Upload
independent
View
0
Download
0
Embed Size (px)
Citation preview
C
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
New and improved tuberculosis
diagnostics: evidence, policy,practice, and impactMadhukar Paia, Jessica Miniona, Karen Steingartb and Andrew Ramsayc
aDepartment of Epidemiology, Biostatistics andOccupational Health, McGill University, Montreal,Canada, bFrancis J. Curry National TuberculosisCenter, University of California, San Francisco,California, USA and cUNICEF/UNDP/World Bank/WHO Special Programme for Research and Training inTropical Diseases (TDR), World Health Organization,Geneva, Switzerland
Correspondence to Madhukar Pai, MD, PhD, AssistantProfessor, Department of Epidemiology, Biostatisticsand Occupational Health, McGill University, 1020 PineAvenue West, Montreal, QC H3A 1A2, CanadaTel: +1 514 398 5422; fax: +1 514 398 4503;e-mail: [email protected]
Current Opinion in Pulmonary Medicine 2010,16:000–000
Purpose of review
The aim is to summarize the evidence base for tuberculosis (TB) diagnostics, review
recent policies on TB diagnostics, and discuss issues such as how evidence is
translated into policy, limitations of the existing evidence base, and challenges involved
in translating policies into impact.
Recent findings
Case detection continues to be a major obstacle to global TB control. Fortunately,
due to an unprecedented level of interest, funding, and activity, the new diagnostics
pipeline for TB has rapidly expanded. There have been several new policies and
guidelines on TB diagnostics. However, there are major gaps in the existing pipeline
(e.g. lack of a point-of-care test) and the evidence base is predominantly made up of
research studies of test accuracy.
Summary
With the availability of new diagnostics and supporting policies, the next major step
is translation of policy into practice. The impact of new tests will depend largely on the
extent of their introduction and acceptance into the global public sector. This will
itself depend in part on policy decisions by international technical agencies and national
TB programs. With the engagement of all key stakeholders, we will need to translate
evidence-based policies into epidemiological and public health impact.
Keywords
diagnostics, evidence, impact, policy, tuberculosis
Curr Opin Pulm Med 16:000–000� 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins1070-5287
IntroductionIn 2010, poor diagnosis remains a major obstacle to global
tuberculosis (TB) control. In most high-burden countries,
TB is still diagnosed using tools such as direct sputum
microscopy and chest radiographs. Fortunately, the past
few years have seen an unprecedented level of interest,
funding support, and activity focused on the development
of new tools for TB diagnosis, and the new diagnostics
pipeline for TB is rapidly expanding. In parallel, there
have been several new policy recommendations on TB
diagnostics by the WHO. Because recent publications
[1�,2,3�,4] have exhaustively reviewed the current pipeline
of new diagnostics and the expanding evidence base for
their use, we focus our attention on how evidence is
translated into policy, limitations of the existing evidence
base, deficiencies in the current diagnostics pipeline, and
challenges involved in translating policies into practice
and impact.
What is the evidence base for tuberculosisdiagnostics?The evidence base for TB diagnostics is ultimately
derived from a large body of original research. Because
opyright © Lippincott Williams & Wilkins. Unauth
1070-5287 � 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
individual studies are seldom sufficient to inform policy
and guideline development, the totality of available
evidence must be synthesized. Thus, systematic reviews
and meta-analyses are often necessary to summarize the
evidence on a given diagnostic test. In the past decade,
there have been over 35 systematic reviews published on
TB diagnostics, on topics ranging from smear microscopy
to molecular diagnostics and in-vitro assays for latent TB
infection (LTBI). All of these systematic reviews have
been made available on a new website ‘Evidence-based
Tuberculosis Diagnosis’ (www.tbevidence.org) compiled
by the Stop TB Partnership’s New Diagnostics Working
Group, in collaboration with several agencies [5�]. While
the key findings of published systematic reviews and
meta-analyses on TB diagnostics have been reviewed
elsewhere [6�], Table 1 provides a brief overview of the
evidence base for TB diagnosis, essentially synthesizing
the evidence from several systematic reviews [7–37].
What is lacking in current evidence base?Although a large number of systematic reviews have been
published on TB diagnostics, almost all focus on test
accuracy (i.e. sensitivity and specificity). This is in part
orized reproduction of this article is prohibited.
DOI:10.1097/MCP.0b013e328338094f
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
2 Infectious diseases
Ta
ble
1S
um
ma
ryo
ffi
nd
ing
sfr
om
syste
ma
tic
revie
ws
on
tub
erc
ulo
sis
dia
gn
osti
cte
sts
Dia
gno
stic
test
Des
crip
tion
Dis
ease
/site
Maj
or
find
ing
s/re
sults
of
syst
emat
icre
view
sM
ajo
rre
fere
nces
Dia
gn
osis
of
acti
ve
TB
Sp
utum
smea
rm
icro
sco
py
Mic
rosc
op
ico
bse
rvat
ion
of
stai
ned
acid
fast
bac
illi
Pul
mo
nary
TB
Flu
ore
scen
cem
icro
sco
py
(FM
)is
on
aver
age
10
%m
ore
sens
itive
than
conv
entio
nal
mic
rosc
op
y.S
pec
ifici
tyo
fb
oth
fluo
resc
ence
and
conv
entio
nal
mic
rosc
op
yis
sim
ilar.
Flu
ore
scen
tm
icro
sco
py
isas
soci
ated
with
imp
rove
dtim
eef
ficie
ncy.
