t
ing
t
um
o
r
het
er
o
g
eneit
y
wit
h g
eno
m
ic
-
im
a
g
ing
t
ec
hn
iqu
es a
nd
clo
u
d
-
ba
s
ed
g
eno
m
ic
a
lg
o
rit
hm
s
T
h
e
ad
v
e
n
t
o
f
g
en
o
m
ic
-
im
ag
i
n
g
an
d
clo
u
d
-
b
ased
g
e
n
o
m
ic
alg
o
r
ith
m
s
h
as
r
ev
o
lu
tio
n
ized
o
n
co
lo
g
y
an
d
tu
m
o
r
h
eter
o
g
en
eity
.
Gr
an
u
lar
tu
m
o
r
h
eter
o
g
en
eity
a
s
s
es
s
m
en
t
alter
s
ca
n
ce
r
r
esear
ch
an
d
tr
ea
tm
e
n
t.
T
u
m
o
r
h
eter
o
g
en
eit
y
ass
ess
m
en
t
u
tili
zin
g
g
en
o
m
ic
im
a
g
in
g
an
d
clo
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
ith
m
s
is
s
ig
n
if
ican
t.
I
n
d
i
v
id
u
alize
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is
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r
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i
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u
ti
o
n
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B
y
s
tu
d
y
in
g
tu
m
o
r
s
'
g
en
etics
an
d
an
ato
m
y
,
d
o
cto
r
s
ca
n
im
p
r
o
v
e
t
r
ea
tm
e
n
t
an
d
r
ed
u
ce
s
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ef
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ec
ts
.
I
n
f
ac
t,
i
n
r
ec
e
n
t
d
ec
a
d
es,
co
m
b
in
atio
n
t
h
er
ap
y
tech
n
iq
u
es
th
at
tar
g
et
ca
n
ce
r
ce
lls
v
ia
s
ev
er
al
p
ath
way
s
h
av
e
em
er
g
ed
to
o
v
er
co
m
e
in
n
ate
ac
q
u
ir
ed
r
esis
tan
ce
.
Step
wis
e
s
o
m
atic
ce
llu
lar
m
u
tatio
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s
ca
u
s
e
ca
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ce
r
th
at
h
as
m
a
n
y
s
u
b
-
clo
n
al
p
o
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u
latio
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s
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as
s
h
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Fig
u
r
e
2
.
Int
e
r
–
T
u
m
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a
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t
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r
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In
t
r
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u
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Heter
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Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J E
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&
C
o
m
p
E
n
g
I
SS
N:
2088
-
8
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va
lu
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o
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2431
Fig
u
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.
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u
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o
r
h
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o
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en
eity
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clo
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al
ev
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lu
tio
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3.
RE
SU
L
T
S AN
D
D
I
SCU
SS
I
O
N
3
.
1
.
A
d
v
a
n
ci
n
g
o
n
c
o
l
o
g
i
c
a
l
r
e
s
e
a
r
c
h
:
s
e
qu
en
c
e
a
li
g
n
me
n
t
a
l
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o
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i
t
h
ms
i
n
e
v
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a
t
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h
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i
t
y
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h
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o
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g
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o
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c
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ma
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e
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d
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b
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s
ed
g
e
no
mi
c
a
l
g
o
r
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h
ms
Gen
o
m
ic
tech
n
o
lo
g
y
h
as
ch
a
n
g
ed
o
n
co
lo
g
y
b
y
ex
p
o
s
in
g
tu
m
o
r
g
en
etics.
C
an
ce
r
r
esear
ch
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s
s
tr
u
g
g
le
to
u
n
d
er
s
tan
d
tu
m
o
r
h
eter
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g
e
n
eity
—
th
e
v
ar
iety
in
ca
n
ce
r
c
ells
with
in
a
tu
m
o
r
o
r
ac
r
o
s
s
n
u
m
er
o
u
s
tu
m
o
r
s
.
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o
m
p
lex
g
en
o
m
ic
an
d
im
a
g
in
g
d
ata
in
teg
r
atio
n
r
e
q
u
ir
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ad
v
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d
m
eth
o
d
o
lo
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ies.
