I
nte
rna
t
io
na
l J
o
urna
l o
f
P
u
bli
c
H
ea
lt
h Science
(
I
J
P
H
S)
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
2
0
2
5
,
p
p
.
1
49
9
~
1
5
1
4
I
SS
N:
2
2
5
2
-
8
8
0
6
,
DOI
: 1
0
.
1
1
5
9
1
/ijp
h
s
.
v
1
4
i3
.
2
5
2
7
6
1499
J
o
ur
na
l ho
m
ep
a
g
e
:
h
ttp
:
//
ijp
h
s
.
ia
esco
r
e.
co
m
H
o
w gene
tic
d
ete
rminis
m a
nd esse
ntialis
m relate
t
o
hea
lth
ca
re
Nind
ia
na
Cho
iru
nis
a
'
1
,
Siti
Z
ub
a
ida
h
1
,
H
endra
Su
s
a
nto
1
,
Chun
-
Yen
C
ha
ng
1,
2
,3
¹D
e
p
a
r
t
me
n
t
o
f
B
i
o
l
o
g
y
,
F
a
c
u
l
t
y
o
f
M
a
t
h
e
m
a
t
i
c
s
a
n
d
S
c
i
e
n
c
e
s,
U
n
i
v
e
r
si
t
a
s
N
e
g
e
r
i
M
a
l
a
n
g
,
M
a
l
a
n
g
,
I
n
d
o
n
e
si
a
²G
r
a
d
u
a
t
e
I
n
st
i
t
u
t
e
o
f
S
c
i
e
n
c
e
E
d
u
c
a
t
i
o
n
,
D
e
p
a
r
t
me
n
t
o
f
Ea
r
t
h
S
c
i
e
n
c
e
s,
a
n
d
I
n
st
i
t
u
t
e
f
o
r
R
e
s
e
a
r
c
h
Ex
c
e
l
l
e
n
c
e
i
n
Le
a
r
n
i
n
g
S
c
i
e
n
c
e
s
,
N
a
t
i
o
n
a
l
Ta
i
w
a
n
N
o
r
ma
l
U
n
i
v
e
r
si
t
y
,
Ta
i
p
e
i
C
i
t
y
,
T
a
i
w
a
n
³G
r
a
d
u
a
t
e
S
c
h
o
o
l
o
f
E
d
u
c
a
t
i
o
n
,
C
h
u
n
g
Y
u
a
n
C
h
r
i
s
t
i
a
n
U
n
i
v
e
r
si
t
y
,
T
a
o
y
u
a
n
C
i
t
y
,
T
a
i
w
a
n
Art
icle
I
nfo
AB
S
T
RAC
T
A
r
ticle
his
to
r
y:
R
ec
eiv
ed
J
u
n
3
,
2
0
2
4
R
ev
is
ed
No
v
1
2
,
2
0
2
4
Acc
ep
ted
Dec
1
3
,
2
0
2
4
G
e
n
e
ti
c
s
h
a
s
b
e
c
o
m
e
imp
o
rtan
t
in
v
a
rio
u
s
a
re
a
s
o
f
l
ife,
e
sp
e
c
ially
in
h
e
a
lt
h
c
a
re
.
P
e
o
p
le
c
a
n
u
n
d
e
r
g
o
a
ra
n
g
e
o
f
g
e
n
e
ti
c
tes
ti
n
g
to
a
ss
e
ss
th
e
ir
su
sc
e
p
ti
b
il
it
y
t
o
a
c
q
u
iri
n
g
d
ise
a
se
s.
Ne
v
e
rth
e
les
s,
d
a
ta
d
e
riv
e
d
fro
m
g
e
n
e
ti
c
tes
ti
n
g
m
i
g
h
t
in
d
ica
te
b
ias
d
u
e
to
g
e
n
e
ti
c
d
e
term
in
ism
a
n
d
e
ss
e
n
ti
a
l
ism
.
Th
is
stu
d
y
a
ime
d
to
p
ro
v
i
d
e
a
c
o
m
p
r
e
h
e
n
siv
e
a
n
a
ly
sis
o
f
t
h
e
imp
a
c
t
o
f
g
e
n
e
ti
c
d
e
term
in
ism
a
n
d
e
ss
e
n
ti
a
li
sm
o
n
se
v
e
ra
l
a
sp
e
c
ts
o
f
h
e
a
lt
h
c
a
re
.
T
h
is
stu
d
y
c
o
n
d
u
c
ted
a
sy
ste
m
a
ti
c
re
v
iew
a
p
p
ro
a
c
h
u
sin
g
th
e
S
c
o
p
u
s
d
a
tab
a
se
a
n
d
fo
ll
o
we
d
th
e
p
re
fe
rre
d
re
p
o
rti
n
g
it
e
m
s
fo
r
sy
ste
m
a
ti
c
re
v
iew
s
a
n
d
m
e
ta
-
a
n
a
ly
sis
(P
RIS
M
A)
se
a
rc
h
fra
m
e
wo
rk
.
We
in
i
ti
a
ll
y
re
c
e
iv
e
d
8
0
2
p
u
b
li
c
a
ti
o
n
s,
th
e
n
re
d
u
c
e
d
to
4
9
a
rti
c
les
b
a
se
d
o
n
in
c
lu
si
o
n
a
n
d
e
x
c
lu
sio
n
c
rit
e
ria,
a
n
d
t
h
e
n
c
o
n
ten
t
a
n
a
l
y
si
s
wa
s
c
o
n
d
u
c
ted
.
Ou
r
re
se
a
rc
h
sh
o
we
d
t
h
a
t
d
e
term
in
ist
b
ias
a
n
d
g
e
n
e
ti
c
e
s
se
n
ti
a
li
sm
m
a
y
re
d
u
c
e
p
a
ti
e
n
t
d
iag
n
o
sis,
trea
tme
n
t
a
c
c
u
ra
c
y
,
a
n
d
e
ffe
c
ti
v
e
n
e
ss
.
M
o
re
o
v
e
r,
b
ias
e
s
re
late
d
to
g
e
n
e
ti
c
d
e
term
in
ism
a
n
d
e
ss
e
n
ti
a
li
sm
m
a
y
g
o
a
g
a
i
n
st
h
e
a
lt
h
c
a
re
re
g
u
la
ti
o
n
s
a
n
d
c
a
u
se
d
isc
rimin
a
ti
o
n
a
n
d
o
th
e
r
n
e
g
a
ti
v
e
c
li
n
ica
l
o
u
tco
m
e
s
fro
m
e
th
ica
l,
so
c
ial,
a
n
d
leg
a
l
a
sp
e
c
ts.
To
i
m
p
ro
v
e
th
is
p
ro
b
lem
,
it
is
e
ss
e
n
ti
a
l
fo
r
lay
p
e
o
p
le,
p
a
rti
c
u
larl
y
m
e
d
ica
l
e
x
p
e
rts,
to
u
n
d
e
rsta
n
d
g
e
n
e
ti
c
p
rin
c
i
p
les
re
late
d
to
th
e
d
e
v
e
lo
p
m
e
n
t
o
f
v
a
rian
c
e
s
in
t
ra
it
s
a
m
o
n
g
in
d
iv
i
d
u
a
ls
in
a
p
re
c
ise
a
n
d
re
lata
b
le ap
p
ro
a
c
h
.
K
ey
w
o
r
d
s
:
Gen
etic
co
n
ce
p
t
Gen
etic
d
eter
m
in
is
m
Gen
etic
ed
u
ca
tio
n
Gen
etic
ess
en
tiali
s
m
Hea
lth
ca
r
e
T
h
is i
s
a
n
o
p
e
n
a
c
c
e
ss
a
rticle
u
n
d
e
r th
e
CC B
Y
-
SA
li
c
e
n
se
.
C
o
r
r
e
s
p
o
nd
ing
A
uth
o
r
:
Sit
i Z
u
b
aid
ah
Dep
ar
tm
en
t o
f
B
io
lo
g
y
,
Facu
lt
y
o
f
Ma
th
e
m
atics a
n
d
Scien
ce
s
,
Un
iv
er
s
itas
Neg
er
i M
alan
g
Sem
ar
an
g
St.
No
.
5
,
Ma
lan
g
,
E
ast J
av
a
65145
,
I
n
d
o
n
esia
E
m
ail:
s
iti.zu
b
aid
ah
.
f
m
ip
a@
u
m
.
ac
.
id
1.
I
NT
RO
D
UCT
I
O
N
R
ec
en
t
ad
v
an
ce
s
in
h
ea
lth
ca
r
e
in
d
icate
th
at
g
en
etics
p
lay
s
a
f
u
n
d
am
e
n
tal
r
o
le
[
1
]
,
with
n
u
m
er
o
u
s
d
iag
n
o
s
es
an
d
tr
ea
tm
e
n
ts
b
ein
g
co
n
d
u
cted
b
ased
o
n
g
en
et
ic
f
ac
to
r
s
.
Ho
wev
er
,
as
g
e
n
etics
h
as
p
r
o
g
r
ess
ed
,
th
er
e
h
as
also
b
ee
n
a
r
is
e
i
n
th
e
p
r
eju
d
ice
ass
o
ciate
d
with
g
e
n
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
,
wh
ich
p
o
s
es
a
r
ea
l,
d
an
g
er
o
u
s
,
an
d
u
n
av
o
id
ab
le
p
r
o
b
lem
[
2
]
.
T
h
e
in
cr
ea
s
in
g
s
tig
m
a
r
elate
d
to
g
en
etic
d
eter
m
in
is
m
is
d
ir
ec
tly
r
esp
o
n
s
ib
le
f
o
r
a
s
ig
n
if
ican
t
n
u
m
b
er
o
f
p
r
eju
d
ice
d
b
elief
s
,
s
u
ch
as
r
ac
is
m
o
r
eu
g
en
ics
[
3
]
,
[
4
]
.
Gen
etic
d
eter
m
in
is
m
is
th
e
c
o
n
ce
p
t
th
at
g
en
es
p
lay
th
e
m
o
s
t
f
u
n
d
am
e
n
tal
r
o
le
i
n
d
ev
el
o
p
in
g
a
p
h
e
n
o
ty
p
e.
Gen
es
ar
e
c
o
n
s
id
er
ed
to
h
av
e
a
m
o
r
e
s
ig
n
if
ican
t
im
p
ac
t
o
n
th
e
d
e
v
elo
p
m
e
n
t
o
f
a
p
h
en
o
ty
p
e
th
an
o
th
e
r
f
ac
to
r
s
,
in
clu
d
in
g
ep
ig
e
n
etics
an
d
en
v
ir
o
n
m
e
n
ts
,
p
ar
ticu
lar
l
y
f
o
r
c
o
m
p
lex
tr
aits
lik
e
b
eh
a
v
io
r
an
d
p
er
s
o
n
ality
[
5
]
,
[
6
]
.
Acc
o
r
d
in
g
to
E
llis
o
n
an
d
d
e
W
ett,
g
e
n
etic
d
eter
m
i
n
is
m
r
ef
er
s
to
th
e
b
elief
t
o
ex
p
l
ain
d
if
f
e
r
en
t h
u
m
a
n
s
o
cial
s
itu
atio
n
s
u
s
in
g
b
io
lo
g
i
ca
l
f
ac
to
r
s
in
a
n
eg
ativ
e
way
[
7
]
.
T
h
is
co
n
ce
p
t
o
f
g
e
n
etic
d
eter
m
in
is
m
ca
m
e
f
r
o
m
a
co
n
v
en
tio
n
al
p
er
s
p
ec
tiv
e
o
n
g
en
etics
th
at
em
p
h
a
s
ized
th
e
co
n
n
ec
tio
n
b
etwe
e
n
g
e
n
es,
p
r
o
tein
s
,
f
u
n
ctio
n
s
,
an
d
tr
aits
.
T
h
e
r
ef
o
r
e,
it
i
n
d
icate
s
m
o
s
t
d
is
o
r
d
er
s
ar
e
ass
o
ciate
d
with
a
s
i
n
g
l
e
g
en
e
[
8
]
.
Gen
etic
d
eter
m
in
is
m
an
d
g
en
etic
ess
en
tialis
m
ar
e
s
tr
o
n
g
ly
lin
k
ed
to
t
h
e
ex
p
lan
atio
n
o
f
v
iews r
eg
ar
d
in
g
in
e
q
u
ality
[
9
]
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
1
4
9
9
-
1
5
1
4
1500
G
e
n
e
t
i
c
e
s
s
e
n
t
i
a
l
i
s
m
i
s
t
h
e
i
d
e
a
t
h
a
t
g
e
n
e
s
a
r
e
f
i
x
e
d
e
n
t
i
t
i
e
s
t
h
a
t
d
e
t
e
r
m
i
n
e
t
h
e
c
h
a
r
a
c
t
e
r
i
s
t
i
c
s
o
f
a
n
i
n
d
i
v
i
d
u
a
l
a
n
d
a
r
e
p
a
s
s
e
d
o
n
t
o
t
h
e
n
e
x
t
g
e
n
e
r
a
t
i
o
n
w
i
t
h
o
u
t
a
n
y
c
h
a
n
g
e
[
1
0
]
.
G
e
n
e
t
i
c
e
s
s
e
n
t
i
a
l
i
s
m
i
s
a
r
e
d
u
c
t
i
o
n
i
s
t
p
e
r
s
p
e
c
t
i
v
e
t
h
a
t
b
e
l
i
e
v
e
s
a
n
i
n
d
i
v
i
d
u
a
l
'
s
g
e
n
e
t
i
c
c
o
m
p
o
s
i
t
i
o
n
i
s
a
n
u
n
c
h
a
n
g
e
a
b
l
e
a
t
t
r
i
b
u
t
e
t
h
a
t
d
e
f
i
n
e
s
t
h
e
i
r
c
h
a
r
a
c
t
e
r
a
n
d
b
e
h
a
v
i
o
r
[
9
]
.
G
e
n
e
t
i
c
e
s
s
e
n
t
i
a
l
i
s
m
b
e
l
i
e
f
s
c
a
n
l
e
a
d
i
n
d
i
v
i
d
u
a
l
s
t
o
d
e
v
e
l
o
p
n
e
g
a
t
i
v
e
p
r
e
j
u
d
i
c
e
s
.
T
h
e
s
e
b
e
l
i
e
f
s
a
s
s
u
m
e
t
h
a
t
p
e
o
p
l
e
f
r
o
m
t
h
e
s
a
m
e
s
o
c
i
a
l
g
r
o
u
p
,
s
u
c
h
a
s
r
a
c
e
o
r
g
e
n
d
e
r
,
s
h
a
r
e
t
h
e
s
a
m
e
g
e
n
e
s
,
r
e
s
u
l
t
i
n
g
i
n
p
h
y
s
i
c
a
l
,
c
o
g
n
i
t
i
v
e
,
a
n
d
b
e
h
a
v
i
o
r
a
l
s
i
m
i
l
a
r
i
t
y
a
n
d
d
i
s
t
i
n
g
u
i
s
h
i
n
g
t
h
e
m
f
r
o
m
o
t
h
e
r
g
r
o
u
p
s
[
3
]
.
G
e
n
e
t
i
c
e
s
s
e
n
t
i
a
l
i
s
m
s
u
b
s
t
a
n
t
i
a
l
l
y
i
m
p
a
c
t
i
n
e
q
u
a
l
i
t
y
i
n
m
u
l
t
i
p
l
e
d
o
m
a
i
n
s
o
f
l
i
f
e
,
i
n
c
l
u
d
i
n
g
t
h
e
r
e
a
l
m
o
f
h
e
a
l
t
h
c
a
r
e
[
1
1
]
,
[
1
2
]
.
G
e
n
e
s
a
r
e
c
u
r
r
e
n
t
l
y
r
e
c
e
i
v
i
n
g
m
a
s
s
i
v
e
i
n
t
e
r
e
s
t
i
n
t
h
e
h
e
a
lth
i
n
d
u
s
t
r
y
f
o
r
t
h
e
i
r
r
o
l
e
i
n
d
e
t
e
r
m
i
n
i
n
g
i
n
d
i
v
i
d
u
a
l
c
h
a
r
a
ct
e
r
is
t
ic
s
.
V
a
r
i
o
u
s
m
e
d
i
a
t
e
n
d
t
o
p
r
o
v
i
d
e
co
v
e
r
a
g
e
o
f
s
ci
e
n
t
i
f
ic
r
es
e
a
r
c
h
t
h
a
t
e
s
t
a
b
l
is
h
e
s
a
c
o
n
n
e
c
t
i
o
n
b
e
t
w
e
e
n
s
p
e
c
i
f
ic
g
e
n
e
t
i
c
v
a
r
i
a
t
i
o
n
s
a
n
d
v
a
r
i
o
u
s
h
u
m
a
n
c
o
n
d
i
t
i
o
n
s
[
1
3
]
.
O
n
e
o
f
t
h
e
p
h
e
n
o
m
e
n
a
l
r
e
p
o
r
t
s
t
h
a
t
r
e
c
e
i
v
e
d
m
u
c
h
p
u
b
l
i
c
a
t
t
e
n
t
i
o
n
w
as
r
e
l
a
t
e
d
t
o
t
h
e
d
e
s
i
g
n
o
f
t
h
e
h
u
m
a
n
g
e
n
o
m
e
s
e
q
u
e
n
c
e
.
T
h
e
e
x
i
s
t
e
n
ce
o
f
t
h
i
s
d
e
s
i
g
n
t
h
e
n
r
ec
e
i
v
e
d
a
n
e
x
t
r
a
o
r
d
i
n
a
r
y
r
e
s
p
o
n
s
e
f
r
o
m
P
r
e
s
i
d
e
n
t
C
l
i
n
t
o
n
,
w
h
o
s
t
a
t
e
d
,
“
T
o
d
a
y
,
w
e
s
t
u
d
y
t
h
e
l
a
n
g
u
a
g
e
t
h
a
t
G
o
d
u
s
e
d
t
o
c
r
ea
t
e
l
i
f
e
,
n
o
w
i
t
i
s
c
o
n
c
e
i
v
a
b
l
e
t
h
at
o
u
r
c
h
i
l
d
r
e
n
w
i
l
l
k
n
o
w
t
h
e
t
e
r
m
‘
c
a
n
c
e
r
’
o
n
l
y
a
s
a
c
o
n
s
t
e
l
l
at
i
o
n
o
f
s
t
a
r
s
”
[
1
4
]
.
T
h
r
o
u
g
h
t
h
i
s
r
e
s
p
o
n
s
e
,
s
c
i
e
n
ti
s
t
s
r
a
is
e
d
d
e
ep
c
o
n
c
e
r
n
s
r
e
g
a
r
d
i
n
g
b
i
a
s
i
n
i
n
t
e
r
p
r
e
ti
n
g
s
c
i
e
n
ti
f
i
c
r
e
s
e
a
r
c
h
f
i
n
d
i
n
g
s
[
1
4
]
,
[
1
5
]
.
G
e
n
e
t
i
c
is
ts
a
ls
o
e
x
p
r
e
s
s
e
d
w
o
r
r
y
t
h
a
t
f
o
c
u
s
i
n
g
t
o
o
m
u
c
h
o
n
t
h
e
r
o
l
e
o
f
g
e
n
e
s
c
a
n
r
e
s
u
l
t
i
n
a
h
e
i
g
h
t
e
n
e
d
b
e
l
i
e
f
in
g
e
n
e
t
i
c
d
e
t
e
r
m
i
n
i
s
m
a
n
d
e
s
s
e
n
t
i
a
l
is
m
,
w
h
i
c
h
,
i
n
t
u
r
n
,
c
a
n
c
o
n
t
r
i
b
u
t
e
t
o
t
h
e
r
is
e
o
f
d
i
s
c
r
i
m
i
n
at
i
n
g
a
t
ti
t
u
d
e
s
t
h
a
t
a
r
e
m
o
r
e
l
i
k
e
l
y
t
o
a
r
is
e
[
1
4
]
,
[
1
6
]
.