[7–
9]
LED
FM
per
form
seq
uiva
lent
lyto
conv
entio
nal
FM
,w
ithad
ded
ben
efits
of
low
cost
,d
urab
ility
,an
dab
ility
tous
ew
itho
uta
dar
kro
om
.C
entr
ifug
atio
nan
do
vern
ight
sed
imen
tatio
n,p
rece
ded
with
any
of
seve
ral
chem
ical
met
hod
s(in
clud
ing
ble
ach)
issl
ight
lym
ore
sens
itive
(6–
9%
)th
and
irect
mic
rosc
op
y;sp
ecifi
city
may
be
slig
htly
dec
reas
ed(1
–3
%)
by
sput
ump
roce
ssin
gm
etho
ds.
Whe
nse
rialsp
utum
spec
imen
sar
eex
amin
ed,
the
mea
nin
crem
enta
lyi
eld
and
/or
incr
ease
inse
nsiti
vity
fro
mex
amin
atio
no
fth
irdsp
utum
spec
imen
rang
esb
etw
een
2an
d5
%.
Nuc
leic
acid
amp
lifica
tion
test
s(N
AA
Ts)
Iso
latio
n,re
plic
atio
n,an
dd
etec
tion
of
nucl
eic
acid
seq
uenc
essp
ecifi
cfo
rM
ycobac
terium
tuber
culo
sis
Pul
mo
nary
and
extr
apul
mo
nary
TB
NA
AT
sha
vehi
gh
spec
ifici
tyan
dp
osi
tive
pre
dic
tive
valu
e.N
AA
Ts,
how
ever
,ha
vere
lativ
ely
low
er(a
ndhi
ghl
yva
riab
le)
sens
itivi
tyan
dne
gat
ive
pre
dic
tive
valu
efo
ral
lfo
rms
of
TB
,es
pec
ially
insm
ear-
neg
ativ
ean
dex
trap
ulm
ona
ryd
isea
se.
In-h
ous
e(‘
hom
eb
rew
’)N
AA
Ts
pro
duc
ehi
ghl
yin
cons
iste
ntre
sults
asco
mp
ared
with
com
mer
cial
,st
and
ard
ized
NA
AT
s.
[10
–1
5]
Co
mm
erci
alse
rolo
gic
alan
tibo
dy
det
ectio
nte
sts
Det
ectio
no
fho
stan
tibo
dy
resp
ons
eto
Myc
obac
terium
tuber
culo
sis
antig
ens
Pul
mo
nary
and
extr
apul
mo
nary
TB
Ser
olo
gic
alte
sts
for
bo
thp
ulm
ona
ryan
dex
trap
ulm
ona
ryT
Bp
rod
uce
hig
hly
inco
nsis
tent
estim
ates
of
sens
itivi
tyan
dsp
ecifi
city
;no
neo
fth
ecu
rren
tas
says
per
form
wel
len
oug
hto
rep
lace
mic
rosc
op
y.[1
2,1
6,1
7]
No
nco
mm
erci
al(in
-ho
use)
sero
log
ical
antib
od
yd
etec
tion
test
s
Det
ectio
no
fho
stan
tibo
dy
resp
ons
eto
Myc
obac
terium
tuber
culo
sis
antig
ens
Pul
mo
nary
TB
Sev
eral
po
tent
ial
cand
idat
ean
tigen
sfo
rin
clus
ion
inan
antib
od
yd
etec
tion-
bas
edd
iag
nost
icte
stfo
rp
ulm
ona
ryT
Bin
HIV
-infe
cted
and
-uni
nfec
ted
ind
ivid
uals
wer
eid
entifi
ed.
[18
]
Co
mb
inat
ions
of
sele
ctan
tigen
sp
rovi
de
hig
her
sens
itivi
ties
than
sing
lean
tigen
s.A
den
osi
ned
eam
inas
e(A
DA
)D
etec
tion
of
host
cellu
lar
enzy
me
rele
ased
by
lym
pho
cyte
sin
resp
ons
eto
live
intr
acel
lula
rp
atho
gen
s
TB
ple
uriti
s,p
eric
ard
itis,
per
itoni
tisM
easu
rem
ent
of
AD
Ale
vels
inp
leur
al,
per
icar
dia
l,an
das
citic
fluid
isa
usef
ulad
junc
tte
stfo
rT
Bp
leur
itis,
per
icar
diti
s,an
dp
erito
nitis
.S
yste
mat
icre
view
sha
vere
po
rted
poo
led
sens
itivi
tyes
timat
esb
etw
een
88
and
10
0%
,an
dsp
ecifi
city
estim
ates
bet
wee
n8
3an
d9
7%
.