S
eq
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en
ce
alig
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en
t
tech
n
iq
u
es
s
h
o
w
tu
m
o
r
h
eter
o
g
en
eity
,
en
a
b
lin
g
p
e
r
s
o
n
alize
d
th
er
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T
h
is
s
tu
d
y
u
s
es
g
e
n
o
m
ic
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ag
in
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b
ased
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en
o
m
ic
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o
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to
s
h
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w
th
e
u
s
ef
u
ln
ess
o
f
s
eq
u
en
ce
alig
n
m
e
n
t
alg
o
r
ith
m
s
in
o
n
co
lo
g
y
tu
m
o
r
h
eter
o
g
en
eity
r
esear
ch
.
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an
ce
r
'
s
u
n
p
r
ed
ictab
ilit
y
co
m
p
licates
d
iag
n
o
s
is
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d
tr
ea
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en
t.
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o
m
ic
an
d
im
ag
i
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g
d
ata
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n
e
ed
ed
to
co
m
p
r
eh
e
n
d
th
is
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m
p
lex
ity
.
T
u
m
o
r
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ato
m
y
an
d
g
e
o
g
r
a
p
h
ic
d
is
tr
ib
u
tio
n
ar
e
s
h
o
wn
b
y
m
ag
n
etic
r
eso
n
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ce
im
a
g
in
g
(
MRI)
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p
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ly
eth
y
len
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te
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ep
h
th
alate
(
PET
)
,
wh
er
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s
g
e
n
et
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e
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led
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y
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n
teg
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atin
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at
a
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d
s
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o
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ly
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eq
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n
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t
tech
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u
es,
to
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m
p
ar
e
d
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x
y
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o
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u
cleic
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id
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eq
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e
n
ce
s
an
d
d
etec
t
tu
m
o
r
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p
r
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m
o
t
in
g
ch
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g
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asic
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l
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n
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e
n
t
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B
L
AST)
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ith
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ater
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a
n
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Nee
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lem
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n
s
ch
ar
e
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u
n
d
am
en
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io
in
f
o
r
m
atics
s
eq
u
en
ce
alig
n
m
en
t
m
eth
o
d
s
.
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esear
ch
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s
u
s
e
alg
o
r
ith
m
s
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a
n
aly
ze
n
u
cle
o
tid
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o
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am
in
o
ac
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eq
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en
ce
s
to
f
in
d
g
e
n
e
o
r
p
r
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im
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ities
,
d
if
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er
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ce
s
,
an
d
ev
o
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tio
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ar
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s
h
i
p
s
.
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ts
ex
h
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it
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tr
atu
m
o
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ter
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m
etastatic,
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d
in
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a
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m
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g
en
eity
.
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tr
a
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tu
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o
r
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eter
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g
e
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eity
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a
s
in
g
le
tu
m
o
r
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ass
with
n
u
m
er
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u
s
ce
ll
s
u
b
p
o
p
u
latio
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ec
ted
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er
en
t
ly
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y
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ea
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t.
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er
e
n
t
tu
m
o
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n
eities
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ak
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tr
ea
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en
t a
n
d
ac
q
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ir
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p
r
o
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lem
atic
is
s
h
o
wn
in
Fig
u
r
e
3
.
Fig
u
r
e
4
in
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icate
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th
at
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eq
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e
n
ce
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n
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e
n
t
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o
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ith
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s
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ed
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eq
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en
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a
n
d
v
a
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1
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0
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v
ar
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n
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in
2
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1
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o
m
ic
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i
m
ag
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tech
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iq
u
es
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aly
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d
7
5
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p
ictu
r
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clo
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ased
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o
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ith
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en
ce
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lig
n
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en
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r
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eq
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en
ce
s
,
v
ar
ian
t
ca
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1
3
5
,
0
0
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v
ar
ia
n
ts
,
g
en
o
m
ic
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im
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g
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u
es
8
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,
0
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ased
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ith
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ata
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ets
b
y
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0
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2
.