I
n
i
t
s
e
v
o
l
u
ti
o
n
,
t
h
i
s
o
v
e
r
-
e
x
p
l
a
n
a
t
i
o
n
a
t
t
h
e
g
e
n
e
l
e
v
e
l
h
a
s
e
v
e
n
r
e
p
l
a
c
e
d
s
o
m
e
o
f
t
h
e
p
r
e
v
i
o
u
s
e
s
s
e
n
c
e
s
,
i
n
cl
u
d
i
n
g
i
d
e
a
s
l
i
k
e
y
o
g
a
a
n
d
t
h
e
C
h
i
n
e
s
e
n
o
t
i
o
n
o
f
c
h
i
,
w
h
i
c
h
a
r
e
c
r
u
c
i
a
l
f
o
r
c
o
m
p
r
e
h
e
n
d
i
n
g
p
e
r
s
o
n
a
l
i
t
y
a
n
d
h
e
a
l
t
h
[
1
7
]
.
An
i
n
c
r
e
a
s
e
i
n
r
e
q
u
es
ts
f
o
r
g
e
n
et
i
c
te
s
t
i
n
g
o
f
i
n
d
i
v
i
d
u
al
s
t
o
d
e
te
r
m
i
n
e
t
h
e
i
r
r
i
s
k
o
f
c
e
r
t
a
i
n
d
is
e
as
e
s
h
a
s
b
e
e
n
s
e
e
n
i
n
t
h
e
p
u
b
l
i
c
,
i
n
d
i
c
a
t
i
n
g
t
h
e
i
r
in
t
e
r
e
s
t
i
n
t
h
e
r
o
l
e
o
f
t
h
is
g
e
n
e
[
1
8
]
–
[
2
3
]
.
S
o
c
i
e
t
i
es
w
i
d
e
l
y
u
s
e
g
e
n
e
t
ic
t
e
s
t
i
n
g
t
o
d
e
t
e
r
m
i
n
e
t
h
e
i
r
o
f
f
s
p
r
i
n
g
'
s
p
o
t
e
n
t
i
a
l
g
e
n
e
ti
c
m
a
k
e
u
p
[
2
4
]
,
t
h
e
l
i
k
e
l
i
h
o
o
d
o
f
c
o
n
t
r
a
c
t
i
n
g
f
a
t
a
l
d
is
e
as
es
[
1
8
]
,
[
2
5
]
,
a
n
d
p
o
s
s
i
b
l
e
p
r
o
f
e
s
s
i
o
n
s
[
1
3
]
.
O
t
h
e
r
,
m
o
r
e
u
n
e
x
p
e
c
t
e
d
,
s
i
t
u
a
ti
o
n
s
i
n
cl
u
d
e
t
h
e
b
e
l
i
e
f
t
h
a
t
g
e
n
e
t
i
c
h
e
r
i
ta
b
i
li
t
y
p
l
a
y
s
a
s
i
g
n
i
f
i
c
a
n
t
r
o
le
i
n
p
r
e
d
i
c
t
i
n
g
a
v
a
r
i
e
t
y
o
f
s
o
c
ia
l
p
h
e
n
o
m
e
n
a
,
i
n
c
l
u
d
i
n
g
d
i
v
o
r
c
e
[
2
6
]
,
[
2
7
]
,
r
e
l
i
g
i
o
s
i
t
y
[
2
8
]
,
m
e
n
t
a
l
h
e
a
l
t
h
[
2
0
]
,
[
2
9
]
,
s
m
o
k
i
n
g
p
r
e
v
a
l
e
n
c
e
[
3
0
]
,
a
n
d
e
v
e
n
i
n
d
i
v
i
d
u
a
l
b
e
h
a
v
i
o
r
[4
]
,
[
3
1
]
.
F
o
r
i
n
s
t
a
n
c
e,
w
h
e
n
d
i
a
g
n
o
s
i
n
g
d
e
p
r
e
s
s
i
o
n
,
a
d
o
c
t
o
r
m
a
y
e
x
c
e
s
s
i
v
e
l
y
p
r
e
f
er
t
h
e
g
e
n
e
t
i
c
te
s
ti
n
g
r
e
s
u
l
ts
o
f
a
p
a
t
i
e
n
t
w
h
o
i
s
d
i
s
c
o
v
e
r
e
d
t
o
h
a
v
e
a
g
e
n
e
t
i
c
p
r
e
d
i
s
p
o
s
it
i
o
n
t
o
d
e
p
r
e
s
s
i
o
n
,
w
h
i
l
e
d
i
s
r
e
g
a
r
d
i
n
g
e
n
v
i
r
o
n
m
e
n
t
a
l
f
a
c
t
o
r
s
l
i
k
e
s
t
r
ess
a
n
d
s
le
e
p
p
a
t
t
e
r
n
s
.
T
h
i
s
c
a
n
le
a
d
t
o
i
n
e
f
f
e
c
t
i
v
e
t
r
e
a
t
m
e
n
t
.
Desp
ite
th
e
d
is
co
v
er
y
o
f
a
g
e
n
etic
co
r
r
elatio
n
with
th
e
o
r
i
g
in
s
o
f
d
if
f
er
en
t
d
is
ea
s
e
f
o
r
m
s
,
ad
d
itio
n
al
th
eo
r
ies,
s
u
ch
as
th
o
s
e
r
elate
d
to
s
o
cial
an
d
en
v
ir
o
n
m
e
n
tal
f
ac
to
r
s
,
ar
e
s
till
r
eq
u
ir
ed
to
s
u
p
p
o
r
t
th
is
g
en
etic
ex
p
lan
atio
n
[
3
2
]
.
I
n
g
e
n
er
al,
m
an
y
d
is
ea
s
es
o
r
ch
ar
ac
ter
is
tics
in
v
esti
g
ated
d
et
er
m
in
is
tically
an
d
ex
is
ten
tialis
tica
lly
ap
p
ea
r
f
r
o
m
th
e
ex
p
r
ess
io
n
o
f
m
u
ltip
le
g
en
es
th
at
in
ter
ac
tin
g
.
So
cial
s
itu
atio
n
s
an
d
en
v
ir
o
n
m
en
tal
f
ac
to
r
s
also
p
lay
an
ess
en
tial r
o
le
[
3
3
]
–
[
3
5
]
.
Peo
p
le
f
r
eq
u
en
tl
y
b
eliev
e
th
at
an
illn
ess
i
s
f
o
r
m
ed
o
n
ly
d
u
e
to
h
er
e
d
itar
y
ca
u
s
e
s
wh
en
d
eter
m
in
is
m
b
ias
an
d
g
en
etic
ess
en
tialis
m
o
cc
u
r
,
d
esp
ite
a
co
m
p
lex
n
etwo
r
k
o
f
etio
lo
g
ical
i
n
ter
ac
tio
n
s
[
3
6
]
.
M
o
r
eo
v
e
r
,
w
h
en
p
e
o
p
le
c
o
n
tin
u
e
m
ain
tai
n
in
g
t
h
is
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
attitu
d
e,
t
h
ey
will
u
n
d
e
r
v
alu
e
im
p
o
r
tan
t
asp
ec
ts
lik
e
ex
p
er
ien
ce
a
n
d
en
v
ir
o
n
m
en
t
wh
ile
tr
y
in
g
to
t
r
ea
t
a
s
p
ec
if
ic
co
n
d
itio
n
.
T
h
e
y
wi
ll
b
eliev
e
m
o
r
e
in
th
e
g
en
etic
co
m
p
o
n
e
n
ts
o
f
th
e
co
n
d
itio
n
[
3
3
]
.
Sev
er
al
s
t
u
d
ies
h
av
e
r
ev
ea
led
th
at
th
e
s
tig
m
a
ass
o
ciate
d
with
ess
en
tialis
m
an
d
g
en
etic
d
eter
m
in
is
m
h
as
d
eter
r
e
d
ce
r
t
ain
g
r
o
u
p
s
o
f
p
eo
p
le
f
r
o
m
h
av
in
g
ch
ild
r
e
n
b
ec
au
s
e
th
e
y
wo
r
r
y
th
at
th
eir
m
e
n
tal
h
ea
lth
is
s
u
es
wo
u
ld
b
e
in
h
er
ited
b
y
th
eir
p
r
o
g
en
y
[
3
7
]
,
[
3
8
]
.
T
h
e
q
u
esti
o
n
o
f
h
o
w
f
a
r
th
e
d
iag
n
o
s
is
an
d
tr
ea
tm
en
t
o
f
d
if
f
e
r
en
t
ty
p
es
o
f
d
is
ea
s
es
o
n
a
g
en
o
m
ic
b
asis
ar
e
ex
p
lain
ed
b
y
v
iews
in
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
is
th
en
b
r
o
u
g
h
t in
to
f
o
c
u
s
th
r
o
u
g
h
t
h
e
em
er
g
en
ce
o
f
th
is
is
s
u
e.
T
h
e
co
m
b
in
atio
n
o
f
ess
en
tiali
s
m
an
d
g
en
etic
d
eter
m
in
is
m
i
n
its
ev
o
lu
tio
n
also
h
as
c
o
n
s
e
q
u
en
ce
s
f
o
r
r
is
in
g
p
u
b
lic
h
ea
lth
is
s
u
es,
e
s
p
ec
ially
s
o
cial,
eth
ical,
a
n
d
leg
al
p
r
o
b
lem
s
.
I
t
is
g
e
n
er
all
y
ac
ce
p
ted
th
at
th
e
s
tr
o
n
g
tr
u
s
t
in
g
en
etic
ess
en
t
ialis
m
an
d
d
ete
r
m
in
is
m
is
an
u
n
u
s
u
al
co
n
ce
p
t
t
h
at
s
u
b
s
ta
n
tially
im
p
ac
ts
th
e
m
ed
ical
f
ield
an
d
ca
n
n
o
t
b
e
alter
ed
o
r
co
m
p
a
r
ed
to
o
th
e
r
m
e
d
ical
th
eo
r
ies.
T
h
is
b
elief
in
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
claim
s
th
at
e
v
en
wea
k
g
en
etic
ex
p
lan
atio
n
s
ca
n
r
ev
ea
l
s
ig
n
if
ican
t
tr
u
th
s
an
d
s
er
v
e
as
th
e
f
o
u
n
d
atio
n
f
o
r
v
ar
io
u
s
ju
d
g
m
en
ts
r
elate
d
to
u
n
iv
er
s
al
h
ea
lth
[
2
5
]
,
[
2
9
]
.
Ho
wev
er
,
th
is
d
e
ep
ly
h
eld
b
elief
h
as
f
o
r
ce
d
d
ec
is
io
n
-
m
a
k
er
s
in
ev
e
r
y
co
u
n
tr
y
to
d
ea
l
with
s
cien
tific
d
ilem
m
as
r
elate
d
to
m
o
r
a
l,
leg
al,
an
d
s
o
cial
h
ea
lth
ca
r
e
co
n
ce
r
n
s
.
Sig
n
if
ic
an
t
wo
r
r
ies
ab
o
u
t
d
is
cr
im
in
at
io
n
ar
e
u
n
av
o
id
ab
le
wh
e
n
a
p
o
licy
d
e
p
en
d
s
o
n
d
eter
m
in
is
tic
b
ias an
d
g
en
etic
ess
en
tiali
s
m
,
p
ar
ticu
lar
ly
wh
en
it c
o
m
es to
v
u
ln
er
ab
le
p
o
p
u
l
atio
n
s
lik
e
ch
ild
r
en
[
3
9
]
,
u
n
b
o
r
n
ch
ild
r
en
[
3
7
]
,
an
d
cr
im
in
als
[
3
4
]
.
E
v
en
f
o
r
s
en
s
itiv
e
d
ata,
th
e
p
o
s
s
ib
ilit
y
o
f
wid
e
u
s
ag
e
o
f
a
ch
i
ld
'
s
g
en
o
m
e
test
r
esu
lts
b
ec
o
m
es g
r
ea
ter
[
4
0
]
.
L
o
n
g
-
ter
m
u
s
ag
e
o
f
a
k
id
'
s
g
en
etic
in
f
o
r
m
atio
n
m
a
y
r
esu
lt
in
im
b
alan
ce
s
,
s
u
ch
as
id
en
tify
in
g
o
r
d
if
f
er
en
tiatin
g
a
c
h
ild
b
ased
o
n
b
e
h
av
io
r
o
r
ac
a
d
em
ic
ca
p
ac
ity
,
wh
ich
will
af
f
ec
t
th
e
ch
ild
'
s
ch
an
ce
s
o
f
em
p
lo
y
m
e
n
t
in
th
e
f
u
tu
r
e
[
4
1
]
.
T
h
ese
eth
ically
d
o
u
b
tf
u
l
g
en
eticiza
tio
n
co
n
ce
r
n
s
m
ig
h
t
also
af
f
ec
t
b
ab
ies
r
ec
eiv
in
g
n
o
n
in
v
asiv
e
p
r
en
ata
l
test
in
g
[4
2]
.
T
h
is
test
in
g
ca
n
im
p
ac
t
a
m
o
th
er
'
s
an
d
in
f
an
t's
ac
ce
s
s
to
h
ea
lth
s
er
v
ices
an
d
th
eir
ab
ilit
y
t
o
ap
p
ly
to
g
o
v
er
n
m
e
n
ts
f
o
r
s
o
cial
s
u
p
p
o
r
t
w
h
en
it
co
m
es
to
co
m
p
licated
tr
aits
lik
e
b
eh
av
io
r
with
a
p
o
o
r
g
en
etic
f
o
u
n
d
atio
n
a
n
d
u
n
clea
r
o
u
tco
m
es
[
3
6
]
,
[
4
3
]
.
Dis
cr
im
in
atio
n
an
d
s
tig
m
atiza
tio
n
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Ho
w
g
en
etic
d
etermin
is
m
a
n
d
ess
en
tia
lis
m
r
ela
te
to
h
ea
lth
c
a
r
e
(
N
in
d
ia
n
a
C
h
o
ir
u
n
is
a
'
)
1501
o
f
cr
im
in
als ar
e
ad
d
itio
n
al
is
s
u
es th
at
m
ay
ar
is
e
f
r
o
m
th
e
m
i
s
u
s
e
o
f
g
en
etic
d
ata
[
3
1
]
.
Peo
p
le
will p
er
ce
iv
e
th
e
cr
im
in
al
b
e
h
av
io
r
o
f
p
r
is
o
n
er
s
as
in
h
e
r
ited
,
m
a
k
in
g
o
th
e
r
s
w
h
o
c
o
m
m
it
s
im
ilar
c
r
im
es
m
o
r
e
lik
ely
t
o
co
n
d
u
ct
th
em
ag
ain
.
I
n
ad
d
itio
n
,
th
ese
co
n
v
icts
m
ay
f
ac
e
p
r
eju
d
ice
i
n
ev
er
y
ar
ea
o
f
life
o
r
ev
en
b
e
r
ejec
ted
b
y
s
o
ciety
.
I
n
v
esti
g
atin
g
th
e
m
o
r
al,
leg
al
,
an
d
s
o
cial
im
p
licatio
n
s
o
f
e
s
s
en
tiali
s
m
an
d
g
en
etic
d
eter
m
in
is
m
o
n
clin
ical
p
r
ac
tice
an
d
p
u
b
lic
h
ea
lth
is
n
ec
ess
ar
y
f
o
r
a
v
o
id
in
g
th
es
e
n
eg
ativ
e
im
p
ac
ts
.
I
t
is
cr
u
cial
to
h
av
e
a
s
o
lid
u
n
d
er
s
tan
d
i
n
g
o
f
g
en
etic
p
r
in
cip
les
to
co
n
d
u
ct
co
m
p
r
eh
en
s
i
v
e
r
esear
ch
,
p
a
r
ticu
lar
ly
g
en
et
ic
d
eter
m
in
is
m
a
n
d
ess
en
tiali
s
m
in
h
ea
lth
ca
r
e.
Un
d
er
s
tan
d
in
g
g
en
etics,
in
g
e
n
er
al,
is
cr
u
cial
to
r
e
d
u
cin
g
o
r
co
r
r
ec
tin
g
th
e
b
ias
o
f
ess
en
tialis
m
an
d
g
en
etic
d
eter
m
in
is
m
,
esp
ec
iall
y
in
h
ea
lth
ca
r
e.
Ge
n
etic
c
o
n
ce
p
ts
m
ay
b
e
lea
r
n
ed
t
h
r
o
u
g
h
a
v
ar
iety
o
f
m
eth
o
d
s
,
h
o
wev
er
,
t
h
is
k
n
o
wled
g
e
is
o
n
ly
a
c
o
m
p
o
n
en
t
th
at
ca
n
b
e
o
b
tain
ed
a
f
ter
s
o
m
e
tim
e.
Sp
ec
ial
ef
f
o
r
ts
ar
e
n
ee
d
ed
t
o
ac
h
iev
e
cr
ed
i
b
le
an
d
ac
cu
r
ate
k
n
o
wled
g
e
o
f
g
en
e
tic
co
n
ce
p
ts
.
Gen
etic
lear
n
in
g
is
o
n
e
m
et
h
o
d
th
at
m
ay
b
e
u
s
ed
to
g
et
a
r
eliab
le
u
n
d
er
s
tan
d
i
n
g
o
f
g
e
n
etic
id
ea
s
[
1
]
.
Acc
o
r
d
in
g
to
ea
r
lier
r
esear
ch
,
s
u
ch
as
[
4
4
]
,
[
4
5
]
,
ge
n
etic
lear
n
in
g
a
b
o
u
t
g
en
e
v
a
r
iatio
n
s
with
in
o
r
ac
r
o
s
s
r
ac
ial
g
r
o
u
p
s
m
ig
h
t
s
er
io
u
s
ly
co
u
n
ter
ac
t
t
h
e
b
ias
o
f
g
e
n
etic
ess
en
tialis
m
an
d
d
eter
m
in
is
m
th
at
p
er
m
ea
tes
m
an
y
f
ac
ets
o
f
life
,
i
n
clu
d
in
g
th
e
m
ed
ical
f
ield
.
R
ac
ial
p
r
eju
d
ice
an
d
th
e
m
is
p
er
ce
p
tio
n
o
f
g
en
et
ic
r
ac
ial
g
r
o
u
p
s
ca
n
b
e
s
u
cc
ess
f
u
lly
r
ed
u
c
ed
wh
en
p
eo
p
le
ar
e
p
r
o
v
id
e
d
ac
cu
r
ate,
s
cien
tific
k
n
o
wled
g
e
a
b
o
u
t
h
u
m
a
n
g
en
etic
d
if
f
er
en
ce
s
[
3
]
,
[
4
6
]
.
Fo
cu
s
in
g
o
n
g
en
eti
c
v
ar
iety
an
d
g
en
etic
lear
n
in
g
m
ay
r
ed
u
ce
s
o
cial
in
e
q
u
it
y
th
at
s
tem
s
f
r
o
m
s
o
lely
g
en
etic
v
ar
iab
les
[
4
7
]
–
[
4
9
]
.
Gen
etic
ed
u
ca
tio
n
m
ay
also
as
s
is
t p
eo
p
le
in
r
ea
lizin
g
th
at
s
o
cial
ch
ar
a
cter
is
tics
,
in
clu
d
in
g
I
Q,
s
o
cial
b
eh
av
io
r
,
an
d
s
o
m
e
illn
ess
es,
ar
e
d
eter
m
in
ed
b
y
s
o
cial
in
ter
ac
tio
n
s
r
ath
er
th
an
b
ein
g
o
n
l
y
a
r
esu
lt
o
f
g
en
etics
[
4
7
]
.