[19
,20
]
Inte
rfer
on-
gam
ma
(IF
N-g
)M
easu
rem
ent
of
IFN
-gT
Bp
leur
itis
Ple
ural
fluid
IFN
-gd
eter
min
atio
nap
pea
rsto
be
aus
eful
dia
gno
stic
for
TB
ple
uriti
s,w
ithsy
stem
atic
revi
ews
rep
ort
ing
po
ole
dse
nsiti
vity
estim
ates
bet
wee
n8
9an
d9
6%
,an
dsp
ecifi
city
estim
ates
bet
wee
n9
6an
d9
7%
.[1
9,2
1]
Pha
ge
amp
lifica
tion
assa
ysD
etec
tion
of
Myc
obac
terium
tuber
culo
sis-
spec
ific
pha
ge
viru
ses,
afte
rth
eir
infe
ctio
nan
dam
plifi
catio
no
fliv
eM
TB
Pul
mo
nary
TB
Des
pite
hig
h-ac
cura
cyes
timat
es,
curr
ent
pha
ge-
bas
edas
says
are
limite
db
yhi
gh
rate
so
fin
det
erm
inat
ere
sults
(up
to3
6%
).[2
2]
Aut
om
ated
liqui
dcu
lture
sA
uto
mat
edd
etec
tion
of
chan
ges
ino
xyg
en,
carb
on
dio
xid
e,o
rp
ress
ure
resu
lting
fro
mb
acte
rial
gro
wth
Pul
mo
nary
TB
Aut
om
ated
liqui
dcu
lture
sar
em
ore
sens
itive
than
solid
cultu
res;
time
tod
etec
tion
ism
ore
rap
idth
anso
lidcu
lture
s.[1
2,2
3]
Dia
gn
osis
of
late
nt
TB
Tub
ercu
linsk
inte
st(T
ST
)M
easu
rem
ent
of
ind
urat
ion
asa
resu
lto
fex
po
sure
toin
trad
erm
altu
ber
culin
Late
ntT
Bin
fect
ion
Ind
ivid
uals
who
have
rece
ived
BC
Gva
ccin
atio
nar
em
ore
likel
yto
have
ap
osi
tive
TS
T;
the
effe
cto
fB
CG
on
TS
Tre
sults
isle
ssaf
ter
15
year
s;p
osi
tive
TS
Tw
ithin
dur
atio
nso
f>
15
mm
are
mo
relik
ely
tob
eth
ere
sult
of
TB
infe
ctio
nth
ano
fB
CG
vacc
inat
ion.
[24
,25
]
The
effe
cto
nT
ST
of
BC
Gre
ceiv
edin
infa
ncy
ism
inim
al,
esp
ecia
lly1
0ye
ars
afte
rva
ccin
atio
n.B
CG
rece
ived
afte
rin
fanc
yp
rod
uces
mo
refr
eque
nt,
mo
rep
ersi
sten
t,an
dla
rger
TS
Tre
actio
ns.
No
ntub
ercu
lous
myc
ob
acte
rial
(NT
M)
infe
ctio
nis
not
acl
inic
ally
imp
ort
ant
caus
eo
ffa
lse-
po
sitiv
eT
ST
,ex
cep
tin
po
pul
atio
nsw
itha
hig
hp
reva
lenc
eo
fN
TM
sens
itiza
tion
and
ave
rylo
wp
reva
lenc
eo
fT
Bin
fect
ion.
T-c
ell-b
ased
inte
rfer
on-
gre
leas
eas
says
(IG
RA
s)M
easu
rem
ent
of
IFN
-gre
leas
edfr
om
lym
pho
cyte
sw
hen
stim
ulat
edb
yM
ycobac
terium
tuber
culo
sis-
spec
ific
antig
ens
Late
ntT
Bin
fect
ion
IGR
As
have
exce
llent
spec
ifici
ty(h
ighe
rth
anth
etu
ber
culin
skin
test
)an
dar
eun
affe
cted
by
prio
rB
CG
vacc
inat
ion.
[12
,26
–2
9]
IGR
As
cann
ot
dis
ting
uish
bet
wee
nLT
BI
and
activ
eT
Ban
dha
veno
role
for
activ
eT
Bd
iag
nosi
sin
adul
ts.
Use
das
anad
junc
tive
dia
gno
stic
,IG
RA
sm
ayai
din
the
inve
stig
atio
no
fp
edia
tric
TB
.IG
RA
sco
rrel
ate
wel
lw
ithm
arke
rso
fT
Bex
po
sure
inlo
w-in
cid
ence
coun
trie
s.IG
RA
per
form
ance
app
ears
tod
iffer
inhi
gh-
end
emic
vs.
low
-end
emic
coun
trie
s.IG
RA
sens
itivi
tyva
ries
acro
ssp
op
ulat
ions
and
tend
sto
be
low
erin
hig
h-en
dem
icco
untr
ies
and
inH
IV-in
fect
edin
div
idua
ls.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
New and improved tuberculosis diagnostics Pai et al. 3
Dia
gn
osis
of
dru
gre
sis
tan
ce
Pha
ge
amp
lifica
tion
assa
ysD
etec
tion
of
Myc
obac
terium
tuber
culo
sis-
spec
ific
pha
ge
viru
ses,
afte
rth
eir
infe
ctio
nan
dam
plifi
catio
no
fliv
eM
TB
þin
hib
itio
no
fg
row
thin
pre
senc
eo
fan
titub
ercu
lous
dru
gs
Rap
idd
etec
tion
of
rifam
pic
inre
sist
ance
Whe
nus
edo
ncu
lture
iso
late
s,p
hag
eas
says
have
hig
hse
nsiti
vity
,b
utva
riab
lean
dlo
wer
spec
ifici
ty.
Inco
ntra
st,
evid
ence
isla
ckin
go
nth
eac
cura
cyo
fth
ese
assa
ysw
hen
they
are
dire
ctly
app
lied
tosp
utum
spec
imen
s.R
ecen
tst
udie
sha
vera
ised
conc
erns
abo
utco
ntam
inat
ion,
fals
e-p
osi
tive
resu
lts,
and
tech
nica
las
say
failu
res.
[30
,31
]
Line
pro
be
assa
ys:
INN
O-L
iPA
Rif.