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en
ce
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n
m
e
n
t
alg
o
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ith
m
s
p
r
o
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s
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ed
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e
n
c
es,
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t
ca
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o
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ith
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s
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ar
ian
ts
,
g
en
o
m
ic
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im
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g
tech
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es
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d
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b
ased
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ic
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o
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ith
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s
1
0
0
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0
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0
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ata
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ets in
2
0
2
3
.
Fig
u
r
e
3
.
E
x
am
p
les o
f
tu
m
o
r
h
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o
g
en
eity
ac
r
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s
s
an
d
am
o
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p
atien
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i
m
e
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l
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l
l
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m
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r
Po
p
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l
a
t
i
o
n
1
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u
m
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p
u
l
a
t
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o
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2
Int
e
r
p
a
t
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e
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t
e
r
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g
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Pa
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n
t
1
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a
t
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t
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t
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r
m
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t
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c
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g
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e
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t
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t
r
a
t
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m
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r
a
n
d
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t
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r
me
t
a
st
a
t
i
c
H
e
t
e
r
o
g
e
n
e
i
t
y
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
0
8
8
-
8
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I
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t J E
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&
C
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m
p
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Vo
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15
,
No
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2
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Ap
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20
25
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2432
Fig
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4
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v
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eq
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en
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v
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t c
allin
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o
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s
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o
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es a
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ased
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ith
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ased
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s
is
'
ac
cu
r
ac
y
an
d
s
ca
lab
ilit
y
.
4.
CO
NCLU
SI
O
N
T
h
e
co
m
p
lex
lan
d
s
ca
p
e
o
f
tu
m
o
r
h
ete
r
o
g
e
n
eity
in
o
n
co
l
o
g
y
h
as
b
ee
n
s
h
ed
lig
h
t
u
p
o
n
th
an
k
s
to
th
e
f
u
s
io
n
o
f
g
e
n
o
m
ic
-
im
a
g
in
g
a
p
p
r
o
ac
h
es
an
d
clo
u
d
-
b
ased
g
en
o
m
ic
alg
o
r
ith
m
s
.
T
h
is
g
r
o
u
n
d
-
b
r
e
ak
in
g
m
et
h
o
d
h
as
im
p
r
o
v
ed
th
e
ac
cu
r
ac
y
a
n
d
s
p
ec
if
icity
o
f
ca
n
ce
r
th
er
a
p
ies
b
y
p
r
o
v
id
i
n
g
a
b
etter
k
n
o
wled
g
e
o
f
g
en
etic
ch
an
g
es
in
s
id
e
tu
m
o
r
s
.
I
m
p
r
o
v
ed
d
iag
n
o
s
tic
p
r
ec
is
io
n
an
d
th
er
a
p
y
o
p
tio
n
s
h
a
v
e
r
esu
lted
f
r
o
m
th
e
co
m
b
in
atio
n
o
f
h
ig
h
-
r
eso
lu
ti
o
n
im
ag
in
g
a
n
d
cu
ttin
g
-
ed
g
e
g
en
etic
an
aly
s
is
o
f
tu
m
o
r
s
.
R
ea
l
-
tim
e
an
aly
s
is
,
m
ad
e
p
o
s
s
ib
le
b
y
th
e
s
im
p
lifie
d
p
r
o
ce
s
s
in
g
o
f
lar
g
e
g
e
n
o
m
ic
in
f
o
r
m
atio
n
u
tili
zin
g
clo
u
d
co
m
p
u
tin
g
,
allo
ws
r
ap
id
m
o
d
if
icatio
n
s
to
th
er
a
p
eu
tic
tr
ea
tm
en
ts
.
T
h
e
im
p
lica
tio
n
s
o
f
th
is
d
is
co
v
er
y
f
o
r
th
e
f
u
tu
r
e
o
f
ca
n
ce
r
th
er
ap
y
an
d
p
atien
t
o
u
tco
m
es
ar
e
en
o
r
m
o
u
s
.
E
x
p
lo
r
in
g
th
e
li
m
its
o
f
p
r
ec
is
io
n
m
ed
icin
e
in
ca
n
ce
r
n
ec
ess
itates
f
u
r
th
er
s
tu
d
y
i
n
to
th
e
b
est
wa
y
s
to
in
teg
r
ate
g
en
etic
an
d
im
ag
in
g
tech
n
o
lo
g
y
.