Giv
en
th
e
p
o
ten
tial
o
f
g
en
etic
s
ed
u
ca
tio
n
,
f
u
r
th
er
in
f
o
r
m
ati
o
n
ab
o
u
t
h
o
w
g
e
n
etics
ed
u
ca
tio
n
m
ig
h
t
in
cr
ea
s
e
g
en
etic
ess
en
tialis
m
an
d
d
eter
m
in
is
m
in
th
e
m
ed
ical
f
ield
r
e
q
u
ir
es p
ar
ticu
lar
f
o
cu
s
.
I
n
o
r
d
er
to
ad
d
r
ess
th
is
p
r
o
b
lem
,
it
is
cr
u
cial
to
ca
r
r
y
o
u
t
an
ex
ten
s
iv
e
s
tu
d
y
o
f
g
en
etic
d
e
ter
m
in
is
m
an
d
ess
en
tialis
m
in
h
ea
lth
ca
r
e.
T
h
is
ca
n
b
e
ac
h
iev
ed
b
y
u
tili
zin
g
d
ata
f
r
o
m
Sco
p
u
s
,
wh
ich
is
wid
ely
r
ec
o
g
n
ized
as
a
r
ep
u
ta
b
le
an
d
well
-
u
s
ed
d
ata
b
ase.
A
th
o
r
o
u
g
h
a
n
aly
s
is
o
f
th
e
p
u
b
licatio
n
s
in
th
is
d
atab
ase
is
r
eq
u
ir
ed
to
o
b
tain
v
alu
a
b
le
in
s
ig
h
ts
in
to
th
e
im
p
ac
t
o
f
d
eter
m
in
is
m
an
d
g
en
etic
ess
en
tialis
m
o
n
th
e
q
u
ality
o
f
h
ea
lth
s
er
v
ices
an
d
th
e
p
o
ten
tial
o
f
g
en
etics
ed
u
ca
tio
n
in
ad
d
r
ess
in
g
th
ese
b
iases
.
A
h
ig
h
ly
r
ec
o
m
m
en
d
e
d
ap
p
r
o
ac
h
f
o
r
e
x
am
in
in
g
a
n
d
an
aly
zin
g
th
ese
is
s
u
es
is
a
s
y
s
tem
atic
liter
atu
r
e
r
ev
iew
(
SLR).
T
h
e
SLR
is
a
r
ig
o
r
o
u
s
an
d
tr
an
s
p
ar
e
n
t
p
r
o
ce
s
s
th
at
in
v
o
lv
es
id
en
tify
in
g
,
s
y
n
th
esizin
g
,
an
d
ev
alu
atin
g
all
r
elev
an
t
d
ata,
wh
eth
er
it
is
q
u
an
titativ
e
o
r
q
u
alitativ
e,
in
o
r
d
er
to
g
en
e
r
at
e
p
r
ec
is
e
an
d
r
eliab
le
r
esp
o
n
s
es
[
5
0
]
.
SLR
o
f
f
er
s
s
ev
er
al
b
en
ef
its
to
r
esear
ch
er
s
,
p
ar
ticu
lar
ly
in
g
iv
in
g
a
b
r
ie
f
an
d
t
h
o
r
o
u
g
h
o
v
e
r
v
iew
o
f
th
e
m
ater
ial
f
o
u
n
d
in
d
atab
ases
r
elate
d
to
t
h
eir
s
tu
d
y
to
p
ics
[
5
1
]
.
SLR
ca
n
ass
i
s
t
r
esear
ch
er
s
in
id
en
tify
in
g
b
o
th
m
eth
o
d
o
lo
g
ical
r
esear
ch
g
ap
s
an
d
is
s
u
es
th
at
n
ec
ess
itate
ad
d
itio
n
al
in
v
esti
g
atio
n
.
I
t
ca
n
also
ai
d
in
d
e
v
el
o
p
in
g
n
ew
r
esear
ch
id
ea
s
an
d
s
y
n
th
esizin
g
m
u
ltip
l
e
r
ef
er
en
ce
s
in
a
cr
itical
an
d
c
o
n
s
tr
u
ctiv
e
ap
p
r
o
ac
h
[
5
2
]
.
I
n
t
h
is
s
tu
d
y
,
th
er
e
a
r
e
r
esear
ch
q
u
esti
o
n
s
wh
ich
in
c
lu
d
e
th
e
f
o
llo
win
g
:
i)
R
Q
1
:
Ho
w
d
o
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
ex
p
lain
th
e
g
e
n
o
m
ic
d
iag
n
o
s
is
an
d
tr
ea
tm
en
t
o
f
v
ar
io
u
s
d
is
ea
s
es?
;
ii)
R
Q
2
:
Ho
w
d
o
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tiali
s
m
im
p
ac
t
p
u
b
lic
h
e
alth
an
d
clin
ical
p
r
ac
tice
f
r
o
m
an
eth
ical,
leg
al,
an
d
s
o
cial
p
er
s
p
ec
tiv
e?
;
iii)
R
Q
3
: H
o
w
ca
n
g
e
n
etics e
d
u
ca
tio
n
d
ec
r
ea
s
e
g
en
etic
ess
en
tialis
m
an
d
d
eter
m
i
n
is
m
lev
els in
th
e
m
ed
ical
f
ield
?
2.
M
E
T
H
O
D
2
.
1
.
R
e
s
e
a
r
c
h
f
r
a
me
w
o
r
k
T
h
is
r
esear
ch
is
a
SLR,
wh
i
ch
is
a
p
r
o
ce
s
s
th
at
in
v
o
l
v
es
th
r
ee
s
tep
s
:
i)
p
r
esen
tin
g
all
p
u
b
lis
h
ed
ev
id
en
ce
r
elate
d
t
o
th
e
r
esear
ch
q
u
esti
o
n
,
ii)
s
y
n
th
esizin
g
s
cien
tific
ev
id
en
ce
to
an
s
wer
a
s
p
ec
if
ic
r
esear
ch
q
u
esti
o
n
in
a
tr
an
s
p
ar
en
t a
n
d
r
ep
r
o
d
u
cib
le
way
,
iii
)
ev
alu
atin
g
th
e
q
u
ality
o
f
th
e
ev
id
e
n
ce
p
r
esen
ted
[
5
1
]
.
T
h
i
s
r
e
s
e
a
r
c
h
u
s
e
s
a
S
L
R
m
e
t
h
o
d
o
l
o
g
y
s
u
p
p
o
r
t
e
d
b
y
n
a
r
r
a
t
i
v
e
a
n
a
l
y
s
i
s
.
T
h
e
n
a
r
r
a
t
i
v
e
a
p
p
r
o
a
c
h
f
a
c
i
l
i
t
a
t
e
s
a
c
o
m
p
r
e
h
e
n
s
i
v
e
a
n
d
c
o
m
p
l
e
x
p
r
e
s
e
n
t
a
t
i
o
n
o
f
f
i
n
d
i
n
g
s
,
p
r
o
v
i
d
i
n
g
a
c
r
e
d
i
b
l
e
r
e
s
p
o
n
s
e
t
o
s
p
e
c
i
f
i
c
r
e
v
i
e
w
t
o
p
i
c
s
,
i
n
c
l
u
d
i
n
g
h
o
w
g
e
n
e
t
i
c
d
e
t
e
r
m
i
n
i
s
m
a
n
d
e
s
s
e
n
t
i
a
l
i
s
m
r
e
l
a
t
e
t
o
h
e
a
l
t
h
c
a
r
e
.
I
t
c
a
n
a
l
s
o
h
i
g
h
l
i
g
h
t
a
r
e
a
s
o
f
o
u
r
u
n
d
e
r
s
t
a
n
d
i
n
g
t
h
a
t
r
e
q
u
i
r
e
a
d
d
i
t
i
o
n
a
l
r
e
s
e
a
r
c
h
.
I
t
c
a
n
a
l
s
o
c
o
n
v
e
y
t
h
e
r
o
b
u
s
t
n
e
s
s
o
f
t
h
e
a
c
c
e
s
s
i
b
l
e
e
v
i
d
e
n
c
e
a
n
d
t
h
e
q
u
a
l
i
t
y
o
f
t
h
e
i
n
c
l
u
d
e
d
s
t
u
d
i
e
s
,
i
n
d
i
c
a
t
i
n
g
t
h
e
c
o
n
f
i
d
e
n
c
e
t
h
a
t
p
r
a
c
t
i
t
i
o
n
e
r
s
,
p
o
l
i
c
y
m
a
k
e
r
s
,
a
n
d
t
h
e
p
o
p
u
l
a
r
m
e
d
i
a
s
h
o
u
l
d
p
l
a
c
e
i
n
t
h
e
r
e
s
u
l
t
s
.
R
e
s
e
a
r
c
h
s
y
n
t
h
e
s
i
s
c
a
n
a
l
s
o
f
a
c
i
l
i
t
a
t
e
a
s
s
e
s
s
m
e
n
t
o
f
t
h
e
e
f
f
i
c
a
c
y
o
f
a
p
o
l
i
c
y
,
p
r
o
g
r
a
m
,
t
e
c
h
n
i
q
u
e
,
o
r
i
n
t
e
r
v
e
n
t
i
o
n
a
c
r
o
s
s
d
i
f
f
e
r
e
n
t
u
s
e
r
s
u
b
g
r
o
u
p
s
a
n
d
p
r
o
v
i
d
e
i
n
s
i
g
h
t
i
n
t
o
p
o
t
e
n
t
i
a
l
s
i
d
e
e
f
f
e
c
t
s
.
2
.
2
.
Sea
rc
h t
er
m
T
h
e
s
e
a
r
c
h
i
n
t
h
e
S
c
o
p
u
s
d
a
t
a
b
a
s
e
u
s
es
t
h
e
"
AN
D
"
o
p
e
r
a
t
o
r
to
c
o
m
b
i
n
e
t
h
e
k
e
y
w
o
r
d
s
d
e
t
e
r
m
i
n
i
s
m
a
n
d
g
e
n
e
t
i
c
es
s
e
n
t
i
al
i
s
m
.
T
h
is
s
e
a
r
c
h
w
a
s
c
o
n
d
u
c
t
e
d
i
n
2
0
2
4
.
W
e
o
b
t
a
i
n
e
d
a
t
o
t
a
l
o
f
8
0
2
a
r
t
i
c
le
s
f
r
o
m
t
h
e
S
c
o
p
u
s
d
a
t
a
b
a
s
e
.
S
e
v
e
r
al
p
a
p
e
r
s
d
is
c
o
v
e
r
e
d
s
h
o
w
p
u
b
l
ic
a
t
i
o
n
y
ea
r
s
r
a
n
g
i
n
g
f
r
o
m
2
0
0
6
t
o
2
0
2
3
.
T
h
e
m
a
j
o
r
i
t
y
o
f
a
r
t
ic
l
es
w
e
r
e
d
i
s
c
o
v
e
r
e
d
i
n
2
0
1
9
.
T
h
e
a
c
q
u
i
r
e
d
d
a
t
a
i
s
k
e
p
t
i
n
c
o
m
m
a
s
e
p
a
r
a
t
e
d
v
a
l
u
es
(
C
S
V
)
an
d
R
I
S
f
o
r
m
a
t
s
a
n
d
s
y
n
c
h
r
o
n
i
z
e
d
w
it
h
M
e
n
d
e
l
e
y
.
T
h
e
s
e
a
r
c
h
h
i
s
t
o
r
y
f
o
r
a
r
t
i
c
le
s
in
S
c
o
p
u
s
r
u
n
s
a
s
A
L
L
(
ess
e
n
t
ia
l
i
s
m
+
g
e
n
e
t
i
c
A
ND
d
e
t
e
r
m
i
n
i
s
m
)
A
N
D
(
L
I
M
I
T
-
T
O
(
D
OC
T
YP
E
,
"
a
r
"
)
)
AND
(
L
I
M
I
T
-
T
O
(
L
A
NG
UA
GE
,
"
E
n
g
l
i
s
h
"
)
)
AN
D
(
L
I
M
I
T
-
T
O
(
O
A
,
"
al
l
"
)
)
AN
D
(
L
I
M
I
T
-
T
O
(
S
UB
J
AR
E
A
,
"M
E
D
I
"
)
OR
L
I
M
I
T
-
T
O
(
S
UB
J
AR
E
A
,
"N
UR
S"
)
)
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
1
4
9
9
-
1
5
1
4
1502
2
.
3
.
Select
io
n o
f
pa
pers f
o
r
i
nclus
io
n i
n r
ev
iew
Ou
r
r
esear
ch
em
p
lo
y
ed
th
e
p
r
ef
er
r
ed
r
ep
o
r
tin
g
i
tem
s
f
o
r
PR
I
SMA
[
5
1
]
to
estab
lis
h
th
e
in
clu
s
io
n
cr
iter
ia
an
d
m
eth
o
d
s
o
f
s
ea
r
c
h
.
Af
ter
a
s
ea
r
ch
f
o
r
k
e
y
wo
r
d
s
,
r
esear
ch
er
s
ex
am
in
e
th
e
titl
es
an
d
ab
s
tr
ac
ts
o
f
ar
ticles
to
id
en
tify
tar
g
et
p
ap
er
s
th
at
m
atch
th
e
s
p
ec
if
ied
cr
iter
ia:
i)
p
u
b
licatio
n
s
in
clu
d
i
n
g
r
esear
ch
/o
r
ig
i
n
al
ar
ticles,
ii)
ar
ticles
p
u
b
lis
h
ed
i
n
E
n
g
lis
h
,
iii)
o
n
ly
a
r
ticles
th
at
ar
e
o
p
en
-
ac
ce
s
s
an
d
in
d
ex
ed
b
y
Sco
p
u
s
,
iv
)
t
h
e
s
u
b
ject
ar
ea
o
f
th
e
ar
ticle
is
n
u
r
s
in
g
an
d
m
ed
icin
e
an
d
,
v
)
o
n
ly
ab
s
tr
ac
ts
an
d
f
u
ll
-
tex
t
ar
ticles
ar
e
s
elec
ted
th
at
ar
e
ap
p
r
o
p
r
iate
to
t
h
e
th
em
e
b
ein
g
d
is
cu
s
s
ed
.
Su
p
p
o
s
e
th
e
ab
s
tr
ac
t
o
f
an
a
r
t
icle
n
ee
d
s
to
p
r
o
v
id
e
m
o
r
e
in
f
o
r
m
atio
n
.
I
n
th
at
ca
s
e,
we
will
an
aly
ze
th
e
im
p
o
r
tan
t
s
ec
tio
n
s
o
f
th
e
p
ar
t,
s
u
ch
as
t
h
e
m
et
h
o
d
o
lo
g
y
an
d
r
esu
lts
,
to
estab
lis
h
a
ju
d
g
m
en
t.
I
n
ad
d
itio
n
,
th
e
r
esear
ch
er
s
ap
p
lied
t
h
e
f
o
llo
win
g
ex
clu
s
i
o
n
c
r
iter
ia
to
f
ilter
o
u
t
p
ap
er
s
th
at
wer
e
n
o
t
in
clu
d
ed
i
n
th
is
s
tu
d
y
:
i
)
Pu
b
licatio
n
s
with
th
e
ty
p
e
o
f
co
n
f
er
e
n
ce
p
ap
er
,
b
o
o
k
c
h
ap
ter
,
co
n
f
er
en
ce
r
e
v
iew,
r
ev
iew,
ed
ito
r
ial,
an
d
b
o
o
k
;
ii
)
No
n
-
E
n
g
lis
h
p
u
b
lis
h
ed
s
tu
d
ies
;
iii
)
No
n
-
o
p
en
a
cc
ess
ar
ticles an
d
n
o
t
in
d
ex
e
d
b
y
Sco
p
u
s
;
iv
)
No
t
r
elev
an
t
to
t
h
e
th
em
e
b
ein
g
d
i
s
cu
s
s
ed
;
an
d
v
)
I
n
co
m
p
lete
te
x
t.
T
h
e
o
r
d
e
r
o
f
r
ev
iew
o
f
in
cl
u
s
io
n
an
d
ex
clu
s
io
n
th
at
we
ca
r
r
ied
o
u
t is p
r
esen
te
d
in
Fig
u
r
e
1
.
F
i
g
u
r
e
1
.
Sy
s
tem
atic
r
ev
iew
f
lo
w
d
iag
r
am
s
o
u
r
ce
:
a
u
th
o
r
s
’
o
wn
elab
o
r
atio
n
Fig
u
r
e
1
s
h
o
ws
th
at
th
e
o
r
ig
i
n
al
s
ea
r
ch
f
o
u
n
d
a
to
tal
o
f
8
0
2
item
s
.
Su
b
s
eq
u
en
tly
,
we
s
elec
tiv
ely
co
n
s
id
er
ed
p
u
b
licatio
n
s
th
at
e
x
clu
s
iv
ely
co
n
tain
ed
r
esear
ch
/
o
r
ig
in
al
p
ap
er
s
,
i
d
en
tify
in
g
5
4
9
ar
ticles
,
an
d
2
5
3
ar
ticles
wer
e
ex
clu
d
ed
.
Nex
t,
we
a
p
p
lied
th
e
s
ec
o
n
d
cr
iter
io
n
,
s
p
ec
if
ically
s
elec
tin
g
o
n
l
y
p
u
b
licatio
n
s
th
at
wer
e
p
u
b
lis
h
ed
in
E
n
g
lis
h
.
Usi
n
g
th
is
cr
iter
io
n
,
we
o
b
ta
in
ed
a
to
tal
o
f
5
4
0
ar
ticles.
C
o
n
s
eq
u
en
tly
,
n
i
n
e
ar
ticles
th
at
u
s
e
Po
lis
h
,
Ger
m
an
,
Po
r
tu
g
u
ese,
Sp
an
is
h
,
an
d
Fre
n
ch
wer
e
r
em
o
v
ed
f
r
o
m
th
e
an
aly
s
is
.
I
n
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Ho
w
g
en
etic
d
etermin
is
m
a
n
d
ess
en
tia
lis
m
r
ela
te
to
h
ea
lth
c
a
r
e
(
N
in
d
ia
n
a
C
h
o
ir
u
n
is
a
'
)
1503
g
en
er
al,
au
th
o
r
s
n
ee
d
m
o
r
e
c
ap
ac
ity
to
co
m
p
r
eh
e
n
d
th
ese
lan
g
u
ag
es.
T
h
e
au
th
o
r
in
ten
ti
o
n
ally
av
o
id
s
u
s
in
g
Go
o
g
le
T
r
an
s
late
to
m
itig
ate
th
e
r
is
k
o
f
tr
an
s
latio
n
in
ac
cu
r
ac
ies
an
d
m
is
in
ter
p
r
etatio
n
s
.
T
h
is
ap
p
r
o
ac
h
als
o
s
av
es
tim
e
co
m
p
ar
ed
to
h
i
r
in
g
p
r
o
f
ess
io
n
al
tr
an
s
latio
n
s
er
v
ices,
wh
ich
ca
n
b
e
p
r
icy
.
Acc
o
r
d
i
n
g
to
Mh
eiss
en
et
a
l
.
,
it
h
as
b
ee
n
d
e
m
o
n
s
tr
ated
th
at
lim
its
d
o
n
o
t
r
esu
lt
in
b
iased
e
f
f
ec
ts
[
5
3
]
.
Fo
r
th
e
n
ex
t
s
tep
,
we
ex
clu
s
iv
ely
u
tili
ze
d
o
p
en
-
ac
c
ess
p
u
b
licatio
n
s
.
Ou
t
o
f
th
em
,
2
5
0
ar
ticles
s
atis
f
ied
th
e
estab
lis
h
ed
cr
iter
ia,
wh
er
ea
s
2
9
0
ar
ticles
wer
e
ex
clu
d
ed
.
Fo
r
th
e
n
ex
t
s
tep
,
we
ap
p
lied
th
e
to
p
ic
ar
ea
in
clu
s
io
n
cr
iter
ia
o
f
"
n
u
r
s
in
g
an
d
m
ed
icin
e
"
an
d
s
elec
ted
8
2
p
ap
er
s
,
ex
clu
d
in
g
1
6
8
p
u
b
li
ca
tio
n
s
.