TB
[LiP
A]
and
Gen
oT
ype
MT
BD
Ras
say
Det
ectio
no
fg
enet
icse
que
nces
asso
ciat
edw
ithre
sist
ance
(aft
erex
trac
tion
and
amp
lifica
tion)
usin
gim
mo
bili
zed
pro
bes
and
colo
rimet
ricd
evel
op
men
t
Rap
idd
etec
tion
of
rifam
pic
inre
sist
ance
LiP
Ais
ahi
ghl
yse
nsiti
vean
dsp
ecifi
cte
stfo
rth
ed
etec
tion
of
rifam
pic
inre
sist
ance
incu
lture
iso
late
s.T
hete
stha
sre
lativ
ely
low
erse
nsiti
vity
whe
nus
edd
irect
lyo
ncl
inic
alsp
ecim
ens.
The
Gen
oTyp
eM
TB
DR
assa
ysha
veex
celle
ntse
nsiti
vity
and
spec
ifici
tyfo
rrif
amp
icin
resi
stan
ceev
enw
hen
dire
ctly
used
on
clin
ical
spec
imen
s.
[32
–3
4]
Co
lorim
etric
red
ox
ind
icat
ors
(CR
Is)
Det
erm
inat
ion
of
MIC
usin
gm
icro
dilu
tion,
follo
wed
by
add
itio
no
fre
agen
tw
hich
will
bec
om
ere
duc
edin
the
pre
senc
eo
fac
tivel
yg
row
ing
MT
Bre
sulti
ngin
aco
lor
chan
ge
Rap
idd
etec
tion
of
rifam
pic
inan
dis
oni
azid
resi
stan
ceC
olo
rimet
ricm
etho
ds
are
sens
itive
and
spec
ific
for
the
det
ectio
no
frif
amp
icin
and
iso
niaz
idre
sist
ance
incu
lture
iso
late
s.C
RIs
use
inex
pen
sive
nonc
om
mer
cial
sup
plie
san
deq
uip
men
tan
dha
vea
rap
idtu
rnar
oun
dtim
e(7
day
s).
[35
]
Nitr
ate
red
ucta
seas
says
(NR
As)
Dire
cto
rin
dire
ctin
ocu
latio
no
fd
rug
-fre
ean
dd
rug
-co
ntai
ning
med
iaco
ntai
ning
KN
O3.
Ad
diti
on
of
Gre
iss
reag
ent
det
ects
early
gro
wth
by
reac
ting
with
enzy
mat
icb
ypro
duc
tan
dre
sulti
ngin
aco
lor
chan
ge.
Rap
idd
etec
tion
of
rifam
pic
inan
dis
oni
azid
resi
stan
ceN
RA
has
hig
hac
cura
cyw
hen
used
tod
etec
trif
amp
icin
and
iso
niaz
idre
sist
ance
incu
lture
iso
late
s.Li
mite
dd
ata
are
avai
lab
leo
nits
use
whe
nd
irect
lyap
plie
dto
clin
ical
spec
imen
s,b
utre
sults
are
pro
mis
ing
.T
heN
RA
issi
mp
le,
uses
inex
pen
sive
nonc
om
mer
cial
sup
plie
san
deq
uip
men
t,an
dha
sa
rap
idtu
rnar
oun
dtim
e(7
–1
4d
ays)
com
par
edto
conv
entio
nal
met
hod
s.
[36
]
Mic
rosc
op
ico
bse
rvat
ion
dru
gsu
scep
tibili
ty(M
OD
S)
Dire
cto
rin
dire
ctin
ocu
latio
no
fd
rug
-fre
ean
dd
rug
-co
ntai
ning
liqui
dm
edia
,fo
llow
edb
yex
amin
atio
nus
ing
anin
vert
edm
icro
sco
pe
tod
etec
tea
rlyg
row
th
Rap
idd
etec
tion
of
rifam
pic
inan
dis
oni
azid
resi
stan
ceM
OD
Sha
shi
gh
accu
racy
whe
nte
stin
gfo
rrif
amp
icin
resi
stan
ce,
but
sho
ws
slig
htly
low
erse
nsiti
vity
whe
nd
etec
ting
iso
niaz
idre
sist
ance
.M
OD
Sap
pea
rsto
per
form
equa
llyw
ellus
ing
dire
ctp
atie
ntsp
ecim
ens
and
cultu
reis
ola
tes.
MO
DS
uses
nonc
om
mer
cial
sup
plie
san
deq
uip
men
t,an
dha
sa
rap
idtu
rnar
oun
dtim
e(1
0d
ays)
com
par
edw
ithco
nven
tiona
lm
etho
ds.
[37
]
Thi
nla
yer
agar
(TLA
)D
irect
or
ind
irect
ino
cula
tion
of
dru
g-f
ree
and
dru
g-c
ont
aini
ngso
lidm
edia
,fo
llow
edb
yex
amin
atio
nus
ing
am
icro
sco
pe
tod
etec
tea
rlyg
row
th
Rap
idd
etec
tion
of
rifam
pic
inan
dis
oni
azid
resi
stan
ceT
here
isa
pau
city
of
dat
aev
alua
ting
TLA
for
the
det
ectio
no
fd
rug
susc
eptib
ility
;ho
wev
er,
all
stud
ies
tod
ate
have
foun
d1
00
%co
nco
rdan
cew
ithth
eir
refe
renc
est
and
ard
s.T
LAus
esin
exp
ensi
veno
nco
mm
erci
alsu
pp
lies
and
equi
pm
ent,
and
has
ara
pid
turn
aro
und
time
(11
day
s)co
mp
ared
with
conv
entio
nal
met
hod
s.