Fu
tu
r
e
r
esear
ch
s
h
o
u
ld
attem
p
t
to
in
cr
ea
s
e
th
e
s
ca
lab
ilit
y
an
d
ac
ce
s
s
ib
ilit
y
o
f
clo
u
d
-
b
ase
d
g
en
o
m
ic
alg
o
r
ith
m
s
,
en
c
o
u
r
ag
in
g
th
eir
wid
er
im
p
lem
en
tatio
n
in
clin
ical
s
et
tin
g
s
.
E
x
p
lo
r
in
g
h
o
w
ar
tific
ial
in
tellig
en
ce
an
d
m
ac
h
in
e
lear
n
in
g
m
ay
b
e
u
s
e
d
to
m
ak
e
s
en
s
e
o
f
c
o
m
p
licated
g
en
o
m
ic
an
d
im
ag
in
g
d
ata
wil
l p
av
e
th
e
way
f
o
r
n
o
v
el
ca
n
ce
r
s
tu
d
ies.
R
esear
ch
th
at
f
o
llo
ws
p
atien
ts
o
v
e
r
tim
e
to
s
ee
h
o
w
i
n
d
iv
id
u
alize
d
th
er
ap
ies
af
f
ec
t
th
eir
h
ea
lth
an
d
h
a
p
p
i
n
e
s
s
o
v
e
r
t
i
m
e
w
o
u
l
d
b
e
r
e
a
l
l
y
h
e
l
p
f
u
l
.
I
t
i
s
i
m
p
e
r
a
t
i
v
e
t
h
a
t
d
o
c
t
o
r
s
,
g
e
n
e
t
i
c
i
s
t
s
,
a
n
d
c
o
m
p
u
t
a
t
i
o
n
a
l
s
c
i
e
n
t
i
s
t
s
w
o
r
k
t
o
g
e
t
h
e
r
t
o
f
u
r
t
h
e
r
t
h
e
s
c
i
e
n
c
e
a
n
d
i
m
p
l
e
m
e
n
t
t
h
e
s
e
f
i
n
d
i
n
g
s
i
n
t
o
p
r
a
c
t
i
c
a
l
a
d
v
a
n
c
e
s
i
n
c
a
n
c
e
r
t
h
e
r
a
p
y
.
RE
F
E
R
E
NC
E
S
[
1
]
S
.
A
n
e
j
a
,
A
.
A
v
e
st
a
,
H
.
X
u
,
a
n
d
L.
O
.
M
a
c
h
a
d
o
,
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C
l
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n
i
c
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l
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n
f
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r
ma
t
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p
p
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t
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s
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r
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,
”
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e
a
r
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k
o
f
Me
d
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c
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rm
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5
/
s
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0
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4
3
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7
6
8
7
2
1
.
[
2
]
Q
.
W
.
Z
h
a
n
g
e
t
a
l
.
,
“
P
e
r
s
o
n
a
l
i
z
e
d
r
a
d
i
o
mi
c
s
si
g
n
a
t
u
r
e
t
o
scre
e
n
f
o
r
K
I
T
-
1
1
mu
t
a
t
i
o
n
g
e
n
o
t
y
p
e
s
a
m
o
n
g
p
a
t
i
e
n
t
s
w
i
t
h
g
a
s
t
r
o
i
n
t
e
s
t
i
n
a
l
st
r
o
ma
l
t
u
m
o
r
s:
a
r
e
t
r
o
sp
e
c
t
i
v
e
mu
l
t
i
c
e
n
t
e
r
s
t
u
d
y
,
”
J
o
u
r
n
a
l
o
f
T
ra
n
sl
a
t
i
o
n
a
l
Me
d
i
c
i
n
e
,
v
o
l
.
2
1
,
n
o
.
1
,
p
.
7
2
6
,
O
c
t
.
2
0
2
3
,
d
o
i
:
1
0
.
1
1
8
6
/
s1
2
9
6
7
-
0
2
3
-
0
4
5
2
0
-
w.
[
3
]
S
.