W
e
p
r
ev
en
t
th
e
in
clu
s
io
n
o
f
in
ap
p
r
o
p
r
iate
s
u
b
ject
ar
ea
s
s
u
ch
as
b
io
ch
e
m
is
tr
y
,
g
en
etics
an
d
m
o
lecu
l
ar
b
io
lo
g
y
,
ag
r
icu
lt
u
r
al
an
d
b
io
lo
g
ical
s
cien
ce
s
,
s
o
cial
s
cien
ce
s
,
en
v
ir
o
n
m
en
t
al
s
cien
ce
,
co
m
p
u
ter
s
cien
ce
,
im
m
u
n
o
lo
g
y
an
d
m
ic
r
o
b
io
l
o
g
y
,
m
a
th
em
atics,
p
s
y
ch
o
lo
g
y
,
n
e
u
r
o
s
cien
ce
,
en
g
in
ee
r
in
g
,
p
h
ar
m
ac
o
lo
g
y
,
to
x
i
co
lo
g
y
a
n
d
p
h
ar
m
ac
eu
tics
,
m
u
ltid
is
cip
lin
ar
y
,
ar
ts
an
d
h
u
m
an
ities
,
h
ea
lth
p
r
o
f
ess
io
n
s
,
en
er
g
y
,
ec
o
n
o
m
ics,
ec
o
n
o
m
etr
ics
an
d
f
in
an
ce
,
ch
em
ica
l
en
g
in
ee
r
in
g
,
a
n
d
b
u
s
in
ess
,
m
an
ag
em
en
t
a
n
d
ac
co
u
n
tin
g
.
Du
r
in
g
th
e
co
n
clu
d
i
n
g
p
h
ase
o
f
th
e
s
ea
r
ch
,
we
th
o
r
o
u
g
h
ly
e
x
am
in
ed
th
e
ex
is
tin
g
ar
ticles
an
d
v
er
if
i
ed
th
eir
r
elev
an
ce
t
o
th
e
to
p
ic
u
n
d
er
d
is
cu
s
s
io
n
.
Fo
u
r
r
esear
ch
er
s
in
d
iv
id
u
ally
r
ev
iewe
d
ea
ch
ar
ticle
in
clu
d
e
d
in
th
is
s
y
s
tem
atic
r
ev
iew.
T
o
d
ea
l
with
t
h
e
d
if
f
er
in
g
o
p
in
io
n
s
th
at
ev
o
lv
e
d
d
u
r
in
g
th
e
r
ev
iew
p
r
o
ce
s
s
,
we
n
ee
d
ed
an
o
p
en
d
is
cu
s
s
io
n
m
eth
o
d
u
n
til
co
n
s
en
s
u
s
was
ac
h
iev
ed
.
I
f
th
e
d
is
cr
ep
an
cies
r
em
ain
u
n
r
eso
l
v
ed
,
a
th
ir
d
r
esear
ch
er
with
d
ee
p
k
n
o
wled
g
e
o
f
th
e
s
u
b
je
ct
was
r
eq
u
ested
to
p
r
o
v
id
e
a
co
n
clu
s
iv
e
ev
alu
atio
n
.
At
th
e
f
in
al
s
tag
e
o
f
th
e
s
ea
r
ch
,
we
f
o
u
n
d
4
9
ar
ticles th
at
wer
e
ap
p
r
o
p
r
iate
o
r
m
et
th
e
cr
iter
ia,
an
d
3
3
ar
ticles
wer
e
ex
clu
d
ed
.
Mo
s
t
o
f
th
e
p
ap
er
s
in
th
is
s
y
s
tem
atic
liter
atu
r
e
r
ev
iew
u
s
ed
q
u
an
titativ
e
m
eth
o
d
s
(
2
4
ar
ti
cles)
,
f
o
llo
wed
b
y
q
u
alitativ
e
m
eth
o
d
s
(
2
1
ar
ticles),
wh
ile
m
ix
ed
a
p
p
r
o
ac
h
es
wer
e
th
e
least a
p
p
lied
(
4
ar
ticles).
3.
RE
SU
L
T
S AN
D
D
I
SCU
SS
I
O
N
T
h
e
in
v
esti
g
atio
n
'
s
f
in
d
in
g
s
will
b
e
p
r
o
v
id
e
d
in
th
is
s
ec
t
io
n
as
a
r
e
v
iew
o
f
th
e
ea
r
lie
r
r
esear
ch
q
u
esti
o
n
s
.
T
h
is
r
ev
iew
will
h
ig
h
lig
h
t
th
e
k
ey
in
s
ig
h
ts
g
ain
ed
f
r
o
m
th
e
s
tu
d
y
,
em
p
h
asizin
g
th
e
r
elatio
n
s
h
ip
b
etwe
en
th
e
r
esu
lts
an
d
th
e
o
r
ig
in
al
h
y
p
o
th
eses
.
T
h
e
f
o
llo
wi
n
g
s
u
b
s
ec
tio
n
s
will
p
r
o
v
id
e
f
u
r
th
er
d
etails
o
n
th
e
f
in
d
in
g
s
a
n
d
d
is
cu
s
s
io
n
o
f
ev
e
r
y
r
esear
ch
s
tu
d
y
.
Ad
d
itio
n
ally
,
th
e
s
e
s
u
b
s
ec
tio
n
s
will
d
is
cu
s
s
th
e
im
p
licatio
n
s
o
f
th
e
r
esu
lts
in
th
e
c
o
n
tex
t
o
f
ex
is
tin
g
r
esear
ch
,
p
r
o
v
id
in
g
a
co
m
p
r
eh
en
s
iv
e
u
n
d
e
r
s
tan
d
in
g
o
f
th
e
s
tu
d
y
'
s
co
n
tr
ib
u
tio
n
s
.
3
.
1
.
E
x
pla
na
t
io
n
o
f
g
enet
ic
det
er
m
ini
s
m
a
nd
ess
ent
ia
lis
m
in
t
he
g
eno
m
ic
dia
g
no
s
is
a
nd
t
re
a
t
m
ent
o
f
v
a
rio
us
dis
ea
s
es
T
h
e
b
ias
o
f
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
h
as
s
ig
n
if
ican
tly
in
f
lu
en
ce
d
th
e
m
e
d
ical
f
ield
.
B
o
th
s
tig
m
as
im
p
ac
t
d
iag
n
o
s
es
an
d
tr
ea
tm
en
t
-
r
elate
d
asp
ec
ts
o
f
m
ed
icin
e.
Fu
r
th
e
r
i
n
f
o
r
m
atio
n
o
n
t
h
e
in
f
lu
en
ce
o
f
d
eter
m
in
is
m
an
d
e
s
s
en
tialis
m
o
n
th
e
s
co
p
e
o
f
d
iag
n
o
s
is
an
d
t
r
ea
tm
en
t
o
f
v
ar
io
u
s
d
is
ea
s
es
o
r
d
is
o
r
d
er
s
ca
n
b
e
r
ev
iewe
d
i
n
T
ab
le
1
.
Acc
o
r
d
in
g
to
t
h
e
d
ata
an
d
in
f
o
r
m
atio
n
s
h
o
wn
in
T
ab
le
1
,
it
ca
n
b
e
d
eter
m
i
n
ed
th
at
g
en
etic
d
eter
m
in
is
m
an
d
g
e
n
etic
ess
en
tialis
m
ar
e
th
e
p
r
im
ar
y
v
a
r
iab
les
th
at
ca
u
s
e
in
ac
cu
r
ate
d
iag
n
o
s
is
an
d
th
e
em
er
g
en
ce
o
f
a
f
atalist
ic
b
elief
th
at
a
d
is
o
r
d
e
r
o
r
d
is
ea
s
e
is
u
n
ch
an
g
ea
b
le
[
4
]
.
B
iases
r
esu
ltin
g
f
r
o
m
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
will
ad
d
itio
n
ally
g
u
id
e
th
e
in
ter
p
r
etatio
n
to
wa
r
d
s
th
e
p
o
s
s
ib
le
s
ig
n
if
ican
ce
o
f
g
en
es
as
ca
u
s
al
f
ac
to
r
s
in
s
p
e
cif
ic
s
itu
atio
n
s
,
b
eh
av
io
r
s
,
a
n
d
d
is
ea
s
es
[
2
3
]
,
[
2
4
]
,
[
5
4
]
.
T
h
e
b
elief
in
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
b
ias
is
s
ee
n
to
b
e
th
e
m
ain
f
ac
to
r
in
f
l
u
en
cin
g
d
ec
is
io
n
-
m
a
k
in
g
i
n
ch
allen
g
in
g
m
ed
ical
s
itu
atio
n
s
,
s
u
ch
as
d
ec
id
in
g
wh
eth
er
to
ter
m
in
ate
a
p
r
eg
n
an
c
y
o
r
m
o
v
e
a
p
atien
t'
s
ca
r
e
to
p
alliativ
e
ca
r
e
[
5
5
]
.
Gen
er
ally
,
th
er
e
n
ee
d
s
to
b
e
m
o
r
e
awa
r
en
ess
am
o
n
g
th
e
p
u
b
lic
r
eg
a
r
d
in
g
th
e
b
ias
o
f
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
in
in
ter
p
r
etin
g
g
en
etic
test
r
esu
lts
[
1
3
]
.
Desp
ite
th
is
,
g
en
etic
test
in
g
r
em
ain
s
th
e
p
r
ef
er
r
e
d
m
eth
o
d
f
o
r
ass
ess
i
n
g
th
e
h
ea
lth
s
tatu
s
o
f
in
d
i
v
id
u
als
[
1
3
]
,
[
2
5
]
,
[
4
3
]
,
[
5
6
]
.
I
n
cr
ea
s
ed
m
ar
k
et
d
em
an
d
h
as led
to
a
q
u
ick
g
r
o
wth
in
s
u
p
p
o
r
t f
r
o
m
co
m
p
a
n
ie
s
p
r
o
v
id
in
g
g
en
etic
test
in
g
s
er
v
ices,
ac
co
m
p
an
ied
by
a
n
o
ta
b
le
d
ec
r
ea
s
e
in
th
e
c
o
s
t
o
f
g
en
o
t
y
p
e
test
in
g
[
4
3
]
.
Var
io
u
s
g
en
etic
test
s
,
in
clu
d
in
g
d
ir
ec
t
-
to
-
c
o
n
s
u
m
e
r
(
DT
C
)
[
1
3
]
,
[
5
6
]
,
PGS
test
s
[
3
2
]
,
a
n
d
W
E
S
[
5
7
]
,
h
a
v
e
b
ee
n
c
o
n
d
u
cted
f
o
r
a
r
a
n
g
e
o
f
o
b
jectiv
es,
f
r
o
m
d
iag
n
o
s
is
to
in
f
o
r
m
in
g
d
ec
is
io
n
s
ab
o
u
t a
m
e
d
ical
co
n
d
itio
n
.
Alth
o
u
g
h
th
er
e
h
as
b
ee
n
s
o
m
e
p
r
o
g
r
ess
,
it
is
s
till
n
ec
ess
ar
y
to
a
d
eq
u
at
ely
ad
d
r
ess
th
e
p
r
o
b
lem
s
o
f
d
eter
m
in
is
m
b
ias
an
d
g
en
etic
ess
en
tiali
s
m
.
Fu
r
th
er
m
o
r
e,
en
s
u
r
in
g
ac
cu
r
ac
y
in
th
e
d
iag
n
o
s
tic
p
r
o
ce
s
s
r
em
ain
s
a
co
m
p
lex
to
p
ic
th
at
r
e
q
u
ir
es
p
ar
ticu
lar
atten
tio
n
.
Ad
d
itio
n
a
l
r
is
k
s
r
elate
d
to
p
r
o
tectin
g
th
e
p
atien
t'
s
id
en
tity
,
s
u
ch
as
a
d
ec
r
ea
s
ed
willin
g
n
ess
to
s
h
ar
e
in
f
o
r
m
atio
n
a
n
d
u
n
d
er
g
o
f
u
tu
r
e
g
e
n
etic
t
esti
n
g
,
s
h
o
u
ld
b
e
in
v
esti
g
ated
[
2
4
]
,
[
2
5
]
,
[
5
4
]
,
[
5
8
]
.
Mo
r
eo
v
e
r
,
if
d
eter
m
in
is
m
b
ias
an
d
g
en
etic
ess
en
tialis
m
m
is
tak
es
d
u
r
in
g
th
e
d
iag
n
o
s
is
p
r
o
ce
s
s
ar
e
n
o
t
i
m
m
ed
iately
f
ix
e
d
,
th
er
e
is
a
s
tr
o
n
g
lik
elih
o
o
d
o
f
in
ac
cu
r
ac
ie
s
em
er
g
in
g
in
later
m
ed
ical
p
r
o
ce
d
u
r
es.
W
h
e
n
g
en
etic
d
eter
m
in
is
m
a
n
d
ess
en
tialis
m
b
ias
co
n
tin
u
e
th
r
o
u
g
h
o
u
t
th
e
d
iag
n
o
s
is
an
d
tr
ea
tm
en
t
p
r
o
ce
s
s
,
th
e
ch
allen
g
es
will
e
s
ca
late
an
d
b
ec
o
m
e
in
cr
ea
s
in
g
ly
in
tr
icate
.
Patien
ts
wh
o
h
a
v
e
ex
p
er
ien
ce
d
th
e
n
eg
ativ
e
p
er
ce
p
tio
n
o
f
d
eter
m
in
is
m
an
d
ess
en
tialis
m
will
h
av
e
an
i
n
f
lated
b
elief
in
t
h
e
r
o
le
o
f
g
e
n
es
in
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
1
4
9
9
-
1
5
1
4
1504
d
eter
m
in
in
g
a
d
is
ea
s
e
[
2
0
]
.
I
n
ad
d
itio
n
,
p
atien
ts
m
ay
lo
s
e
o
r
h
av
e
a
d
im
in
is
h
ed
lev
el
o
f
m
o
tiv
atio
n
to
u
n
d
er
g
o
tr
ea
tm
en
t
d
u
e
t
o
th
eir
p
er
ce
p
tio
n
o
f
th
e
lim
ited
im
p
ac
t
o
f
th
eir
e
n
v
ir
o
n
m
en
t,
p
er
s
o
n
al
ex
p
er
ien
ce
s
,
a
n
d
life
s
ty
le
o
n
th
e
h
ea
lin
g
p
r
o
c
ess
o
f
th
eir
s
p
ec
if
ic
co
n
d
itio
n
[
2
]
,
[
3
3
]
,
[
5
5
]
.
I
n
co
n
tr
ast
,
a
r
o
b
u
s
t
g
e
n
etic
ex
p
lan
atio
n
is
o
n
ly
ass
o
ciate
d
with
a
m
o
n
o
g
en
ic
etio
lo
g
y
o
f
a
co
n
d
itio
n
,
s
u
ch
as
in
ca
s
e
s
lik
e
Hu
n
tin
g
to
n
'
s
d
is
ea
s
e
wh
en
th
e
d
is
ea
s
e
-
ca
u
s
in
g
g
e
n
e
h
as
a
well
-
d
e
f
in
ed
co
n
n
ec
tio
n
[
2
]
.
Nev
e
r
th
eless
,
p
at
ien
ts
will
co
n
tin
u
e
to
h
o
ld
o
n
to
th
ese
m
o
n
o
g
en
ic
id
ea
s
an
d
g
en
er
a
lize
th
em
to
d
if
f
er
en
t
ch
a
r
ac
ter
is
tics
o
r
ev
en
s
o
cial
p
h
en
o
m
en
a
s
u
c
h
as
d
i
v
o
r
ce
[
2
6
]
,
[
2
7
]
,
[
5
9
]
,
r
elig
i
o
n
[
2
8
]
,
m
en
tal
h
ea
lth
[
2
0
]
,
a
n
d
s
m
o
k
in
g
[
3
0
]
,
as
well
as
th
e
b
eh
av
i
o
r
o
f
in
d
iv
i
d
u
als
[
4
]
,
[
2
0
]
,
[
3
1
]
,
[
6
0
]
,
[
6
1
]
.
T
ab
le
1
.
I
m
p
licatio
n
s
o
f
g
en
et
ic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
in
th
e
d
ia
g
n
o
s
is
an
d
tr
ea
tm
e
n
t o
f
v
a
r
io
u
s
ty
p
es
o
f
d
is
ea
s
es o
r
d
is
o
r
d
er
s
No
A
sp
e
c
t
I
n
f
o
r
ma
t
i
o
n
R
e
f
e
r
e
n
c
e
1
D
i
a
g
n
o
si
s
•
Th
e
c
o
n
c
e
p
t
s
o
f
d
e
t
e
r
mi
n
i
s
m
a
n
d
g
e
n
e
t
i
c
e
ss
e
n
t
i
a
l
i
sm
b
i
a
s
e
s
c
a
n
e
a
s
i
l
y
a
r
i
se
d
u
r
i
n
g
g
e
n
e
t
i
c
t
e
st
i
n
g
,
w
h
i
c
h
i
s u
se
d
t
o
m
a
k
e
d
e
c
i
si
o
n
s
r
e
g
a
r
d
i
n
g
v
a
r
i
o
u
s
m
e
d
i
c
a
l
p
r
o
c
e
d
u
r
e
s.
T
h
e
s
e
p
r
o
c
e
d
u
r
e
s
i
n
c
l
u
d
e
t
e
r
mi
n
a
t
i
n
g
a
p
r
e
g
n
a
n
c
y
,
t
r
a
n
si
t
i
o
n
i
n
g
p
a
t
i
e
n
t
c
a
r
e
t
o
p
a
l
l
i
a
t
i
v
e
c
a
r
e
,
w
h
i
c
h
f
o
c
u
s
e
s
o
n
i
mp
r
o
v
i
n
g
q
u
a
l
i
t
y
o
f
l
i
f
e
r
a
t
h
e
r
t
h
a
n
c
u
r
i
n
g
t
h
e
c
o
n
d
i
t
i
o
n
,
p
r
o
v
i
d
i
n
g
r
e
c
o
m
men
d
a
t
i
o
n
s
t
o
p
a
t
i
e
n
t
s
f
o
r
f
u
t
u
r
e
h
e
a
l
t
h
p
r
e
p
a
r
a
t
i
o
n
,
d
i
a
g
n
o
si
n
g
c
o
n
d
i
t
i
o
n
s
l
i
k
e
p
o
l
y
c
y
st
i
c
o
v
a
r
y
sy
n
d
r
o
m
e
(
P
C
O
S
)
,
d
i
a
g
n
o
si
n
g
c
o
n
g
e
n
i
t
a
l
d
i
s
e
a
ses
su
c
h
a
s
A
l
p
h
a
-
1
A
n
t
i
t
r
y
p
si
n
D
e
f
i
c
i
e
n
c
y
,
a
n
d
d
e
t
e
r
mi
n
i
n
g
a
n
i
n
d
i
v
i
d
u
a
l
's ris
k
o
f
d
e
v
e
l
o
p
i
n
g
c
h
r
o
n
i
c
d
i
se
a
ses
.
[
5
5
]
,
[
6
2
]
–
[
6
5
]
•
O
n
e
e
x
a
m
p
l
e
o
f
a
g
e
n
e
t
i
c
t
e
s
t
t
h
a
t
i
s
v
u
l
n
e
r
a
b
l
e
t
o
d
e
t
e
r
mi
n
i
s
m
a
n
d
g
e
n
e
t
i
c
e
ss
e
n
t
i
a
l
i
sm
b
i
a
s
i
s
t
h
e
d
i
r
e
c
t
-
to
-
c
o
n
su
mer
(
D
T
C
)
g
e
n
e
t
i
c
o
r
i
g
i
n
t
e
st
.