[37
]
BC
G,b
acill
usC
alm
ette
-Gue
rin;L
ED
,lig
htem
ittin
gd
iod
e;LT
BI,
late
ntT
Bin
fect
ion;
MIC
,min
imal
inhi
bito
ryco
ncen
trat
ion;
MT
B,M
ycobat
eriu
mtu
ber
culo
sis;
TB
,tub
ercu
losi
s.A
dap
ted
fro
m[6� ]
.(O
pen
Acc
ess
und
erC
reat
ive
Co
mm
ons
Att
ribut
ion
Lice
nse)
.
C
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
4 Infectious diseases
because a large proportion of TB diagnostic research
studies are focused on measuring test accuracy. Findings
from systematic reviews suggest that even relatively
straightforward studies of test accuracy are often poorly
designed and reported [38,39]. Both researchers of
primary TB diagnostic studies and authors of systematic
reviews and meta-analyses need to make efforts to follow
published guidelines for conducting and reporting their
work [40,41], to make the most of their contribution to a
useful and unbiased literature base.
Although the quality of diagnostic studies measuring test
accuracy is important, evidence about test accuracy is
only one link in a long chain of activities that make up the
pathway to developing and implementing a new TB
diagnostic. In 2009, the Stop TB Partnership’s New
Diagnostics Working Group published a scientific blue-
print for development of new TB diagnostics [42��]. This
publication provides a comprehensive, well referenced
plan to guide researchers, clinicians, industry partners,
academics, and TB controllers in all sectors in all aspects
of TB diagnostics development [42��], starting from
needs’ assessment, concept, feasibility, proof-of-concept,
to test development, validation, and, ultimately, delivery,
scale-up, access, and epidemiological and public health
impact.
As shown in Fig. 1, evidence on test accuracy is essential,
but policy development requires more than estimation of
test accuracy. Along with data on test accuracy, we need
to consider user-important as well as patient-important
outcomes. Patient-important outcomes require more
sophisticated and often more resource-intensive research
[43,44], wherein a study shows that implementing a
diagnostic test in a given situation results in clinically
relevant improvements in patient care and/or patient
outcomes. For TB diagnostics, this might mean an
opyright © Lippincott Williams & Wilkins. Unautho
Figure 1 Level of evidence required for policy process
Adapted from [42��].
increased number of patients detected and receiving
appropriate treatment, fewer patients defaulting from
the diagnostic pathway due to reduced number of patient
visits, or more patients cured due to accurate detection of
drug resistance. Studies may also investigate the values
and preferences patients have when choosing one diag-
nostic test compared to another. Although the challenges
and costs of demonstrating these types of outcomes
make them unattractive for many researchers and fund-
ing agencies, it is no less important than proving a
therapeutic intervention actually changes the course of
a disease and not just the level of a biomarker or surrogate
endpoint.
User-important outcomes consist of practical concerns for
the usability of a test in real-world situations. Although
these generally do not require fundamentally different
strategies to evaluate, it is important that they are
assessed under implementation or real-world settings.
These include the ease of use of a technology, the
hands-on time of performing the test, the expertise or
training required, and the infrastructure needed. It is
important to consider biosafety, robustness of any equip-
ment involved, as well as pragmatic issues such as the
shelf-life of reagents, the need for special shipping or
storage of materials, the availability and reliability of
supply chains, and of course cost.
These types of evidence must be taken into account,
along with test accuracy and reliability, when policy
makers or programs are evaluating a diagnostic for recom-
mendation or widespread use. Systematic reviews of
diagnostics should make an effort to summarize data
on these outcomes in addition to accuracy, appraise
the quality of available evidence, and explore the uncer-
tainty regarding the often assumed values and prefer-
ences of patients associated with these tests. However,
rized reproduction of this article is prohibited.
C
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
New and improved tuberculosis diagnostics Pai et al. 5
an obstacle here is a lack of methodology for collecting
and analyzing such evidence even if the data were
reported in primary research. In other words, currently
used systematic review methods are mainly aimed at test
accuracy.
Where is the current diagnostics pipelinedeficient?Although there are many more TB diagnostics in the
pipeline today than in the past, the existing TB diag-
nostics pipeline itself has limitations and neglects some
important aspects of the TB epidemic. Table 2 sum-
marizes the major research priorities for TB diagnostics.
The biggest concern continues to be the lack of a rapid,
simple, inexpensive, point-of-care (POC) test for active
TB. As yet nothing has emerged from the pipeline or
looks likely to emerge from the pipeline in the near
future that could supplant smear microscopy. An easy-
to-use, inexpensive diagnostic that can perform as well or
better than smear microscopy and can deliver results
within minutes without sophisticated equipment or
highly-trained laboratory personnel would be a major
step forward in TB diagnostics and could have a tremen-
dous impact on global TB control [45,46�].
Another area still lacking in adequate diagnostic options
is smear-negative TB, especially in HIV-infected persons
[47]. Undiagnosed TB is very common in persons
infected with HIV; therefore, intensive active case find-
ing is required as strategies that rely on passive detection,
or screening with smear microscopy alone, will miss a
large number of coinfected patients [47]. Considering the
proven benefit of TB preventive therapy using isoniazid
in HIV-infected persons, ruling out active TB before
initiation of single drug treatment is important not only
for the care of the individual patient, but also to prevent
the inadvertent selection for drug resistance. The devel-
opment and validation of an algorithm, taking advantage
of newly available tests, to aggressively target this high-
risk population remains a priority for TB control.