C
h
o
e
n
,
M
.
S
.
K
e
n
t
,
A
.
J.
C
h
a
u
d
h
a
r
i
,
S
.
R
.
C
h
e
r
r
y
,
A
.
K
r
t
o
l
i
c
a
,
a
n
d
A
.
L.
Zw
i
n
g
e
n
b
e
r
g
e
r
,
“
K
i
n
e
t
i
c
e
v
a
l
u
a
t
i
o
n
o
f
t
h
e
h
y
p
o
x
i
a
r
a
d
i
o
t
r
a
c
e
r
s
[
1
8
F
]
F
M
I
S
O
a
n
d
[
1
8
F
]
F
A
ZA
i
n
d
o
g
s
w
i
t
h
s
p
o
n
t
a
n
e
o
u
s
t
u
m
o
r
s
u
si
n
g
d
y
n
a
m
i
c
P
ET/
C
T
i
ma
g
i
n
g
,
”
N
u
c
l
e
a
r
Me
d
i
c
i
n
e
a
n
d
Mo
l
e
c
u
l
a
r Im
a
g
i
n
g
,
v
o
l
.
5
7
,
n
o
.
1
,
p
p
.
1
6
–
2
5
,
F
e
b
.
2
0
2
3
,
d
o
i
:
1
0
.
1
0
0
7
/
s
1
3
1
3
9
-
0
2
2
-
0
0
7
8
0
-
4.
[
4
]
K
.
E
.
L
i
n
k
e
t
a
l
.
,
“
L
o
n
g
i
t
u
d
i
n
a
l
d
e
e
p
n
e
u
r
a
l
n
e
t
w
o
r
k
s
f
o
r
a
ssess
i
n
g
m
e
t
a
st
a
t
i
c
b
r
a
i
n
c
a
n
c
e
r
o
n
a
l
a
r
g
e
o
p
e
n
b
e
n
c
h
m
a
r
k
,
”
N
a
t
u
r
e
C
o
m
m
u
n
i
c
a
t
i
o
n
s
,
v
o
l
.
1
5
.
p
p
.
1
–
1
0
,
J
a
n
.
1
1
,
2
0
2
4
,
d
o
i
:
1
0
.
2
1
2
0
3
/
r
s.
3
.
r
s
-
2
4
4
4
1
1
3
/
v
1
.
[
5
]
S
.
N
i
n
g
e
t
a
l
.
,
“
I
mag
i
n
g
g
e
n
e
t
i
c
a
ss
o
c
i
a
t
i
o
n
a
n
a
l
y
si
s
o
f
t
r
i
p
l
e
-
n
e
g
a
t
i
v
e
b
r
e
a
st
c
a
n
c
e
r
b
a
s
e
d
o
n
t
h
e
i
n
t
e
g
r
a
t
i
o
n
o
f
p
r
i
o
r
sam
p
l
e
i
n
f
o
r
mat
i
o
n
,
”
Fro
n
t
i
e
rs
i
n
G
e
n
e
t
i
c
s
,
v
o
l
.
1
4
,
F
e
b
.
2
0
2
3
,
d
o
i
:
1
0
.
3
3
8
9
/
f
g
e
n
e
.
2
0
2
3
.
1
0
9
0
8
4
7
.
[
6
]
U
.
K
.
H
i
s
a
n
a
n
d
M
.
M
.
A
mr
i
,
“
R
e
c
o
mm
e
n
d
a
t
i
o
n
o
f
p
r
e
c
i
si
o
n
m
e
d
i
c
i
n
e
a
p
p
l
i
c
a
t
i
o
n
i
n
I
n
d
o
n
e
s
i
a
f
r
o
m
m
u
l
t
i
p
l
e
p
e
r
s
p
e
c
t
i
v
e
:
a
r
e
v
i
e
w
,
”
I
n
t
e
r
n
a
t
i
o
n
a
l
J
o
u
r
n
a
l
o
f
Pu
b
l
i
c
H
e
a
l
t
h
S
c
i
e
n
c
e
,
v
o
l
.
1
2
,
n
o
.
1
,
p
p
.