T
h
e
D
T
C
t
e
s
t
c
a
n
h
a
v
e
a
si
g
n
i
f
i
c
a
n
t
i
mp
a
c
t
o
n
v
a
r
i
o
u
s a
sp
e
c
t
s,
i
n
c
l
u
d
i
n
g
:
a.
A
n
i
n
d
i
v
i
d
u
a
l
'
s se
l
f
-
i
d
e
n
t
i
t
y
.
b.
Th
e
i
r
i
n
c
l
i
n
a
t
i
o
n
t
o
s
h
a
r
e
g
e
n
e
t
i
c
i
n
f
o
r
ma
t
i
o
n
w
i
t
h
f
a
mi
l
y
mem
b
e
r
s
a
n
d
me
d
i
c
a
l
p
r
o
f
e
ss
i
o
n
a
l
s
.
c.
Th
e
i
r
w
i
l
l
i
n
g
n
e
ss
t
o
d
o
a
d
d
i
t
i
o
n
a
l
g
e
n
e
t
i
c
t
e
s
t
i
n
g
.
G
e
n
e
t
i
c
t
e
st
i
n
g
b
i
a
s c
a
n
l
e
a
d
t
o
n
e
g
a
t
i
v
e
c
o
n
s
e
q
u
e
n
c
e
s
f
o
r
p
a
t
i
e
n
t
s
,
i
n
c
l
u
d
i
n
g
r
e
d
u
c
e
d
m
o
t
i
v
a
t
i
o
n
t
o
mai
n
t
a
i
n
t
h
e
i
r
o
v
e
r
a
l
l
w
e
l
l
n
e
ss
.
[
2
5
]
,
[
5
4
]
•
A
c
t
i
v
e
p
a
r
t
i
c
i
p
a
t
i
o
n
f
r
o
m
g
e
n
e
t
i
c
c
o
u
n
s
e
l
l
o
r
s
,
d
o
c
t
o
r
s,
a
n
d
t
h
e
p
u
b
l
i
c
i
s
n
e
c
e
ssar
y
f
o
r
s
a
f
e
l
y
u
si
n
g
g
e
n
e
t
i
c
sc
o
r
i
n
g
t
e
s
t
s
(
p
o
l
y
g
e
n
i
c
sco
r
e
s/
P
G
S
)
.
Th
i
s
i
n
v
o
l
v
e
m
e
n
t
i
s
c
r
u
c
i
a
l
i
n
u
n
d
e
r
s
t
a
n
d
i
n
g
t
h
e
a
d
v
a
n
t
a
g
e
s
a
n
d
d
i
sa
d
v
a
n
t
a
g
e
s
o
f
P
G
S
t
e
st
s
a
n
d
e
n
s
u
r
i
n
g
t
h
e
i
r
e
q
u
i
t
a
b
l
e
a
p
p
l
i
c
a
t
i
o
n
i
n
a
c
c
o
r
d
a
n
c
e
w
i
t
h
p
a
t
i
e
n
t
-
c
e
n
t
r
e
d
h
e
a
l
t
h
c
a
r
e
p
r
i
n
c
i
p
l
e
s.
S
u
p
p
o
r
t
i
n
g
t
h
e
e
q
u
i
t
a
b
l
e
a
n
d
i
n
c
l
u
si
v
e
i
mp
l
e
m
e
n
t
a
t
i
o
n
o
f
h
e
a
l
t
h
p
r
o
g
r
a
ms
t
h
a
t
i
n
c
l
u
d
e
P
G
S
t
e
s
t
s
r
e
q
u
i
r
e
s
t
h
e
p
a
r
t
i
c
i
p
a
t
i
o
n
o
f
mu
l
t
i
p
l
e
st
a
k
e
h
o
l
d
e
r
s.
I
t
i
s
c
r
u
c
i
a
l
t
o
p
r
e
v
e
n
t
a
n
y
b
i
a
s
e
s
r
e
l
a
t
e
d
t
o
g
e
n
e
t
i
c
d
e
t
e
r
m
i
n
i
sm
a
n
d
e
sse
n
t
i
a
l
i
sm
w
h
i
l
e
a
l
s
o
a
l
i
g
n
i
n
g
t
h
e
p
r
o
g
r
a
ms w
i
t
h
t
h
e
c
o
m
mu
n
i
t
y
's s
p
e
c
i
f
i
c
n
e
e
d
s.
[
3
2
]
,
[
6
2
]
•
T
o
p
r
e
v
e
n
t
t
h
e
i
n
f
l
u
e
n
c
e
o
f
g
e
n
e
t
i
c
d
e
t
e
r
mi
n
i
s
m a
n
d
g
e
n
e
t
i
c
e
sse
n
t
i
a
l
i
sm
i
n
d
i
a
g
n
o
si
n
g
a
d
i
s
o
r
d
e
r
so
l
e
l
y
b
a
se
d
o
n
g
e
n
e
t
i
c
t
e
s
t
r
e
su
l
t
s
,
i
t
i
s
n
e
c
e
ssar
y
t
o
c
o
n
d
u
c
t
t
h
o
r
o
u
g
h
r
e
s
e
a
r
c
h
o
n
t
h
e
i
n
t
r
i
c
a
t
e
i
n
t
e
r
p
l
a
y
o
f
d
i
f
f
e
r
e
n
t
t
y
p
e
s
o
f
g
e
n
e
s
a
n
d
t
h
e
i
m
p
a
c
t
o
f
e
n
v
i
r
o
n
me
n
t
a
l
f
a
c
t
o
r
s
t
h
a
t
c
a
n
c
o
n
t
r
i
b
u
t
e
t
o
t
h
e
d
e
v
e
l
o
p
m
e
n
t
o
f
a
s
p
e
c
i
f
i
c
d
i
s
o
r
d
e
r
o
r
d
i
s
e
a
se
.
[
3
3
]
,
[
4
6
]
•
W
h
o
l
e
e
x
o
m
e
se
q
u
e
n
c
i
n
g
(
W
ES)
i
s
a
n
e
ss
e
n
t
i
a
l
t
o
o
l
u
s
e
d
t
o
d
i
a
g
n
o
se
a
n
d
p
r
e
v
e
n
t
m
a
n
y
k
i
n
d
s
o
f
g
e
n
e
t
i
c
a
b
n
o
r
m
a
l
i
t
i
e
s
i
n
i
n
d
i
v
i
d
u
a
l
s.
T
o
e
n
su
r
e
a
c
c
u
r
a
t
e
o
u
t
c
o
m
e
s,
e
n
g
a
g
i
n
g
i
n
e
f
f
i
c
i
e
n
t
a
n
d
c
o
m
p
a
ss
i
o
n
a
t
e
c
o
mm
u
n
i
c
a
t
i
o
n
r
e
g
a
r
d
i
n
g
t
h
e
c
o
n
s
e
q
u
e
n
c
e
s
o
f
t
h
i
s
n
o
v
e
l
a
p
p
r
o
a
c
h
a
n
d
e
st
a
b
l
i
s
h
i
n
g
a
d
e
f
i
n
i
t
i
v
e
s
t
r
a
t
e
g
y
f
o
r
p
r
e
sen
t
i
n
g
t
e
s
t
r
e
su
l
t
s
t
o
p
r
e
v
e
n
t
a
n
y
i
n
f
l
u
e
n
c
e
f
r
o
m
g
e
n
e
t
i
c
d
e
t
e
r
mi
n
i
sm a
n
d
e
sse
n
t
i
a
l
i
sm
b
i
a
s
e
s i
s e
sse
n
t
i
a
l
.
[
5
7
]
2
T
r
e
a
t
me
n
t
•
B
e
l
i
e
v
i
n
g
i
n
d
e
t
e
r
mi
n
i
s
m
b
i
a
s
a
n
d
g
e
n
e
t
i
c
e
ss
e
n
t
i
a
l
i
sm
c
a
n
a
m
p
l
i
f
y
t
h
e
n
e
g
a
t
i
v
e
st
i
g
m
a
a
r
o
u
n
d
p
a
t
i
e
n
t
s
b
y
a
t
t
r
i
b
u
t
i
n
g
a
n
e
x
c
e
ss
i
v
e
i
n
f
l
u
e
n
c
e
o
f
g
e
n
e
s
i
n
t
h
e
d
e
v
e
l
o
p
m
e
n
t
o
f
sp
e
c
i
f
i
c
d
i
s
e
a
s
e
s
o
r
d
i
s
o
r
d
e
r
s.
I
n
d
i
v
i
d
u
a
l
s
w
i
t
h
a
f
i
r
m
c
o
n
v
i
c
t
i
o
n
i
n
d
e
t
e
r
m
i
n
i
sm
a
n
d
g
e
n
e
t
i
c
e
sse
n
t
i
a
l
i
s
m
t
e
n
d
t
o
u
n
d
e
r
e
st
i
ma
t
e
t
h
e
i
n
f
l
u
e
n
c
e
o
f
t
h
e
e
n
v
i
r
o
n
m
e
n
t
a
n
d
l
i
f
e
s
t
y
l
e
o
n
t
h
e
r
e
c
o
v
e
r
y
p
r
o
c
e
ss
o
f
d
i
so
r
d
e
r
s
o
r
d
i
s
e
a
s
e
s
su
c
h
a
s
A
l
z
h
e
i
mer'
s,
d
e
m
e
n
t
i
a
,
s
c
h
i
z
o
p
h
r
e
n
i
a
,
d
e
p
r
e
ss
i
o
n
,
a
l
c
o
h
o
l
a
d
d
i
c
t
i
o
n
,
sm
o
k
i
n
g
h
a
b
i
t
s,
o
r
w
e
i
g
h
t
l
o
ss
.
[
2
0
]
,
[
3
0
]
,
[
6
5
]
–
[
7
4
]
•
D
i
ssemi
n
a
t
i
n
g
i
n
f
o
r
m
a
t
i
o
n
t
o
t
r
e
a
t
s
p
e
c
i
f
i
c
d
i
so
r
d
e
r
s
o
r
d
i
s
e
a
se
s
i
n
p
a
t
i
e
n
t
s
w
i
t
h
d
e
t
e
r
m
i
n
i
sm
b
i
a
s
a
n
d
g
e
n
e
t
i
c
e
sse
n
t
i
a
l
i
sm
c
a
n
b
e
f
a
c
i
l
i
t
a
t
e
d
b
y
b
r
o
a
d
c
a
st
i
n
g
t
h
r
o
u
g
h
e
l
e
c
t
r
o
n
i
c
a
n
d
n
o
n
-
e
l
e
c
t
r
o
n
i
c
m
a
ss
me
d
i
a
.
N
e
v
e
r
t
h
e
l
e
s
s,
i
t
m
u
st
r
e
c
e
i
v
e
s
u
p
p
o
r
t
f
r
o
m
a
r
a
n
g
e
o
f
a
d
d
i
t
i
o
n
a
l
i
n
t
e
r
v
e
n
t
i
o
n
a
c
t
i
v
i
t
i
e
s
.
[
3
0
]
•
G
e
n
e
t
i
c
d
e
t
e
r
m
i
n
i
sm a
n
d
e
ss
e
n
t
i
a
l
i
sm
b
i
a
s
i
n
g
e
n
e
t
i
c
t
e
s
t
r
e
s
u
l
t
s
c
a
n
l
e
a
d
p
a
t
i
e
n
t
s t
o
f
i
x
a
t
e
o
n
t
h
e
sy
m
p
t
o
ms
o
f
p
a
r
t
i
c
u
l
a
r
d
i
se
a
ses
o
r
d
i
s
o
r
d
e
r
s e
x
c
e
ssi
v
e
l
y
.
[
7
5
]
•
P
r
o
v
i
d
i
n
g
e
d
u
c
a
t
i
o
n
o
n
d
e
t
e
r
m
i
n
i
sm
b
i
a
s
a
n
d
g
e
n
e
t
i
c
e
ss
e
n
t
i
a
l
i
sm,
sp
e
c
i
f
i
c
a
l
l
y
a
b
o
u
t
t
h
e
i
m
p
a
c
t
o
f
g
e
n
e
s
o
n
c
o
n
d
i
t
i
o
n
s l
i
k
e
o
b
e
si
t
y
,
h
a
s
t
h
e
p
o
t
e
n
t
i
a
l
t
o
b
e
a
v
a
l
u
a
b
l
e
e
l
e
me
n
t
i
n
t
h
e
e
f
f
o
r
t
t
o
t
r
e
a
t
b
o
t
h
a
d
u
l
t
s a
n
d
c
h
i
l
d
r
e
n
s
u
c
c
e
ssf
u
l
l
y
.
[
3
9
]
,
[
7
6
]
•
B
e
l
i
e
f
i
n
d
e
t
e
r
m
i
n
i
sm
o
r
g
e
n
e
t
i
c
e
sse
n
t
i
a
l
i
sm
a
m
o
n
g
f
a
mi
l
y
m
e
mb
e
r
s
a
t
h
i
g
h
r
i
s
k
o
f
i
n
h
e
r
i
t
i
n
g
a
c
o
n
g
e
n
i
t
a
l
d
i
sea
se,
su
c
h
a
s
c
a
n
c
e
r
,
m
a
y
i
n
c
r
e
a
s
e
t
h
e
i
r
w
i
l
l
i
n
g
n
e
ss
t
o
t
a
k
e
p
r
e
v
e
n
t
i
v
e
me
a
su
r
e
s,
su
c
h
a
s
a
d
o
p
t
i
n
g
a
h
e
a
l
t
h
y
l
i
f
e
s
t
y
l
e
.
A
d
d
i
t
i
o
n
a
l
r
e
s
e
a
r
c
h
i
s
r
e
q
u
i
r
e
d
t
o
c
o
mp
r
e
h
e
n
d
t
h
e
v
a
r
i
a
t
i
o
n
s
i
n
r
e
sp
o
n
se
,
p
a
r
t
i
c
u
l
a
r
l
y
a
m
o
n
g
p
e
r
so
n
s w
h
o
h
a
v
e
o
b
t
a
i
n
e
d
p
o
s
i
t
i
v
e
t
e
st
o
u
t
c
o
m
e
s.
[
6
1
]
,
[
7
7
]
Pre
v
io
u
s
ca
s
e
s
tu
d
ies
h
av
e
co
n
s
is
ten
tly
s
h
o
wn
th
at
p
s
y
ch
iatr
ic
illn
ess
e
s
,
s
u
ch
as
d
ep
r
ess
io
n
,
ar
e
o
f
ten
ass
o
ciate
d
with
a
m
o
n
o
g
en
ic
g
en
e
in
ter
ac
tio
n
.
W
h
en
in
d
iv
id
u
als
with
d
ep
r
ess
io
n
ar
e
in
f
o
r
m
e
d
ab
o
u
t
th
eir
g
en
etic
p
r
e
d
is
p
o
s
itio
n
to
d
ep
r
ess
io
n
,
th
ey
ten
d
to
r
ep
o
r
t
in
cr
ea
s
ed
lev
els
o
f
d
ep
r
ess
ed
s
y
m
p
to
m
s
d
u
r
in
g
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Ho
w
g
en
etic
d
etermin
is
m
a
n
d
ess
en
tia
lis
m
r
ela
te
to
h
ea
lth
c
a
r
e
(
N
in
d
ia
n
a
C
h
o
ir
u
n
is
a
'
)
1505
th
e
p
r
io
r
two
wee
k
s
[
6
7
]
.
Un
d
er
d
if
f
er
en
t c
ir
c
u
m
s
tan
ce
s
,
p
e
o
p
le
wh
o
ar
e
awa
r
e
o
f
th
eir
g
e
n
etic
p
r
ed
is
p
o
s
itio
n
to
alco
h
o
lis
m
r
ec
o
g
n
ize
th
at
t
h
eir
ca
p
ac
ity
to
r
eg
u
late
alco
h
o
l
co
n
s
u
m
p
tio
n
d
e
cr
ea
s
es
co
m
p
ar
ed
to
th
o
s
e
wh
o
ar
e
u
n
awa
r
e
o
f
th
is
r
is
k
[
3
3
]
,
[
6
9
]
W
h
at
is
ev
en
m
o
r
e
s
u
r
p
r
is
in
g
is
th
at
wh
en
d
e
p
r
ess
iv
e
d
is
o
r
d
er
s
o
r
alco
h
o
lis
m
ar
e
f
r
eq
u
en
tly
ass
o
ciate
d
with
g
en
etic
an
d
o
th
er
b
io
lo
g
ical
ch
a
r
ac
ter
is
tics
,
in
d
iv
id
u
als
ten
d
to
h
av
e
a
less
o
p
tim
is
tic
p
er
s
p
e
ctiv
e
o
n
th
eir
ch
an
ce
s
o
f
r
ec
o
v
er
in
g
in
th
e
f
u
tu
r
e
[
6
7
]
.
D
esp
ite
r
ec
eiv
in
g
an
in
ter
v
en
tio
n
v
id
eo
f
r
o
m
th
e
m
ass
m
ed
ia
th
at
clar
if
ied
th
e
n
o
n
-
d
eter
m
in
is
tic
n
atu
r
e
o
f
g
en
es
in
ca
u
s
in
g
d
ep
r
ess
io
n
o
r
alco
h
o
l
ad
d
ictio
n
,
th
e
d
eter
m
in
is
tic
ef
f
ec
t
k
ep
t
g
o
in
g
in
th
ese
in
d
iv
id
u
als.
T
h
is
co
n
d
itio
n
was
o
b
s
er
v
ed
ev
en
th
o
u
g
h
n
ea
r
ly
all
p
ar
ticip
an
ts
co
m
p
r
e
h
en
d
e
d
th
e
v
id
eo
'
s
m
ain
m
ess
ag
e
[
6
7
]
,
[
6
9
]
.
Failu
r
e
to
s
u
cc
ee
d
in
r
ec
o
v
er
y
ca
n
also
b
e
attr
ib
u
ted
to
g
en
etic
d
ete
r
m
in
is
m
an
d
ess
en
tialis
m
b
ia
s
.
T
h
is
b
ias
v
iew
s
p
r
o
b
lem
s
in
t
h
e
b
r
ain
o
r
s
p
ec
if
ic
g
en
es a
s
in
h
er
en
t sy
m
p
to
m
s
th
at
ar
e
u
n
c
h
an
g
ea
b
le
[
9
]
.
Gen
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
p
o
s
e
a
p
er
s
is
ten
t
p
r
o
b
lem
in
th
e
co
n
tex
t
o
f
o
b
esit
y
.
C
er
tain
o
b
ese
p
er
s
o
n
s
in
th
e
Un
ited
States
wh
o
attr
ib
u
te
th
eir
we
ig
h
t
to
b
io
lo
g
ical
f
ac
to
r
s
s
u
c
h
as
g
en
etics
h
av
e
r
aised
th
e
id
ea
th
at
weig
h
t
is
an
im
m
u
tab
le
an
d
u
n
ch
an
g
i
n
g
ch
a
r
ac
ter
is
tic
[
1
8
]
,
[
3
9
]
,
[
6
5
]
.
A
d
d
itio
n
ally
,
it
was
d
is
co
v
er
ed
th
at
h
er
e
d
itar
y
v
ar
iab
les
in
in
d
iv
id
u
als
with
o
b
esit
y
wer
e
in
v
e
r
s
ely
ass
o
ciate
d
with
t
h
e
b
elief
th
at
b
o
d
y
weig
h
t
co
u
ld
b
e
m
an
ag
e
d
[
7
3
]
.