Childhood TB presents similar challenges [48]. By virtue
of the pathophysiology of TB in pediatrics and the
inability to obtain adequate sputum samples, microbio-
logic confirmation of active TB remains an insensitive
and inadequate standard. Similar to patients with HIV
and smear-negative TB, the development and improve-
ment in diagnostic algorithms that take advantage of
available new diagnostics is needed. As good quality
sputum specimens are difficult to collect, novel diag-
nostics that can be used on urine, saliva, breath con-
densate, and so on could have a greater impact in
these populations, especially if a POC format could be
developed.
opyright © Lippincott Williams & Wilkins. Unauth
The control of drug-resistant TB requires accurate and
rapid diagnostics for the detection of critical patterns of
drug resistance. The need to identify cases of multidrug-
resistant TB (MDR-TB) through detecting resistance to
rifampicin and isoniazid is now well recognized. The next
step is to accurately and rapidly identify cases of exten-
sively drug-resistant TB (XDR-TB) through the detec-
tion of resistance to key second-line drugs.
Although new tests [such as interferon-gamma release
assays (IGRAs)] have emerged for LTBI diagnosis, these
tests cannot resolve the various phases of the latent TB
spectrum [49,50]. This means existing tests cannot be
used to target preventive therapy at the subgroup that is
most likely to benefit from treatment. Thus, there is a
need for a highly predictive biomarker or combination of
biomarkers, which will allow accurate prediction of the
subgroup of latently infected individuals who are at
highest risk of progression to disease.
How is evidence translated into policy?The WHO has taken the lead on developing policies and
guidelines on TB diagnostics. The WHO policy process
is summarized in a recent statement entitled ‘Moving
research findings into new WHO policies [51�].’ The key
steps in the WHO policy process are given in Table 3
[51�]. This process takes into account the importance of
not only identifying areas in need of policy guidance, but
also ensuring that policies are evidence-based and then
followed up with dissemination and promotion of new
recommendations. For step 2, reviewing the evidence,
WHO may commission a systematic review and meta-
analysis of available data (published and unpublished)
using standard methods appropriate for diagnostic accu-
racy studies [52�].
Table 4 provides an overview of all the recent WHO
policies on TB diagnostics [51�,53–57]. Since 2007,
the WHO has endorsed several diagnostic tests and
strategies, including liquid cultures, optimized smear
microscopy, line probe assays, and noncommercial
culture systems for drug-susceptibility testing.
The foundation of the WHO policy process is now the
Grading of Recommendations Assessment, Develop-
ment, and Evaluation (GRADE) approach [58��]. This
is in part a response to the criticism that systematic
reviews are rarely used for developing WHO recommen-
dations and that WHO policy processes usually rely
heavily on expert opinion [59]. The GRADE approach
provides a system for rating the quality of evidence
and the strength of recommendations that is explicit,
comprehensive, transparent, and pragmatic and is
being adopted increasingly by organizations worldwide
[58��,60]. The WHO now requires the use of GRADE for
orized reproduction of this article is prohibited.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
6 Infectious diseases
Ta
ble
2M
ajo
rp
rio
riti
es
for
rese
arc
ha
nd
de
ve
lop
me
nt
an
dim
ple
me
nta
tio
no
ftu
be
rcu
losis
dia
gn
osti
cs
Res
earc
hp
riorit
yR
esea
rch
met
hod
sE
xpec
ted
out
com
eJu
stifi
catio
n
Dev
elo
pm
ent
of
ara
pid
,ac
cura
tep
oin
t-o
f-ca
re(P
OC
)te
stfo
rp
ulm
ona
ryT
B.
Bio
mar
ker
dis
cove
ry,
follo
wed
by
inco
rpo
ratio
nin
ahi
ghl
yse
nsiti
veP
OC
pla
tfo
rman
dth
encl
inic
alva
lidat
ion.
AP
OC
test
for
pul
mo
nary
TB
that
will
mee
tth
eus
er-d
efine
dsp
ecifi
catio
ns(s
uch
asth
ose
pro
po
sed
by
MS
F).
Cur
rent
ly,
ther
eis
noP
OC
test
for
TB
that
can
be
used
atth
ehe
alth
clin
icle
vel.
Dia
gno
stic
del
ays,
ther
efo
re,
are
com
mo
n.D
evel
op
men
tan
dva
lidat
ion
of
tools
for
rap
idd
etec
tion
of
dru
gre
sist
ance
,in
clud
ing
for
XD
R-T
Ban
dst
and
ard
izat
ion
of
DS
Tfo
rse
cond
-line
dru
gs.
Iden
tifica
tion
and
char
acte
rizat
ion
of
mut
atio
nsas
soci
ated
with
seco
nd-li
ned
rug
resi
stan
ce;
dev
elo
pm
ent
of
new
erg
ener
atio
nm
ole
cula
ras
says
for
MD
R/X
DR
-TB
;im
pro
ved
stan
dar
diz
atio
no
fex
istin
gte
sts
for
seco
nd-li
neD
ST
.
Rap
idm
ole
cula
r(g
eno
typ
ic)
assa
ysfo
rM
DR
/XD
R-T
Bth
atw
illal
low
rap
idid
entifi
catio
no
fd
rug
-res
ista
ntT
B.
Alth
oug
hlin
e-p
rob
eas
says
are
hig
hly
accu
rate
for
rifam
pic
inre
sist
ance
,ac
cura
cyis
low
erfo
ris
oni
azid
and
oth
erd
rug
s.S
eco
nd-li
neD
ST
cont
inue
sto
be
ach
alle
nge;
mut
atio
nsar
eno
tw
elld
efine
dan
dst
and
ard
izat
ion
isa
pro
ble
mw
ithp
heno
typ
icm
etho
ds.
Inte
nsifi
ed,
activ
eca
sed
etec
tion
stra
teg
ies
for
early
det
ectio
no
fac
tive
TB
inH
IV-in
fect
edp
erso
ns(a
tth
ecl
inic
leve
lan
din
the
com
mun
ity).