2
2
5
–
2
3
8
,
M
a
r
.
2
0
2
3
,
d
o
i
:
1
0
.
1
1
5
9
1
/
i
j
p
h
s
.
v
1
2
i
1
.
2
2
0
1
0
.
[
7
]
V
.
A
.
A
r
r
i
e
t
a
e
t
a
l
.
,
“
I
mm
u
n
e
c
h
e
c
k
p
o
i
n
t
b
l
o
c
k
a
d
e
i
n
g
l
i
o
b
l
a
st
o
m
a
:
f
r
o
m
t
u
mo
r
h
e
t
e
r
o
g
e
n
e
i
t
y
t
o
p
e
r
so
n
a
l
i
z
e
d
t
r
e
a
t
m
e
n
t
,
”
J
o
u
rn
a
l
o
f
C
l
i
n
i
c
a
l
I
n
v
e
s
t
i
g
a
t
i
o
n
,
v
o
l
.
1
3
3
,
n
o
.
2
,
Ja
n
.
2
0
2
3
,
d
o
i
:
1
0
.
1
1
7
2
/
J
C
I
1
6
3
4
4
7
.
[
8
]
M
.
M
i
j
i
t
i
e
t
a
l
.
,
“
C
R
I
S
P
R
-
c
a
s
9
s
c
r
e
e
n
i
n
g
i
d
e
n
t
i
f
i
e
d
l
e
t
h
a
l
g
e
n
e
s
e
n
r
i
c
h
e
d
i
n
H
i
p
p
o
k
i
n
a
se
p
a
t
h
w
a
y
a
n
d
o
f
p
r
e
d
i
c
t
i
v
e
s
i
g
n
i
f
i
c
a
n
c
e
i
n
p
r
i
mary
l
o
w
-
g
r
a
d
e
g
l
i
o
m
a
,
”
M
o
l
e
c
u
l
a
r
Me
d
i
c
i
n
e
,
v
o
l
.
2
9
,
n
o
.
1
,
p
.
6
4
,
M
a
y
2
0
2
3
,
d
o
i
:
1
0
.
1
1
8
6
/
s
1
0
0
2
0
-
0
2
3
-
0
0
6
5
2
-
3.
[
9
]
R
.
K
.
V
a
n
a
k
a
mam
i
d
i
,
N
.
A
b
i
r
a
mi
,
C
.
S
a
si
K
u
m
a
r
,
L
.
R
a
ma
l
i
n
g
a
m,
S
.
P
r
i
y
a
n
k
a
,
a
n
d
S
.
M
u
r
u
g
a
n
,
“
I
o
T
se
c
u
r
i
t
y
b
a
se
d
o
n
ma
c
h
i
n
e
l
e
a
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tr
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imiz
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ro
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th
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s
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m
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h
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stry
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r.
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ra
m
m
a
n
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g
e
r
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c
a
n
b
e
c
o
n
tac
ted
a
t
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m
a
il
:
g
u
ru
m
o
o
rt
h
ig
1
9
8
@g
m
a
il
.
c
o
m
.
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v
e
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d
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a
N
.
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a
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th
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c
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d
p
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g
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t
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p
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in
v
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ftwa
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str
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sid
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a
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is
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ra
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tes
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ip
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rica
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it
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siti
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o
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h
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ig
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s we
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VA
a
n
d
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NET
a
p
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ti
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is
e
q
u
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ll
y
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ll
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th
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tri
c
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ES
T
APIs.
He
c
a
n
b
e
c
o
n
tac
ted
a
t
e
m
a
il
:
ra
v
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e
n
d
ra
.
tec
h
ie@
g
m
a
il
.
c
o
m
.
Evaluation Warning : The document was created with Spire.PDF for Python.
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c
a
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c
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ted
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siv
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ra
sa
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k
a
@g
m
a
il
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c
o
m
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Mu
n
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o
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Re
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h
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d
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re
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fr
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ip
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r
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n
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a
ry
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n
d
t
h
e
M
.
Tec
h
.
d
e
g
re
e
in
VLS
I
d
e
sig
n
fr
o
m
th
e
Vig
a
n
a
n
Un
i
v
e
rsity
,
AP,
In
d
ia
,
in
2
0
1
1
a
n
d
t
h
e
B.