Fu
r
th
er
m
o
r
e,
r
esear
ch
h
as
d
em
o
n
s
tr
ated
th
at
th
is
g
e
n
etic
ex
p
lan
atio
n
d
u
r
in
g
th
e
d
e
v
elo
p
m
en
t
p
r
o
ce
s
s
m
ig
h
t
d
ec
r
ea
s
e
o
n
e'
s
b
elief
in
th
eir
ab
i
lity
to
ac
h
iev
e
g
o
als
an
d
th
eir
m
o
tiv
atio
n
to
en
g
ag
e
in
p
h
y
s
ical
ac
tiv
ity
[
7
6
]
wh
ile
in
cr
ea
s
in
g
th
eir
d
esire
to
co
n
s
u
m
e
u
n
h
ea
lth
y
f
o
o
d
s
[
6
5
]
.
T
h
is
p
r
e
d
is
p
o
s
itio
n
to
wa
r
d
s
g
en
etic
d
ete
r
m
in
is
m
an
d
e
s
s
en
tiali
s
m
ca
n
also
m
an
if
est
in
f
am
ily
m
e
m
b
er
s
wh
o
h
av
e
a
h
eig
h
ten
ed
s
u
s
ce
p
tib
ilit
y
to
in
h
er
ited
co
n
d
itio
n
s
,
s
u
ch
as
ca
n
ce
r
.
As
s
ci
en
tific
k
n
o
wled
g
e
im
p
r
o
v
es,
f
a
m
ily
m
em
b
er
s
m
ay
ex
h
i
b
it
p
o
s
itiv
e
b
eh
a
v
i
o
r
b
y
b
ec
o
m
i
n
g
m
o
r
e
m
o
tiv
ated
to
en
g
ag
e
i
n
p
r
ev
en
tiv
e
m
ea
s
u
r
es,
s
u
ch
a
s
ad
o
p
tin
g
a
h
ea
lth
y
life
s
ty
l
e
[
5
7
]
.
Nev
er
th
eless
,
ad
d
itio
n
al
in
v
esti
g
atio
n
is
r
eq
u
ir
ed
t
o
co
m
p
r
eh
en
d
th
ese
d
is
cr
ep
an
cies
in
r
ea
ctio
n
,
p
ar
ticu
lar
ly
am
o
n
g
p
e
r
s
o
n
s
wh
o
h
av
e
o
b
tain
e
d
p
o
s
itiv
e
test
o
u
tco
m
es.
B
ased
o
n
th
e
s
tu
d
y
,
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
b
iases
ca
n
lead
to
d
iag
n
o
s
tic
in
ac
cu
r
ac
ies
an
d
im
p
ac
t
tr
ea
tm
en
t
d
ec
is
io
n
s
,
p
ar
ticu
lar
ly
in
co
m
p
lex
ca
s
es
wh
er
e
g
en
etic
f
ac
to
r
s
a
r
e
o
v
er
em
p
h
asized
at
th
e
ex
p
en
s
e
o
f
e
n
v
ir
o
n
m
en
tal
o
r
life
s
ty
le
co
n
s
id
er
atio
n
s
.
T
h
is
ca
n
r
esu
lt
in
a
h
ea
lth
ca
r
e
en
v
ir
o
n
m
en
t
w
h
er
e
p
atien
ts
f
ee
l
r
esig
n
ed
to
th
e
ir
g
en
etic
f
ate,
r
e
d
u
cin
g
th
e
ir
en
g
ag
em
e
n
t
with
tr
ea
tm
e
n
t
an
d
p
r
ev
en
tiv
e
m
ea
s
u
r
es.
As
g
en
etic
tes
ti
n
g
b
ec
o
m
es
m
o
r
e
co
m
m
o
n
,
h
ea
lth
ca
r
e
p
r
o
v
id
er
s
m
u
s
t
b
e
v
ig
ilan
t
in
co
m
m
u
n
icatin
g
th
e
lim
itatio
n
s
an
d
co
n
tex
t
o
f
g
en
etic
in
f
o
r
m
atio
n
to
p
r
ev
en
t
t
h
ese
b
iases
f
r
o
m
lead
in
g
to
a
s
en
s
e
o
f
in
ev
itab
ilit
y
in
p
ati
en
ts
.
Ad
d
r
ess
in
g
th
ese
b
iases
is
es
s
en
tial
f
o
r
en
s
u
r
in
g
t
h
at
g
en
etic
in
s
ig
h
ts
co
n
tr
ib
u
te
p
o
s
itiv
ely
to
p
atien
t
ca
r
e,
f
o
s
ter
in
g
a
h
ea
lth
ca
r
e
s
y
s
tem
th
at
p
r
o
m
o
tes
h
o
lis
tic
an
d
in
d
iv
id
u
alize
d
tr
ea
tm
en
t
s
tr
ateg
ies
r
at
h
er
th
a
n
o
n
e
co
n
s
tr
ain
ed
b
y
d
eter
m
i
n
is
tic
v
iews
o
f
d
is
ea
s
e
an
d
h
ea
lth
o
u
tco
m
es.
T
o
ad
d
r
ess
th
ese
b
iases
,
tr
ain
i
n
g
p
r
o
g
r
a
m
s
an
d
p
o
licy
-
m
a
k
in
g
p
r
o
to
co
ls
ca
n
h
elp
m
ed
ical
p
r
o
f
ess
io
n
als
in
ter
p
r
et
g
en
etic
test
r
esu
lt
s
m
o
r
e
ef
f
ec
tiv
ely
.
Po
licy
m
ak
er
s
ca
n
en
s
u
r
e
t
h
e
eth
ical
u
s
e
an
d
in
ter
p
r
etatio
n
o
f
g
en
etic
test
in
g
,
wh
ile
p
u
b
lic
awa
r
en
ess
ca
m
p
aig
n
s
ca
n
ed
u
ca
te
th
e
p
u
b
lic
o
n
h
er
e
d
itar
y
in
f
lu
en
ce
s
o
n
h
ea
lth
.
E
m
b
r
ac
in
g
n
o
n
-
g
e
n
etic
f
ac
to
r
s
an
d
p
r
o
m
o
tin
g
r
esear
ch
in
to
g
en
e
-
en
v
ir
o
n
m
en
t
in
ter
ac
ti
o
n
s
ca
n
also
h
elp
m
itig
ate
b
iases
.
I
m
p
lem
en
tin
g
th
ese
m
ea
s
u
r
es
ca
n
im
p
r
o
v
e
d
iag
n
o
s
tic
ac
cu
r
ac
y
,
th
er
ap
eu
tic
in
ter
v
en
tio
n
s
,
an
d
p
atien
t
g
en
etic
test
in
g
r
es
u
lts
.
3
.
2
.
I
m
pli
ca
t
io
ns
o
f
g
enet
ic
det
er
m
ini
s
m
a
nd
ess
ent
i
a
lis
m
o
n
pu
bli
c
hea
lt
h
a
nd
clinica
l
pra
ct
ice
re
v
iewe
d ba
s
ed
o
n e
t
hic
a
l,
le
g
a
l
,
a
nd
s
o
cia
l a
s
pect
s
I
n
g
e
n
er
al,
th
e
em
er
g
e
n
ce
o
f
d
eter
m
in
is
m
b
ias
an
d
g
e
n
etic
ess
en
tialis
m
ca
n
h
av
e
a
wid
esp
r
ea
d
im
p
ac
t,
ex
ten
d
in
g
to
v
ar
io
u
s
asp
ec
ts
o
f
life
,
in
clu
d
in
g
h
ea
lth
.
T
h
er
ef
o
r
e,
d
o
cto
r
s
,
n
u
r
s
es,
an
d
m
ed
ical
p
r
o
f
ess
io
n
als
m
u
s
t
co
m
p
r
eh
e
n
d
th
e
p
r
in
ci
p
les
ass
o
ciate
d
with
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
b
ias
with
in
th
e
h
ea
lth
ca
r
e
.
T
ab
le
2
p
r
o
v
id
es
in
f
o
r
m
atio
n
r
eg
ar
d
in
g
th
e
i
n
f
lu
en
ce
o
f
d
eter
m
in
is
m
b
ias
an
d
g
en
etic
ess
en
tiali
s
m
o
n
p
u
b
lic
h
ea
lth
a
n
d
clin
ical
p
r
ac
tice,
s
p
ec
if
icall
y
ab
o
u
t
et
h
ical,
leg
al,
an
d
s
o
ci
al
co
n
s
id
er
atio
n
s
.
B
ased
o
n
th
e
f
in
d
in
g
s
an
d
co
m
p
r
eh
en
s
iv
e
an
al
y
s
is
o
f
th
e
d
ata
in
T
ab
le
2
,
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tiali
s
m
b
ias
n
eg
ativ
ely
in
f
lu
en
ce
e
v
er
y
asp
ec
t.
T
h
ese
b
i
ases
ca
n
lead
to
m
is
co
n
ce
p
tio
n
s
ab
o
u
t
th
e
r
o
le
o
f
g
en
etic
s
,
f
o
s
ter
in
g
a
b
elief
th
a
t
in
d
iv
id
u
als
h
av
e
litt
le
co
n
t
r
o
l
o
v
er
th
eir
h
ea
lth
o
u
tco
m
es.
T
h
ese
b
iases
d
is
to
r
t
th
e
p
er
ce
p
tio
n
o
f
g
en
etic
in
f
o
r
m
atio
n
a
n
d
co
n
tr
ib
u
te
to
d
eter
m
in
is
tic
m
in
d
s
ets
th
at
ca
n
lim
it
in
d
iv
id
u
als'
b
elief
s
in
th
eir
ab
ilit
y
to
in
f
l
u
en
ce
th
e
ir
h
ea
lth
a
n
d
well
-
b
ei
n
g
.
Fu
r
th
er
m
o
r
e,
t
h
e
v
a
r
io
u
s
n
eg
ativ
e
in
f
lu
en
ce
s
o
f
g
e
n
etic
d
ete
r
m
in
is
m
an
d
e
s
s
en
tiali
s
m
o
n
v
ar
io
u
s
asp
ec
ts
ar
e
s
u
m
m
ar
ize
d
in
th
e
illu
s
tr
atio
n
in
Fig
u
r
e
2
.
T
h
is
f
ig
u
r
e
h
ig
h
lig
h
ts
h
o
w
th
e
s
e
b
iases
ca
n
af
f
ec
t
d
ec
is
io
n
-
m
ak
in
g
,
p
er
s
o
n
al
m
o
tiv
atio
n
,
an
d
p
u
b
lic
attitu
d
es
to
war
d
g
en
etic
f
ac
to
r
s
,
u
n
d
e
r
s
co
r
in
g
th
e
n
ee
d
f
o
r
m
o
r
e
n
u
an
ce
d
co
m
m
u
n
icatio
n
an
d
ed
u
ca
tio
n
ab
o
u
t
g
en
etics.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
1
4
9
9
-
1
5
1
4
1506
T
ab
le
2
.
I
m
p
licatio
n
s
o
f
g
en
et
ic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
o
n
eth
ical,
le
g
al,
an
d
s
o
cial
asp
ec
ts
o
f
clin
ical
p
r
ac
tice
No
A
sp
e
c
t
I
n
f
o
r
ma
t
i
o
n
R
e
f
e
r
e
n
c
e
1
Et
h
i
c
s
•
S
o
me
a
r
g
u
e
t
h
a
t
t
h
e
g
e
n
e
t
i
c
e
l
e
m
e
n
t
s o
f
e
a
c
h
i
n
d
i
v
i
d
u
a
l
a
r
e
a
d
i
st
i
n
c
t
a
s
p
e
c
t
t
h
a
t
n
e
e
d
s
s
p
e
c
i
f
i
c
e
t
h
i
c
a
l
g
u
i
d
e
l
i
n
e
s
.
T
h
e
c
o
n
c
e
p
t
s o
f
g
e
n
e
t
i
c
d
e
t
e
r
m
i
n
i
sm a
n
d
e
ss
e
n
t
i
a
l
i
sm
m
a
y
u
n
d
e
r
v
a
l
u
e
t
h
e
s
e
d
i
s
t
i
n
c
t
i
v
e
c
o
n
s
i
d
e
r
a
t
i
o
n
s
.
[
6
6
]
,
[
7
8
]
•
G
e
n
e
t
i
c
d
e
t
e
r
m
i
n
i
sm
a
n
d
e
ss
e
n
t
i
a
l
i
s
m
st
i
g
ma
c
o
u
l
d
r
e
s
t
r
i
c
t
a
p
a
t
i
e
n
t
's
a
u
t
o
n
o
m
y
i
n
m
a
k
i
n
g
d
e
c
i
si
o
n
s
a
b
o
u
t
t
h
e
i
r
t
r
e
a
t
m
e
n
t
o
r
o
t
h
e
r
me
d
i
c
a
l
p
r
o
c
e
d
u
r
e
s
r
e
l
a
t
e
d
t
o
t
h
e
i
r
g
e
n
e
t
i
c
c
o
m
p
o
si
t
i
o
n
.
[
7
9
]
•
I
ssu
e
s re
l
a
t
e
d
t
o
d
e
t
e
r
mi
n
i
s
m b
i
a
s
a
n
d
g
e
n
e
t
i
c
e
sse
n
t
i
a
l
i
s
m fr
e
q
u
e
n
t
l
y
a
r
i
s
e
i
n
t
h
e
t
r
e
a
t
me
n
t
a
n
d
g
e
n
e
t
i
c
r
e
se
a
r
c
h
o
f
m
a
n
y
m
e
n
t
a
l
d
i
se
a
ses,
g
i
v
i
n
g
r
i
s
e
t
o
e
t
h
i
c
a
l
c
o
n
c
e
r
n
s.
A
n
e
t
h
i
c
a
l
c
o
n
c
e
r
n
i
n
g
e
n
e
t
i
c
r
e
se
a
r
c
h
o
n
m
e
n
t
a
l
d
i
s
o
r
d
e
r
s
i
n
v
o
l
v
e
s
t
h
e
u
t
i
l
i
z
a
t
i
o
n
o
f
p
h
o
t
o
g
r
a
p
h
y
i
n
s
t
u
d
y
i
n
g
n
e
u
r
o
d
e
v
e
l
o
p
m
e
n
t
a
l
p
r
o
b
l
e
ms
,
t
h
e
d
e
v
e
l
o
p
m
e
n
t
o
f
a
n
t
i
s
o
c
i
a
l
c
l
a
ssi
f
i
c
a
t
i
o
n
sy
s
t
e
ms
b
a
s
e
d
o
n
b
i
o
mar
k
e
r
s,
a
n
d
t
h
e
a
v
a
i
l
a
b
i
l
i
t
y
o
f
g
e
n
e
t
i
c
t
e
s
t
i
n
g
t
h
a
t
c
a
n
p
r
e
d
i
c
t
su
i
c
i
d
e
r
i
sk
a
n
d
i
s
a
c
c
e
ss
i
b
l
e
t
o
e
v
e
r
y
o
n
e
e
l
s
e
.
[
2
9
]
,
[
8
0
]
–
[
8
2
]
•
Th
e
p
r
e
se
n
c
e
o
f
d
e
t
e
r
m
i
n
i
sm
b
i
a
s
a
n
d
g
e
n
e
t
i
c
e
ss
e
n
t
i
a
l
i
sm
c
a
n
c
r
e
a
t
e
e
t
h
i
c
a
l
d
i
l
e
mm
a
s
w
h
e
n
i
n
t
e
r
p
r
e
t
i
n
g
g
e
n
e
t
i
c
t
e
s
t
i
n
g
r
e
s
u
l
t
s
f
o
r
i
n
d
i
v
i
d
u
a
l
s
w
i
t
h
m
e
n
t
a
l
d
i
s
o
r
d
e
r
s.
T
h
i
s
p
h
e
n
o
m
e
n
o
n
c
a
n
r
e
su
l
t
i
n
d
e
c
r
e
a
s
e
d
p
a
t
i
e
n
t
m
o
t
i
v
a
t
i
o
n
t
o
r
e
c
o
v
e
r
,
l
e
ss
p
s
y
c
h
o
s
o
c
i
a
l
s
u
p
p
o
r
t
,
a
n
d
i
ss
u
e
s
r
e
l
a
t
e
d
t
o
so
c
i
a
l
j
u
s
t
i
c
e
.
[
8
3
]
•
Et
h
i
c
a
l
d
i
l
e
m
mas
c
a
u
se
d
b
y
g
e
n
e
t
i
c
d
e
t
e
r
m
i
n
i
sm
a
n
d
e
sse
n
t
i
a
l
i
sm
c
a
n
a
l
so
o
c
c
u
r
w
h
e
n
c
o
n
d
u
c
t
i
n
g
g
e
n
o
m
i
c
se
q
u
e
n
c
i
n
g
o
n
n
e
w
b
o
r
n
s
a
n
d
v
u
l
n
e
r
a
b
l
e
p
o
p
u
l
a
t
i
o
n
s,
l
i
k
e
c
r
i
mi
n
a
l
s
a
n
d
w
o
me
n
.
[
3
7
]
,
[
8
4
]
2
S
o
c
i
a
l
•
G
e
n
e
t
i
c
d
e
t
e
r
mi
n
i
sm a
n
d
e
ss
e
n
t
i
a
l
i
sm
b
i
a
s
r
e
su
l
t
i
n
g
f
r
o
m g
e
n
e
t
i
c
t
e
st
i
n
g
o
f
p
e
o
p
l
e
w
i
t
h
me
n
t
a
l
p
r
o
b
l
e
ms
m
i
g
h
t
f
o
s
t
e
r
u
n
f
a
v
o
r
a
b
l
e
s
o
c
i
e
t
a
l
st
i
g
m
a
t
o
w
a
r
d
s
t
h
e
se
p
a
t
i
e
n
t
s
a
n
d
p
o
t
e
n
t
i
a
l
l
y
l
e
a
d
t
o
a
c
t
s
o
f
d
i
s
c
r
i
mi
n
a
t
i
o
n
.
[
3
3
]
,
[
8
3
]
•
Th
e
p
r
e
s
e
n
c
e
o
f
d
e
t
e
r
m
i
n
i
sm
b
i
a
s
a
n
d
g
e
n
e
t
i
c
e
sse
n
t
i
a
l
i
sm
i
n
t
h
e
g
e
n
e
t
i
c
t
e
s
t
f
i
n
d
i
n
g
s
o
f
c
h
i
l
d
r
e
n
w
h
o
h
a
v
e
e
x
p
e
r
i
e
n
c
e
d
p
h
y
si
c
a
l
v
i
o
l
e
n
c
e
c
a
n
i
m
p
a
c
t
so
c
i
e
t
y
's
p
e
r
c
e
p
t
i
o
n
o
f
t
h
e
c
h
i
l
d
'
s
p
o
t
e
n
t
i
a
l
r
i
s
k
t
o
o
t
h
e
r
s
a
n
d
,
c
o
n
s
e
q
u
e
n
t
l
y
,
t
h
e
n
e
c
e
ss
i
t
y
o
f
me
d
i
c
a
l
i
n
t
e
r
v
e
n
t
i
o
n
.
[
8
5
]
•
G
e
n
e
t
i
c
d
e
t
e
r
m
i
n
i
sm
a
n
d
e
ss
e
n
t
i
a
l
i
s
m
b
i
a
s
c
o
u
l
d
r
e
st
r
i
c
t
t
h
e
d
i
s
t
r
i
b
u
t
i
o
n
o
f
c
l
i
n
i
c
a
l
r
e
so
u
r
c
e
s
a
n
d
t
h
e
d
e
l
i
v
e
r
y
o
f
h
e
a
l
t
h
serv
i
c
e
s
i
n
a
r
e
st
r
i
c
t
e
d
ma
n
n
e
r
t
h
a
t
p
r
i
o
r
i
t
i
z
e
s
t
h
e
p
r
e
f
e
r
e
n
c
e
s
o
f
sp
e
c
i
f
i
c
p
o
p
u
l
a
t
i
o
n
s.