Dev
elo
pm
ent
and
valid
atio
no
fan
alg
orit
hm(in
clud
ing
new
test
s)fo
rra
pid
det
ectio
no
fT
Bin
HIV
-infe
cted
per
sons
.
Ava
lidat
edal
go
rithm
that
will
enab
led
etec
tion
of
TB
ina
larg
ep
rop
ort
ion
of
HIV
-infe
cted
per
sons
with
TB
dis
ease
.
Pas
sive
case
det
ectio
nm
etho
ds
do
not
wo
rkw
ellin
area
sw
ithhi
gh
HIV
pre
vale
nce;
und
iag
nose
dT
Bis
freq
uent
inH
IV-in
fect
edp
erso
nsan
dca
nca
use
eno
rmo
usm
orb
idity
and
mo
rtal
ity.
Ag
gre
ssiv
eca
sed
etec
tion
app
roac
hes
are
need
edto
enha
nce
case
det
ectio
n,re
duc
em
ort
ality
,an
dre
duc
etr
ansm
issi
on.
Imp
rovi
ngcu
rren
td
iag
nost
ical
gorit
hms
tosh
ort
enth
etim
ere
qui
red
for
esta
blis
hing
ad
iag
nosi
so
fsm
ear-
neg
ativ
ep
ulm
ona
ryT
Ban
dex
trap
ulm
ona
ryT
Bin
HIV
-infe
cted
per
sons
and
child
ren.
Dev
elo
pm
ent
and
valid
atio
no
fan
alg
orit
hm(in
clud
ing
new
test
s)fo
rra
pid
det
ectio
no
fsm
ear-
neg
ativ
ean
dex
trap
ulm
ona
ryT
Bin
HIV
-infe
cted
per
sons
and
child
ren.
Ava
lidat
edal
go
rithm
that
will
rap
idly
enab
led
etec
tion
of
smea
r-ne
gat
ive
and
extr
apul
mo
nary
TB
ina
larg
ep
rop
ort
ion
of
HIV
-infe
cted
per
sons
and
child
ren.
Sm
ear-
neg
ativ
eT
B,
extr
apul
mona
ryT
B,
and
child
hoo
dT
Bar
ed
iag
nost
icch
alle
nges
and
avai
lab
lete
sts
per
form
poo
rlyin
thes
eca
ses
of
pau
cib
acill
ary
TB
.N
ewer
alg
orit
hms
and
test
sar
ene
eded
tog
etar
oun
dth
elim
itatio
nso
fcu
rren
tm
etho
ds.
Dev
elo
pm
ent
of
ate
sto
ral
go
rithm
that
can
accu
rate
lyru
leo
utac
tive
TB
dis
ease
inH
IV-in
fect
edp
erso
ns[t
oal
low
initi
atio
no
fp
reve
ntiv
eth
erap
y(I
PT
)]
Dev
elo
pm
ent
and
valid
atio
no
fan
alg
orit
hm(in
clud
ing
new
test
s)fo
rra
pid
lyru
ling
out
activ
eT
B(in
clud
ing
smea
r-ne
gat
ive
and
extr
apul
mo
nary
TB
)in
HIV
-infe
cted
per
sons
.
Ava
lidat
edal
go
rithm
that
will
enab
leex
clus
ion
of
TB
ina
larg
ep
rop
ort
ion
of
HIV
-infe
cted
per
sons
prio
rto
IPT
.
InH
IV-in
fect
edp
erso
ns,
und
iag
nose
dac
tive
TB
isco
mm
on.
Bef
ore
IPT
,it
isne
cess
ary
toru
leo
utac
tive
TB
.H
ow
ever
,th
ere
isno
easy
and
accu
rate
met
hod
tod
oth
isin
hig
h-b
urd
enco
untr
ies.
Whi
chb
iom
arke
rso
rco
mb
inat
ions
of
mar
kers
will
help
dis
ting
uish
the
vario
usst
ages
of
the
spec
trum
of
late
ntT
Bin
fect
ion
(fro
mst
erili
zing
imm
unity
tosu
bcl
inic
alac
tive
dis
ease
)an
dw
illal
low
accu
rate
pre
dic
tion
of
the
sub
gro
upo
fla
tent
lyin
fect
edin
div
idua
lsw
hoar
eat
hig
hest
risk
of
pro
gre
ssio
nto
dis
ease
.
Bio
mar
ker
dis
cove
ry,
follo
wed
by
valid
atio
nin
clin
ical
and
long
itud
inal
(co
hort
)st
udie
sfo
rm
arke
rsth
atca
np
red
ict
risk
of
pro
gre
ssio
nto
activ
eT
B.
Iden
tifica
tion
of
ab
iom
arke
ro
rco
mb
inat
ion
of
bio
mar
kers
that
will
allo
wac
cura
tep
red
ictio
no
fth
esu
bg
roup
of
late
ntly
infe
cted
ind
ivid
uals
who
are
athi
ghe
stris
ko
fp
rog
ress
ion
tod
isea
se.
Exi
stin
gte
sts
for
late
ntT
B(T
ST
and
IGR
As)
cann
ot
reso
lve
the
vario
usp
hase
so
fth
ela
tent
TB
spec
trum
.T
his
mea
nsex
istin
gte
sts
cann
ot
be
used
tota
rget
IPT
atth
esu
bg
roup
that
ism
ost
likel
yto
ben
efit
fro
mtr
eatm
ent.