Tec
h
.
d
e
g
re
e
in
e
lec
tro
n
ics
a
n
d
c
o
m
m
u
n
ica
ti
o
n
e
n
g
in
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rin
g
fro
m
JN
TU
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k
in
a
d
a
,
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d
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in
2
0
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a
n
d
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l
o
m
a
in
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fr
o
m
G
u
d
lav
a
ll
e
ru
En
g
in
e
e
rin
g
Co
ll
e
g
e
.
His
re
se
a
rc
h
in
tere
sts
i
n
c
lu
d
e
Wi
r
e
les
s
Co
m
m
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s,
Em
b
e
d
d
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d
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m
s
a
n
d
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I
d
e
sig
n
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h
a
s
p
u
b
li
s
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e
d
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se
a
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h
p
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tern
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re
n
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a
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ro
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p
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rtme
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l
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y
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u
n
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r,
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d
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ra
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ra
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sh
,
5
2
2
4
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8
.
H
e
c
a
n
b
e
c
o
n
tac
ted
a
t
e
m
a
il
:
k
o
ti
u
c
e
t@g
m
a
il
.
c
o
m
.
Na
g
a
r
a
ja
n
M
o
h
a
n
k
u
m
a
r
wa
s
b
o
rn
i
n
I
n
d
ia
i
n
1
9
7
8
.
He
re
c
e
iv
e
d
h
is
B.
E.
De
g
re
e
fro
m
Bh
a
ra
th
iy
a
r
U
n
iv
e
r
sity
,
Tam
il
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d
u
,
I
n
d
ia
in
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n
d
M
.
E.
a
n
d
P
h
.
D
.
d
e
g
re
e
fro
m
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d
a
v
p
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r
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iv
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rsity
,
Ko
l
k
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ta
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a
n
d
2
0
1
0
.
He
jo
in
e
d
t
h
e
Na
n
o
De
v
ice
S
imu
latio
n
Lab
o
ra
to
r
y
in
2
0
0
7
a
n
d
wo
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k
e
d
a
s
a
se
n
io
r
re
se
a
r
c
h
fe
ll
o
w
u
n
d
e
r
CS
IR
d
irec
t
S
c
h
e
m
e
ti
ll
S
e
p
tem
b
e
r
2
0
0
9
.
Late
r
h
e
jo
i
n
e
d
S
KP
En
g
i
n
e
e
rin
g
C
o
ll
e
g
e
a
s
a
p
r
o
fe
ss
o
r
to
d
e
v
e
l
o
p
re
se
a
rc
h
a
c
ti
v
it
ies
in
th
e
fiel
d
o
f
VLS
I
a
n
d
NA
NO
tec
h
n
o
lo
g
y
.
He
is
c
u
rre
n
tl
y
wo
r
k
in
g
a
s
a
re
se
a
rc
h
p
ro
fe
ss
o
r
a
t
S
y
m
b
io
sis
In
stit
u
te
o
f
Tec
h
n
o
l
o
g
y
,
Na
g
p
u
r
Ca
m
p
u
s
,
S
y
m
b
io
sis
(In
tern
a
t
io
n
a
l)
De
e
m
e
d
Un
iv
e
rsity
,
P
u
n
e
,
In
d
i
a
.
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is
a
se
n
io
r
m
e
m
b
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r
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f
IEE
E.
He
h
a
s
a
b
o
u
t
8
5
In
tern
a
ti
o
n
a
l
jo
u
rn
a
l
p
u
b
li
c
a
ti
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re
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d
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ter
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ti
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l
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re
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d
in
g
s.
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re
c
e
iv
e
d
t
h
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c
a
rrier
a
wa
rd
fo
r
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o
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tea
c
h
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rs
(
CAY
T)
fro
m
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,
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w
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lh
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in
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h
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y
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a
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.
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se
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rc
h
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tere
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latio
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teriz
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r
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n
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r
s
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m
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c
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t
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n
.