[
8
6
]
•
Th
e
r
e
a
r
e
s
t
i
l
l
n
u
mer
o
u
s
c
o
n
f
l
i
c
t
s
i
n
p
r
a
c
t
i
c
e
b
e
t
w
e
e
n
d
i
f
f
e
r
e
n
t
t
r
e
a
t
me
n
t
m
e
c
h
a
n
i
sms
b
a
se
d
o
n
g
e
n
e
t
i
c
d
e
t
e
r
mi
n
i
sm
o
r
e
sse
n
t
i
a
l
i
s
m
t
h
r
o
u
g
h
o
u
t
l
o
c
a
l
c
o
mm
u
n
i
t
i
e
s'
s
o
c
i
a
l
,
p
o
l
i
t
i
c
a
l
,
a
n
d
c
u
l
t
u
r
a
l
v
a
l
u
e
s
.
[
1
2
]
,
[
8
7
]
3
La
w
a
n
d
P
o
l
i
c
y
•
Th
e
p
r
e
se
n
c
e
o
f
d
e
t
e
r
m
i
n
i
sm
a
n
d
g
e
n
e
t
i
c
e
ss
e
n
t
i
a
l
i
sm
c
a
n
c
o
n
t
r
i
b
u
t
e
t
o
si
g
n
i
f
i
c
a
n
t
a
c
h
i
e
v
e
me
n
t
s
i
n
c
h
a
l
l
e
n
g
i
n
g
a
n
d
c
o
mp
l
e
x
si
t
u
a
t
i
o
n
s
,
su
c
h
a
s
i
d
e
n
t
i
f
y
i
n
g
v
i
c
t
i
ms
i
n
t
h
e
a
f
t
e
r
ma
t
h
o
f
t
h
e
2
0
0
4
A
c
e
h
T
s
u
n
a
m
i
d
i
s
a
st
e
r
.
H
o
w
e
v
e
r
,
t
h
e
w
i
d
e
sp
r
e
a
d
i
m
p
l
e
me
n
t
a
t
i
o
n
o
f
t
h
i
s
c
o
n
c
e
p
t
i
s
n
o
t
f
e
a
si
b
l
e
d
u
e
t
o
t
h
e
l
a
c
k
o
f
g
l
o
b
a
l
l
y
a
c
c
e
p
t
e
d
g
u
i
d
e
l
i
n
e
s
t
h
a
t
g
o
v
e
r
n
t
h
e
se
a
c
t
i
v
i
t
i
e
s
.
[
8
8
]
•
Th
e
c
r
i
t
e
r
i
a
f
o
r
d
e
t
e
r
m
i
n
i
n
g
t
h
e
l
e
g
i
t
i
mac
y
o
f
s
t
u
d
i
e
s
o
n
g
e
n
e
t
i
c
d
e
t
e
r
m
i
n
i
s
m
a
n
d
e
sse
n
t
i
a
l
i
sm
,
i
n
c
l
u
d
i
n
g
r
e
se
a
r
c
h
o
n
r
e
p
r
o
g
e
n
e
t
i
c
s
,
h
a
v
e
y
e
t
t
o
b
e
e
s
t
a
b
l
i
sh
e
d
.
[
7
8
]
•
N
u
mer
o
u
s
t
e
c
h
n
i
c
a
l
r
e
g
u
l
a
t
i
o
n
s
st
i
l
l
n
e
e
d
t
o
b
e
e
x
p
l
i
c
i
t
l
y
d
e
f
i
n
e
d
t
o
p
r
e
v
e
n
t
d
e
t
e
r
mi
n
i
sm
b
i
a
s
o
r
g
e
n
e
t
i
c
e
s
se
n
t
i
a
l
i
sm
a
t
d
i
f
f
e
r
e
n
t
s
t
a
g
e
s
o
f
g
e
n
e
t
i
c
t
e
st
i
n
g
.
T
h
e
s
e
r
e
g
u
l
a
t
i
o
n
s
s
h
o
u
l
d
c
o
v
e
r
p
r
i
v
a
c
y
,
p
l
a
n
n
i
n
g
,
i
n
t
e
r
p
r
e
t
a
t
i
o
n
,
a
n
d
t
h
e
d
i
s
c
l
o
su
r
e
o
f
t
e
st
r
e
s
u
l
t
s.
A
d
d
i
t
i
o
n
a
l
l
y
,
p
e
n
a
l
t
i
e
s
sh
o
u
l
d
b
e
e
s
t
a
b
l
i
s
h
e
d
f
o
r
a
n
y
mi
s
u
se
o
f
g
e
n
e
t
i
c
t
e
st
r
e
su
l
t
s
b
y
p
a
t
i
e
n
t
s
o
r
r
e
sp
o
n
d
e
n
t
s
.
[
6
6
]
,
[
7
9
]
,
[
8
0
]
•
Th
e
r
e
n
e
e
d
s
t
o
b
e
mo
r
e
c
o
m
p
r
e
h
e
n
si
v
e
g
l
o
b
a
l
a
n
d
d
o
m
e
st
i
c
l
e
g
i
sl
a
t
i
o
n
t
h
a
t
m
o
n
i
t
o
r
s
t
h
e
e
v
a
l
u
a
t
i
o
n
o
f
r
e
se
a
r
c
h
a
n
d
t
e
c
h
n
o
l
o
g
y
a
d
v
a
n
c
e
me
n
t
s
w
i
t
h
o
u
t
t
h
e
p
o
t
e
n
t
i
a
l
t
o
i
n
c
r
e
a
s
e
t
h
e
t
e
n
d
e
n
c
y
t
o
w
a
r
d
s
g
e
n
e
t
i
c
d
e
t
e
r
mi
n
i
s
m o
r
e
sse
n
t
i
a
l
i
sm
.
[
1
2
]
,
[
6
2
]
,
[
8
9
]
•
A
d
d
i
t
i
o
n
a
l
mo
r
a
l
a
n
d
l
e
g
a
l
j
u
s
t
i
f
i
c
a
t
i
o
n
i
s
r
e
q
u
i
r
e
d
t
o
e
n
s
u
r
e
t
h
e
i
m
p
l
e
men
t
a
t
i
o
n
o
f
g
e
n
e
t
i
c
q
u
a
l
i
t
y
e
n
h
a
n
c
e
me
n
t
i
n
h
u
m
a
n
s
i
s
n
o
t
s
u
sc
e
p
t
i
b
l
e
t
o
d
e
t
e
r
mi
n
i
st
i
c
o
r
g
e
n
e
t
i
c
e
ss
e
n
t
i
a
l
i
st
p
r
e
j
u
d
i
c
e
.
[
8
4
]
,
[
8
5
]
B
ased
o
n
Fig
u
r
e
2
,
s
ev
er
al
et
h
ical
is
s
u
es
r
elate
d
to
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
b
ias
ar
e
d
is
cu
s
s
ed
in
asp
ec
ts
o
f
clin
ica
l
p
r
ac
tice
th
at
p
r
e
d
o
m
in
a
n
tly
o
cc
u
r
i
n
th
e
tr
ea
tm
en
t
o
f
in
d
iv
id
u
als
with
m
e
n
tal
d
is
o
r
d
er
s
[
8
3
]
,
as
well
as
n
o
n
in
v
asiv
e
p
r
e
n
atal
test
in
g
f
o
r
b
ab
ies
[
4
3
]
.
A
co
n
ce
r
n
i
n
g
asp
ec
t
o
f
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
b
ias
in
p
s
y
ch
iatr
ic
r
esear
ch
is
th
e
ap
p
licatio
n
o
f
p
h
o
to
g
r
ap
h
y
i
n
g
e
n
etic
in
v
esti
g
atio
n
s
o
n
n
eu
r
o
d
e
v
el
o
p
m
en
tal
d
is
o
r
d
er
s
[
8
0
]
,
a
class
if
icatio
n
s
y
s
tem
b
ased
o
n
b
io
m
a
r
k
er
s
f
o
r
an
tis
o
cial
b
eh
av
io
r
[
8
1
]
,
an
d
g
en
etic
test
s
to
p
r
ed
ict
th
e
r
is
k
o
f
s
u
icid
e
in
th
e
p
o
p
u
latio
n
in
g
en
er
al
[
2
9
]
.
T
h
e
r
esear
ch
h
as
f
ac
ed
cr
iticis
m
f
r
o
m
s
ev
er
al
s
o
u
r
ce
s
as
a
r
esu
lt
o
f
s
ev
er
al
g
en
etic
b
iases
.
T
h
ese
b
iases
h
av
e
b
ee
n
ar
g
u
ed
to
r
e
q
u
ir
e
eth
ical
g
u
id
elin
es
f
o
r
u
s
in
g
in
d
i
v
id
u
als'
g
en
etic
ch
ar
ac
ter
is
tics
[
7
8
]
.
W
h
en
th
er
e
ar
e
b
iases
o
f
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
i
n
a
p
atien
t
'
s
g
en
etic
m
ec
h
an
is
m
s
,
it
ca
n
lead
to
an
u
n
d
er
esti
m
atio
n
o
f
th
e
i
n
d
iv
id
u
alize
d
co
n
s
id
er
atio
n
o
f
ea
ch
p
atien
t'
s
g
en
etic
s
tate.
T
h
e
n
e
g
ativ
e
p
e
r
ce
p
tio
n
o
f
g
e
n
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
m
ig
h
t
r
estrict
p
atie
n
ts
'
au
to
n
o
m
y
in
ch
o
o
s
in
g
th
eir
tr
e
atm
e
n
t
o
r
o
th
er
m
ed
ical
p
r
o
ce
d
u
r
es a
s
s
o
ciate
d
with
th
eir
g
en
etic
m
ak
e
u
p
[
7
9
]
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Pu
b
lic
Hea
lth
Sci
I
SS
N:
2252
-
8
8
0
6
Ho
w
g
en
etic
d
etermin
is
m
a
n
d
ess
en
tia
lis
m
r
ela
te
to
h
ea
lth
c
a
r
e
(
N
in
d
ia
n
a
C
h
o
ir
u
n
is
a
'
)
1507
T
h
e
eth
ical
p
r
o
b
lem
s
ass
o
ciate
d
with
g
e
n
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
b
ias
ca
n
als
o
ar
is
e
in
in
f
an
ts
wh
o
u
n
d
er
g
o
n
o
n
in
v
a
s
iv
e
p
r
en
atal
test
in
g
[
3
6
]
.
Usu
ally
,
co
m
m
er
cial
lab
o
r
ato
r
ie
s
ex
clu
s
iv
ely
o
f
f
er
th
is
ty
p
e
o
f
test
in
g
an
d
a
r
e
s
p
ec
if
ically
d
esig
n
ed
to
id
e
n
tify
s
p
ec
if
ic
tr
is
o
m
y
d
is
o
r
d
e
r
s
,
s
u
ch
as
Do
wn
s
y
n
d
r
o
m
e,
Patau
s
y
n
d
r
o
m
e,
a
n
d
E
d
war
d
s
s
y
n
d
r
o
m
e
[
4
3
]
.
D
esp
ite
th
e
ex
ten
s
iv
e
im
p
lem
en
tatio
n
o
f
th
is
test
in
g
o
n
a
lar
g
e
s
ca
le,
th
er
e
ar
e
c
o
n
ce
r
n
s
r
e
g
ar
d
in
g
in
cr
ea
s
ed
d
eter
m
in
is
m
b
ias
an
d
g
en
etic
ess
en
tialis
m
.
T
h
is
co
n
d
itio
n
is
b
ec
a
u
s
e
th
e
wid
e
s
p
r
ea
d
av
ailab
ilit
y
o
f
test
in
g
th
r
o
u
g
h
co
m
m
er
cial
s
o
u
r
ce
s
i
s
b
eliev
ed
to
h
a
v
e
in
ad
eq
u
ate
r
eg
u
latio
n
s
an
d
q
u
ality
co
n
tr
o
l
s
y
s
tem
s
[
5
8
]
.
T
h
is
co
n
ce
r
n
m
ay
r
esu
lt
i
n
th
e
m
is
in
ter
p
r
etatio
n
o
f
p
atien
t
g
en
etic
test
in
g
r
esu
lts
,
ca
u
s
in
g
a
d
ec
r
ea
s
e
in
th
e
in
d
i
v
id
u
al'
s
d
esire
to
r
ec
o
v
er
,
p
s
y
ch
o
lo
g
ical
s
u
p
p
o
r
t,
an
d
is
s
u
es
r
elate
d
to
s
o
cial
j
u
s
tice
[
8
3
]
.
Patien
t
ad
v
o
ca
cy
g
r
o
u
p
s
,
lik
e
t
h
e
Natio
n
a
l
D
o
wn
Sy
n
d
r
o
m
e
So
ciety
,
h
av
e
e
x
p
r
ess
ed
c
o
n
ce
r
n
s
r
eg
a
r
d
in
g
t
h
e
u
tili
za
tio
n
o
f
n
o
n
in
v
a
s
iv
e
p
r
en
atal
test
in
g
.
T
h
ey
wo
r
r
y
t
h
at
th
is
test
in
g
m
ay
p
r
o
m
o
te
s
o
cial
d
is
cr
im
in
atio
n
ag
ain
s
t
in
d
iv
id
u
als
with
Do
wn
s
y
n
d
r
o
m
e.
T
h
is
d
is
cr
im
in
atio
n
ca
n
o
cc
u
r
th
r
o
u
g
h
h
ig
h
er
r
ates
o
f
ter
m
in
atin
g
p
r
eg
n
an
cies
an
d
d
ec
r
ea
s
ed
m
o
tiv
atio
n
to
d
ev
elo
p
tr
ea
t
m
en
ts
f
o
r
p
atien
ts
with
Do
wn
s
y
n
d
r
o
m
e
[
3
8
]
.
Fig
u
r
e
2
.
I
ll
u
s
tr
atio
n
ab
o
u
t th
e
im
p
ac
t o
f
g
en
etic
p
r
ej
u
d
ice
o
n
v
ar
io
u
s
asp
ec
ts
o
f
life
s
o
u
r
c
e:
a
u
th
o
r
s
’
o
w
n
elab
o
r
atio
n
Sev
er
al
co
m
p
r
e
h
en
s
iv
e
g
en
eti
c
in
v
esti
g
atio
n
s
h
av
e
b
ee
n
co
n
d
u
cted
to
d
eter
m
in
e
s
ev
e
r
al
asp
ec
ts
o
f
b
eh
av
io
r
,
in
clu
d
in
g
m
o
r
al
ju
d
g
m
en
ts
[
9
]
an
d
th
e
d
im
e
n
s
io
n
s
a
n
d
co
g
n
itiv
e
ca
p
a
b
ilit
ies
o
f
b
r
ain
r
eg
io
n
s
ass
o
ciate
d
with
lan
g
u
ag
e,
m
em
o
r
y
,
d
e
cisi
o
n
-
m
ak
in
g
,
an
d
ju
d
g
m
e
n
t
[
2
7
]
.
A
s
tu
d
y
co
n
d
u
cte
d
in
2
0
1
1
d
is
co
v
er
ed
a
co
r
r
elatio
n
b
et
wee
n
"in
n
ate
n
u
m
b
e
r
s
en
s
e"
b
ef
o
r
e
r
ec
eiv
in
g
m
ath
em
a
tics
ed
u
ca
tio
n
an
d
ac
h
iev
em
en
t
in
m
ath
em
atics
lear
n
in
g
.
T
h
o
s
e
in
v
esti
g
atio
n
s
s
u
g
g
est
th
at
g
en
etics
m
ay
p
lay
a
r
o
le
in
d
eter
m
in
in
g
m
ath
em
atica
l
ab
i
lity
to
s
o
m
e
ex
te
n
t
[
9
0
]
.
Gen
o
m
ics
h
as
g
ain
e
d
wid
esp
r
ea
d
p
o
p
u
lar
ity
an
d
is
n
o
lo
n
g
er
lim
ited
to
lab
o
r
ato
r
ies
o
r
clin
ics.
I
t
is
n
o
w
a
r
eg
u
l
ar
ly
d
is
cu
s
s
ed
is
s
u
e
in
p
o
p
u
l
ar
m
ed
ia
an
d
h
as
p
ar
tially
b
ee
n
u
s
ed
to
ex
p
lai
n
th
e
u
n
d
er
l
y
in
g
.
R
ea
s
o
n
s
f
o
r
d
if
f
er
en
t
c
o
m
m
o
n
b
e
h
av
i
o
r
s
.
Usi
n
g
g
en
etic
f
in
d
in
g
s
t
o
ex
p
lain
th
is
b
eh
av
io
r
will
s
u
b
s
eq
u
e
n
tly
b
e
r
e
g
ar
d
ed
as
h
av
in
g
p
o
licy
im
p
licat
io
n
s
an
d
h
o
l
d
s
th
e
p
o
ten
tial f
o
r
tar
g
eted
im
p
lem
e
n
tatio
n
.
W
h
en
a
s
o
cial
p
o
licy
is
im
p
lem
en
ted
with
a
p
r
ed
is
p
o
s
i
tio
n
to
war
d
s
g
en
etic
d
eter
m
i
n
is
m
an
d
ess
en
tiali
s
m
,
it
h
as
a
h
ig
h
lik
elih
o
o
d
o
f
ca
u
s
in
g
s
tig
m
atiza
tio
n
an
d
p
r
eju
d
ice
am
o
n
g
th
e
p
u
b
lic.
Dis
cr
im
in
atio
n
ca
n
m
a
n
if
est
in
v
u
l
n
er
ab
le
g
r
o
u
p
s
,
in
clu
d
in
g
cr
im
in
als
[
3
1
]
,
[
3
4
]
.
C
r
im
in
als
'
illeg
al
b
eh
av
io
r
m
ay
b
e
p
e
r
ce
iv
ed
b
y
s
o
ciety
as
h
av
in
g
a
g
en
etic
b
asis
,
m
ak
in
g
th
e
m
m
o
r
e
lik
ely
to
en
g
ag
e
in
s
im
ilar
ac
tiv
ities
in
th
e
f
u
tu
r
e.
C
o
n
s
eq
u
en
tly
,
th
ese
in
d
iv
id
u
als
m
ay
b
e
ex
clu
d
e
d
f
r
o
m
s
ev
e
r
al
asp
ec
ts
o
f
life
,
in
clu
d
in
g
ac
ce
s
s
to
h
ea
lth
ca
r
e
s
er
v
ices
[
9
1
]
.
T
h
e
ten
d
en
c
y
to
war
d
s
g
en
etic
d
eter
m
in
is
m
an
d
ess
en
tialis
m
m
ay
r
estrict
th
e
allo
ca
t
io
n
o
f
clin
ical
r
eso
u
r
ce
s
an
d
th
e
s
u
p
p
ly
o
f
h
ea
lth
s
er
v
ices,
as
it
p
r
io
r
itiz
es
s
p
ec
if
ic
r
ac
es
o
r
g
r
o
u
p
s
[
8
6
]
.
C
h
ild
r
en
wh
o
h
a
v
e
b
ee
n
v
ictim
s
o
f
p
h
y
s
ical
v
io
len
ce
an
d
h
av
e
u
n
d
er
g
o
n
e
g
en
etic
test
in
g
m
ay
ex
p
er
ien
ce
s
im
ilar
is
s
u
es
[
8
5
]
.
Giv
en
th
e
o
u
tco
m
es
o
f
c
o
n
d
u
cted
test
s
an
d
th
e
p
r
esen
ce
o
f
d
eter
m
in
is
m
b
ias
an
d
g
en
etic
ess
en
tialis
m
,
s
o
ciety
will
b
ec
o
m
e
in
cr
ea
s
in
g
ly
co
n
v
in
ce
d
o
f
t
h
e
ch
ild
'
s
p
o
ten
tial
r
is
k
to
o
th
e
r
ch
ild
r
en
.
T
h
e
r
ef
o
r
e,
it is
im
p
er
ativ
e
to
estab
lis
h
a
d
is
tin
ct
g
r
o
u
p
ap
ar
t
f
r
o
m
t
h
e
wid
er
s
o
ciet
y
.
Hen
ce
f
o
r
th
,
th
is
ac
t
o
f
d
is
cr
im
in
atio
n
m
ay
h
av
e
co
n
s
eq
u
en
ce
s
o
n
t
h
e
ca
teg
o
r
izatio
n
o
f
ch
ild
r
e
n
,
im
p
ac
tin
g
th
eir
p
r
o
s
p
ec
ts
f
o
r
em
p
lo
y
m
e
n
t o
r
in
v
o
lv
em
e
n
t i
n
o
th
er
d
o
m
ain
s
o
f
life
,
s
u
ch
a
s
cu
ltu
r
e
o
r
p
o
liti
cs
[
4
1
]
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
0
6
I
n
t J Pu
b
lic
Hea
lth
Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
1
4
9
9
-
1
5
1
4
1508
Dete
r
m
in
is
m
b
ias
an
d
g
e
n
etic
ess
en
tiali
s
m
n
o
t o
n
ly
in
f
lu
e
n
c
e
eth
ical
an
d
s
o
cial
asp
ec
ts
,
b
u
t
th
ey
ca
n
also
h
av
e
a
n
im
p
ac
t
o
n
r
elate
d
leg
is
latio
n
.
Gen
o
m
ic
test
in
g
h
as
b
ee
n
ex
ten
s
iv
ely
u
tili
ze
d
as
ev
id
en
ce
i
n
c
o
u
r
t
[
9
2
]
,
an
d
it
h
as
th
e
p
o
ten
tial
to
h
av
e
a
last
in
g
im
p
ac
t
o
n
th
e
f
ield
o
f
law
an
d
cr
im
in
al
ju
s
tice
in
th
e
f
u
tu
r
e
[
9
1
]
.
I
n
th
e
cr
im
in
al
p
r
o
ce
d
u
r
e,
th
e
d
eter
m
in
atio
n
o
f
r
esp
o
n
s
ib
ilit
y
f
o
r
an
ac
t
r
eq
u
ir
es
th
e
id
en
tific
atio
n
o
f
two
ess
en
tial
asp
ec
ts
o
f
th
e
cr
im
e:
ac
tu
s
r
eu
s
,
wh
ich
r
ef
er
s
to
th
e
ac
tu
al
v
io
latio
n
o
f
th
e
law,
an
d
m
e
n
s
r
ea
,
wh
ich
r
ef
e
r
s
to
th
e
m
en
tal
s
tate
th
at
d
e
m
o
n
s
tr
ates
r
esp
o
n
s
i
b
ilit
y
[
9
3
]
.
Gen
etic
p
r
o
o
f
ca
n
b
e
u
s
ed
in
th
is
p
h
ase
o
f
th
e
tr
ial
to
d
en
y
ac
tu
s
r
eu
s
b
y
ass
er
tin
g
th
at
th
e
d
ef
en
d
an
t's
ac
tio
n
s
ar
e
co
n
s
i
s
ten
t
with
in
n
o
ce
n
ce
,
s
u
ch
as
s
elf
-
d
ef
en
s
e
o
r
ac
cid
en
tal
b
e
h
av
io
r
,
o
r
to
co
n
f
r
o
n
t
o
r
m
itig
ate
m
en
s
r
ea
b
y
claim
in
g
th
at
th
e
d
ef
en
d
an
t
h
a
d
n
o
in
ten
tio
n
to
co
m
m
it
a
cr
im
e,
s
u
ch
as
p
lead
in
g
in
s
an
ity
[
3
8
]
.
C
o
n
s
is
ten
t
wi
th
th
is
id
ea
,
b
eh
av
io
r
al
g
en
etic
d
ata
ca
n
b
e
p
r
esen
ted
to
d
im
i
n
is
h
cr
im
in
al
r
esp
o
n
s
ib
ilit
y
b
y
d
ec
r
ea
s
in
g
th
e
q
u
an
tity
o
r
s
ev
er
ity
o
f
p
u
n
is
h
m
e
n
ts
g
iv
en
[
3
4
]
,
[
9
4
]
.
Ho
wev
e
r
,
th
e
p
r
esen
ce
o
f
g
e
n
etic
d
ata
is
also
ex
tr
em
ely
v
u
ln
er
ab
le
t
o
d
eter
m
in
is
m
an
d
g
en
etic
ess
en
tialis
m
b
ias.
T
h
i
s
b
ias
as
s
u
m
es
th
at
a
p
er
s
o
n
's
id
en
tity
is
ex
clu
s
iv
ely
s
h
ap
ed
b
y
th
eir
in
h
e
r
en
t
g
en
etic
m
ak
e
u
p
,
im
p
ly
i
n
g
t
h
a
t
asp
ec
ts
o
f
t
h
eir
b
io
lo
g
y
h
a
v
e
af
f
ec
te
d
th
e
d
ef
en
d
an
t'
s
ab
ilit
y
to
m
a
k
e
c
h
o
ices
f
r
ee
ly
.
Sit
u
atio
n
s
lik
e
th
is
ar
e
in
cr
ea
s
in
g
ly
co
m
m
o
n
in
h
y
p
o
th
etica
l
s
itu
atio
n
s
,
illu
s
tr
atin
g
th
at,
o
n
av
er
ag
e
,
s
u
r
v
ey
ed
ju
d
g
es
ten
d
to
im
p
o
s
e
r
ed
u
ce
d
p
r
is
o
n
ter
m
s
o
n
o
f
f
en
d
er
s
wh
e
n
t
h
er
e
is
b
io
lo
g
ical
e
v
id
en
ce
in
d
icatin
g
th
at
th
e
s
u
s
p
ec
t
h
as a
p
r
ed
is
p
o
s
itio
n
to
p
s
y
ch
o
p
ath
y
[
9
4
]
.
3
.
3
.
T
he
p
o
t
ent
ia
l o
f
g
enet
ic
lea
rning
in im
pro
v
ing
t
he
lev
el
o
f
g
enet
ic
det
er
m
ini
s
m
a
nd
ess
e
ntia
lis
m
in
t
he
hea
lt
h sect
o
r
As
th
e
h
ea
lth
s
ec
to
r
ex
p
an
d
s
r
ap
id
ly
,
h
an
d
lin
g
d
eter
m
i
n
is
m
b
ias
an
d
g
en
etic
ess
en
tiali
s
m
is
cr
u
cial
to
av
o
id
p
o
ten
tial
r
is
k
s
to
f
u
tu
r
e
h
ea
lth
s
er
v
ices.
Ge
n
etic
ed
u
ca
tio
n
is
a
k
e
y
p
ath
way
to
e
n
h
an
cin
g
th
e
d
e
g
r
ee
o
f
g
e
n
etic
d
eter
m
in
is
m
an
d
ess
en
tiali
s
m
in
th
e
f
u
tu
r
e
.
T
ab
le
3
p
r
o
v
id
es
in
f
o
r
m
atio
n
o
n
h
o
w
g
en
etics
ed
u
ca
tio
n
m
i
g
h
t e
n
h
an
ce
th
e
a
war
en
ess
o
f
g
en
etic
d
eter
m
in
i
s
m
an
d
ess
en
tialis
m
in
h
ea
lth
ca
r
e.
T
ab
le
3
.
T
h
e
r
o
le
o
f
g
e
n
etics e
d
u
ca
tio
n
in
im
p
r
o
v
in
g
t
h
e
lev
e
l o
f
g
en
etic
d
eter
m
in
is
m
an
d
e
s
s
en
tiali
s
m
in
th
e
h
ea
lth
s
ec
to
r
No
A
sp
e
c
t
I
n
f
o
r
ma
t
i
o
n
R
e
f
e
r
e
n
c
e
1
K
n
o
w
l
e
d
g
e
•
Th
e
p
r
e
s
e
n
c
e
o
f
d
e
t
e
r
m
i
n
i
sm
a
n
d
g
e
n
e
t
i
c
e
ss
e
n
t
i
a
l
i
sm
i
n
a
n
i
n
d
i
v
i
d
u
a
l
'
s
c
o
m
p
r
e
h
e
n
si
o
n
o
f
g
e
n
e
t
i
c
t
e
s
t
r
e
su
l
t
s
c
a
n
b
e
i
n
f
l
u
e
n
c
e
d
b
y
:
(
a
)
t
h
e
i
r
p
e
r
s
o
n
a
l
a
n
d
f
a
mi
l
i
a
l
e
x
p
e
r
i
e
n
c
e
s
w
i
t
h
d
i
s
o
r
d
e
r
s
o
r
d
i
sea
ses
t
h
e
y
h
a
v
e
e
n
d
u
r
e
d
,
a
n
d
(
b
)
t
h
e
i
r
p
r
i
o
r
e
x
p
e
r
i
e
n
c
e
s
w
i
t
h
h
e
a
l
t
h
c
a
r
e
serv
i
c
e
s
.
T
o
mi
t
i
g
a
t
e
t
h
e
b
i
a
s
o
f
b
o
t
h
c
o
mp
o
n
e
n
t
s
,
i
t
i
s
n
e
c
e
ssar
y
t
o
p
r
o
v
i
d
e
a
g
e
n
e
t
i
c
e
x
p
l
a
n
a
t
i
o
n
t
h
a
t
i
s
c
o
n
c
e
p
t
u
a
l
l
y
r
e
l
e
v
a
n
t
a
n
d
u
n
d
e
r
s
t
a
n
d
a
b
l
e
t
o
t
h
e
g
e
n
e
r
a
l
a
u
d
i
e
n
c
e
.
[
3
5
]
,
[
9
5
]
•
T
o
e
n
h
a
n
c
e
t
h
e
e
f
f
e
c
t
i
v
e
n
e
ss
o
f
p
u
b
l
i
c
h
e
a
l
t
h
r
e
se
a
r
c
h
i
n
p
r
o
mo
t
i
n
g
b
e
t
t
e
r
h
e
a
l
t
h
o
u
t
c
o
mes
a
n
d
a
v
o
i
d
i
n
g
b
i
a
se
d
v
i
e
w
s
o
n
d
e
t
e
r
m
i
n
i
s
m
a
n
d
g
e
n
e
t
i
c
e
sse
n
t
i
a
l
i
sm
,
i
t
i
s
c
r
u
c
i
a
l
t
o
a
d
d
r
e
s
s
t
h
e
k
n
o
w
l
e
d
g
e
g
a
p
s i
n
s
o
c
i
e
t
y
,
p
a
r
t
i
c
u
l
a
r
l
y
t
h
o
se
c
o
n
n
e
c
t
e
d
t
o
g
e
n
e
t
i
c
c
o
n
c
e
p
t
s.
[
6
7
]
,
[
7
0
]
•
P
r
o
v
i
d
i
n
g
f
a
c
t
u
a
l
e
d
u
c
a
t
i
o
n
a
b
o
u
t
t
h
e
i
m
p
a
c
t
o
f
n
o
n
-
a
b
s
o
l
u
t
e
g
e
n
e
s
i
n
d
e
v
e
l
o
p
i
n
g
a
s
p
e
c
i
f
i
c
c
o
n
d
i
t
i
o
n
c
a
n
e
n
h
a
n
c
e
t
h
e
p
a
t
i
e
n
t
's m
o
t
i
v
a
t
i
o
n
t
o
r
e
c
o
v
e
r
.
[
6
7
]
•
P
u
b
l
i
c
o
p
i
n
i
o
n
s
o
f
sc
i
e
n
c
e
a
r
e
f
r
e
q
u
e
n
t
l
y
i
n
f
l
u
e
n
c
e
d
b
y
c
u
l
t
u
r
e
s
t
h
a
t
may
o
n
l
y
s
o
m
e
t
i
mes
p
r
o
v
i
d
e
c
o
r
r
e
c
t
i
n
f
o
r
ma
t
i
o
n
.
C
u
l
t
u
r
e
i
s
f
r
e
q
u
e
n
t
l
y
r
e
g
a
r
d
e
d
a
s
t
h
e
so
u
r
c
e
o
f
e
r
r
o
n
e
o
u
s
i
n
f
o
r
mat
i
o
n
i
n
e
d
u
c
a
t
i
o
n
a
n
d
s
c
i
e
n
c
e
.
H
o
w
e
v
e
r
,
c
u
l
t
u
r
e
c
a
n
a
l
s
o
s
e
r
v
e
a
s a
so
u
r
c
e
o
f
n
a
r
r
a
t
i
v
e
s
a
n
d
me
t
a
p
h
o
r
s
t
h
a
t
f
a
c
i
l
i
t
a
t
e
d
i
s
c
u
ss
i
o
n
s
o
n
g
e
n
e
t
i
c
s,
w
h
i
c
h
a
r
e
mo
r
e
a
c
c
u
r
a
t
e
a
n
d
f
r
e
e
f
r
o
m
t
h
e
i
n
f
l
u
e
n
c
e
s
o
f
d
e
t
e
r
mi
n
i
sm
o
r
g
e
n
e
t
i
c
e
ss
e
n
t
i
a
l
i
sm.
[
9
6
]
2
S
k
i
l
l
s
•
I
n
t
h
e
c
u
r
r
e
n
t
g
e
n
o
m
i
c
s
e
r
a
,
n
u
m
e
r
o
u
s
p
r
o
g
r
a
m
s
h
a
v
e
b
e
e
n
d
e
v
e
l
o
p
e
d
t
o
a
s
s
i
s
t
t
h
e
p
u
b
l
i
c
i
n
e
n
h
a
n
c
i
n
g
t
h
e
i
r
u
n
d
e
r
s
t
a
n
d
i
n
g
o
f
g
e
n
e
t
i
c
i
d
e
a
s
.
W
i
t
h
i
n
h
i
g
h
e
r
e
d
u
c
a
t
i
o
n
p
r
o
g
r
a
m
s
,
m
u
l
t
i
p
l
e
p
r
o
j
e
c
t
s
i
n
v
o
l
v
i
n
g
i
n
v
e
s
t
i
g
a
t
i
n
g
t
h
e
C
C
R
5
g
e
n
e
u
s
i
n
g
b
i
o
i
n
f
o
r
m
a
t
i
c
s
d
a
t
a
b
a
s
e
s
h
a
v
e
b
e
e
n
c
o
n
d
u
c
t
e
d
.
S
t
u
d
e
n
t
s
c
a
n
d
e
v
e
l
o
p
t
h
e
a
b
i
l
i
t
y
t
o
e
x
a
m
i
n
e
p
r
e
e
x
i
s
t
i
n
g
d
a
t
a
t
o
a
v
o
i
d
o
v
e
r
s
i
m
p
l
i
f
i
c
a
t
i
o
n
a
n
d
b
i
a
s
e
d
i
n
t
e
r
p
r
e
t
a
t
i
o
n
s
o
f
g
e
n
e
t
i
c
c
o
n
c
e
p
t
s
,
i
n
c
l
u
d
i
n
g
b
o
t
h
d
e
t
e
r
m
i
n
i
s
t
i
c
a
n
d
e
s
s
e
n
t
i
a
l
i
s
t
i
c
b
i
a
s
e
s
.
[
4
6
]
•
N
u
r
ses
m
u
st
h
a
v
e
a
st
r
o
n
g
u
n
d
e
r
s
t
a
n
d
i
n
g
o
f
c
o
n
su
m
e
r
g
e
n
e
t
i
c
t
e
s
t
i
n
g
t
o
h
e
l
p
p
a
t
i
e
n
t
s
i
n
t
e
r
p
r
e
t
t
h
e
i
r
g
e
n
e
t
i
c
t
e
st
r
e
su
l
t
s
.
T
h
i
s k
n
o
w
l
e
d
g
e
i
s
c
r
u
c
i
a
l
f
o
r
h
e
l
p
i
n
g
p
a
t
i
e
n
t
s
m
a
k
e
e
d
u
c
a
t
e
d
me
d
i
c
a
l
c
h
o
i
c
e
s
a
n
d
p
r
e
v
e
n
t
i
n
g
t
h
e
i
n
f
l
u
e
n
c
e
o
f
g
e
n
e
t
i
c
d
e
t
e
r
mi
n
i
sm
a
n
d
e
ss
e
n
t
i
a
l
i
s
m b
i
a
se
s.
[
5
6
]
Acc
o
r
d
in
g
t
o
T
ab
le
3
,
g
en
eti
c
ed
u
ca
tio
n
ca
n
d
im
in
is
h
th
e
p
r
eju
d
ice
o
f
g
en
etic
d
eter
m
i
n
is
m
an
d
ess
en
tiali
s
m
th
r
o
u
g
h
two
m
ain
asp
ec
ts
: k
n
o
wled
g
e
an
d
s
k
ills
.
T
h
e
m
ain
f
o
cu
s
in
th
is
k
n
o
wled
g
e
d
o
m
ain
is
o
n
in
d
iv
id
u
al
ex
p
er
tis
e
in
an
ac
cu
r
ate
an
d
th
o
r
o
u
g
h
u
n
d
er
s
tan
d
i
n
g
o
f
g
en
etic
in
f
o
r
m
atio
n
an
d
liter
ac
y
.
W
h
en
ev
e
r
it
in
v
o
lv
es
s
k
ills
,
th
e
f
o
c
u
s
is
o
n
th
e
s
p
ec
if
ic
c
o
m
p
eten
cies
o
f
m
e
d
ical
p
r
o
f
ess
io
n
als
in
d
e
liv
er
in
g
h
ea
lth
ca
r
e
s
er
v
ices.
Mo
r
eo
v
er
,
th
e
ca
p
a
city
o
f
g
e
n
etic
lear
n
in
g
to
d
ec
r
ea
s
e
n
eg
ativ
e
s
tig
m
a
is
s
u
p
p
o
r
ted
b
y
s
ev
er
al
f
ield
s
,
as
s
ee
n
in
Fig
u
r
e
3
.
B
y
p
r
o
v
id
in
g
s
p
ec
if
ic
s
u
p
p
o
r
t
an
d
im
p
lem
en
tin
g
a
r
o
b
u
s
t
ed
u
c
atio
n
al
f
r
am
ewo
r
k
,
we
ca
n
ac
h
ie
v
e
a
s
ig
n
if
ican
t
e
d
u
ca
tio
n
al
e
x
p
er
ien
ce
th
at
wil
l
m
itig
ate
g
en
etic
p
r
eju
d
ice
a
n
d
en
h
an
ce
o
v
er
all
well
-
b
ein
g
an
d
co
m
p
r
eh
en
s
io
n
in
d
iv
e
r
s
e
d
o
m
ain
s
,
in
cl
u
d
in
g
h
ea
lth
ca
r
e,
e
d
u
ca
tio
n
,
an
d
s
o
cial
m
atter
s
.
G
e
n
e
t
i
c
e
d
u
c
a
t
i
o
n
ca
n
e
f
f
e
c
ti
v
e
l
y
d
i
m
i
n
is
h
i
d
e
as
i
n
d
e
t
e
r
m
i
n
i
s
m
a
n
d
g
e
n
et
i
c
ess
e
n
t
i
al
is
m
b
i
a
s
w
h
e
n
c
o
n
d
u
c
t
e
d
w
i
t
h
c
o
m
m
i
t
m
e
n
t
a
n
d
b
y
i
n
c
l
u
d
i
n
g
m
u
l
t
i
p
l
e
e
d
u
c
a
t
i
o
n
a
l
c
o
m
p
o
n
e
n
t
s
.
C
u
r
r
i
cu
l
u
m
[
9
7
]
,
l
e
a
r
n
i
n
g
a
c
t
i
v
i
ti
es
[
9
8
]
,
t
e
a
c
h
i
n
g
m
a
t
e
r
i
a
l
s
,
a
n
d
l
e
a
r
n
i
n
g
m
e
d
i
a
[
9
9
]
s
i
g
n
i
f
i
c
a
n
t
l
y
e
n
c
o
u
r
a
g
e
m
e
a
n
i
n
g
f
u
l
g
e
n
e
t
i
c
s
Evaluation Warning : The document was created with Spire.PDF for Python.