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e
c
a
n
b
e
c
o
n
tac
ted
a
t
e
m
a
il
:
n
m
k
p
r
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ss
o
r@g
m
a
il
.
c
o
m
.
S
u
r
u
li
v
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l
u
Mu
t
h
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m
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r
il
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k
shm
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n
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ss
o
c
iate
p
r
o
fe
ss
o
r
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n
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o
m
p
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ter
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ien
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e
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n
d
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n
g
in
e
e
rin
g
a
t
Ch
e
n
n
a
i
I
n
stit
u
te
o
f
Tec
h
n
o
l
o
g
y
,
K
u
n
d
ra
th
u
r.
Wi
t
h
o
v
e
r
1
3
y
e
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rs
o
f
tea
c
h
in
g
e
x
p
e
rien
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e
,
m
y
p
rima
ry
f
o
c
u
s
re
v
o
lv
e
s
a
r
o
u
n
d
c
o
m
p
u
ter
n
e
two
rk
s
.
S
h
e
is
p
a
rti
c
u
larly
in
tere
ste
d
i
n
i
n
v
e
sti
g
a
ti
n
g
n
e
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k
p
ro
t
o
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o
ls,
se
c
u
rit
y
m
e
a
su
re
s,
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n
d
wa
y
s to
o
p
ti
m
ize
n
e
two
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k
p
e
rfo
rm
a
n
c
e
.
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h
e
p
a
ss
io
n
li
e
s
i
n
r
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se
a
rc
h
in
g
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n
d
p
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s
h
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g
a
rti
c
les
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a
t
d
e
lv
e
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n
to
th
e
se
a
re
a
s,
a
imin
g
t
o
e
n
h
a
n
c
e
o
u
r
u
n
d
e
rsta
n
d
i
n
g
o
f
ro
b
u
st
n
e
tw
o
rk
sy
ste
m
s
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n
d
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o
n
tri
b
u
te
v
a
l
u
a
b
le
in
sig
h
ts t
o
th
e
a
c
a
d
e
m
ic co
m
m
u
n
it
y
.
S
h
e
c
a
n
b
e
c
o
n
tac
ted
a
t:
m
u
t
h
u
3
0
4
1
9
7
4
@g
m
a
il
.
c
o
m
.
Chelli
a
h
S
r
i
n
iv
a
sa
n
is
a
n
a
d
j
u
n
c
t
p
r
o
fe
ss
o
r
a
t
De
p
a
rtme
n
t
o
f
Co
m
p
u
ter
S
c
ien
c
e
a
n
d
En
g
in
e
e
ri
n
g
,
S
a
v
e
e
th
a
S
c
h
o
o
l
o
f
En
g
in
e
e
rin
g
,
S
a
v
e
e
th
a
In
stit
u
te o
f
M
e
d
ica
l
a
n
d
Tec
h
n
ica
l
S
c
ien
c
e
s:
Ch
e
n
n
a
i,
Tam
il
Na
d
u
,
In
d
ia.
His
re
se
a
rc
h
a
re
a
s
in
c
lu
d
e
ima
g
e
p
ro
c
e
ss
in
g
,
sig
n
a
l
p
ro
c
e
ss
in
g
,
p
a
tt
e
rn
re
c
o
g
n
i
ti
o
n
a
n
d
d
e
e
p
lea
rn
i
n
g
.
He
p
u
b
li
sh
e
d
a
b
o
o
k
‘Di
g
it
a
l
Im
a
g
e
P
ro
c
e
ss
in
g
’
b
y
Di
p
ti
P
re
ss
OPC
P
riv
a
te
Li
m
it
e
d
.
He
p
u
b
li
sh
e
d
h
i
s
re
se
a
rc
h
a
rti
c
les
in
m
a
n
y
in
tern
a
ti
o
n
a
l
a
n
d
n
a
ti
o
n
a
l
c
o
n
fe
re
n
c
e
s
a
n
d
jo
u
rn
a
ls.
He
c
a
n
b
e
c
o
n
tac
t
ed
a
t
e
m
a
il
:
srin
iv
a
sa
n
c
h
e
ll
iah
@
g
m
a
il
.
c
o
m
.
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