Thi
sre
sults
ino
vert
reat
men
to
fa
larg
enu
mb
ero
fla
tent
lyin
fect
edp
erso
ns.
Dev
elo
pm
ent
of
ara
pid
test
for
child
hoo
dT
Bth
atw
illno
td
epen
do
nsp
utum
spec
imen
test
ing
.D
evel
op
men
tan
dva
lidat
ion
of
ate
sto
ran
alg
orit
hm(in
clud
ing
new
test
s)fo
rra
pid
det
ectio
no
fT
Bin
child
ren,
with
out
req
uirin
gsp
utum
spec
imen
s.
Ate
st(p
refe
rab
lyP
OC
)th
atca
nus
eno
nsp
utum
spec
imen
s(e
.g.
urin
eo
rb
reat
hco
nden
sate
or
saliv
a)fo
rra
pid
det
ectio
no
fT
Bin
child
ren.
Chi
ldho
od
TB
isa
dia
gno
stic
chal
leng
ean
dav
aila
ble
test
sp
erfo
rmp
oo
rlyin
thes
eca
ses
of
pau
cib
acill
ary
TB
.A
lso
,as
youn
gch
ildre
nar
eun
able
top
rod
uce
sput
um,
itw
illb
ehe
lpfu
lto
use
alte
rnat
ive
spec
imen
ssu
chas
urin
e,sa
liva,
or
bre
ath
cond
ensa
te.
Defi
ned
iffer
ent
way
so
fo
per
atio
naliz
ing
and
imp
lem
entin
gex
istin
gp
olic
ies
on
HIV
test
ing
of
TB
pat
ient
san
dT
Bsc
reen
ing
of
HIV
-infe
cted
per
sons
.
Op
erat
iona
lre
sear
cho
nd
iffer
ent
way
so
fim
ple
men
ting
exis
ting
po
licie
so
nH
IVte
stin
go
fT
Bp
atie
nts
and
TB
scre
enin
go
fH
IV-in
fect
edp
erso
ns.
Iden
tifica
tion
of
atle
ast
one
feas
ible
app
roac
hth
atm
ight
wo
rkb
est
and
ther
efo
reca
nb
esc
aled
-up
.
Exi
stin
gp
olic
ies
on
HIV
test
ing
of
TB
pat
ient
san
dT
Bsc
reen
ing
of
HIV
-infe
cted
per
sons
are
poo
rlyim
ple
men
ted
.A
larg
ep
rop
ort
ion
of
TB
pat
ient
sar
eno
tte
sted
for
HIV
,an
dH
IV-in
fect
edp
erso
nsar
eno
tsc
reen
edfo
rT
B.
Thi
sre
sults
inun
dia
gno
sed
co-in
fect
ion
mo
rbid
ity/m
ort
ality
and
cont
inue
dtr
ansm
issi
on
inth
eco
mm
unity
.O
nce
new
dia
gno
stic
sar
eap
pro
ved
and
avai
lab
le,
wha
tfa
cto
rsca
nen
hanc
eth
eir
actu
ald
eliv
ery
and
imp
lem
enta
tion
atth
ep
rog
ram
mat
icle
velin
hig
h-b
urd
enco
untr
ies?
Op
erat
iona
lre
sear
cho
nd
iffer
ent
way
so
fim
ple
men
ting
new
dia
gno
stic
sin
natio
nal
TB
pro
gra
ms
inhi
gh-
bur
den
sett
ing
s.
Iden
tifica
tion
of
atle
ast
one
feas
ible
imp
lem
enta
tion
app
roac
hth
atm
ight
wo
rkb
est
and
ther
efo
reca
nb
esc
aled
-up
.
Ava
ilab
ility
of
new
tools
do
esno
tne
cess
arily
ensu
reth
eir
adop
tion
and
imp
lem
enta
tion.
Tra
nsla
tion
of
po
licy
into
pra
ctic
ere
qui
res
bet
ter
und
erst
and
ing
of
bar
riers
toim
ple
men
tatio
nan
dm
etho
ds
too
verc
om
esu
chb
arrie
rs.
Wha
tis
the
likel
yep
idem
iolo
gic
alim
pac
to
fw
ides
pre
adLT
BI
dia
gno
sis
and
trea
tmen
tin
hig
h-b
urd
enco
untr
ies,
and
wha
tco
ntrib
utio
nw
illLT
BI
dia
gno
sis
and
trea
tmen
tm
ake
tow
ard
the
atta
inm
ent
of
the
Sto
pT
BP
artn
ersh
ip’s
targ
etfo
rT
Bel
imin
atio
n?
Mat
hem
atic
alm
od
elin
gst
udy.
The
mo
del
ing
stud
yw
illin
form
the
deb
ate
on
whe
nhi
gh-
bur
den
coun
trie
ssh
oul
db
egin
tofo
cus
atte
ntio
no
nLT
BI
dia
gno
sis
and
trea
tmen
t.
LTB
Id
iag
nosi
san
dtr
eatm
ent
iscu
rren
tlyno
ta
prio
rity
inhi
gh-
bur
den
coun
trie
s.H
ow
ever
,as
TB
inci
den
cefa
lls,
itca
nb
eco
me
ap
riorit
y.A
lso
,so
me
rece
ntm
od
elin
gst
udie
ssu
gg
est
that
TB
elim
inat
ion
will
req
uire
stra
teg
ies
aim
edat
LTB
Im
anag
emen
t.
DS
T,
dru
gsu
scep
tibili
tyte
stin
g;
LTB
I,la
tent
tub
ercu
losi
sin
fect
ion;
MD
R,
mul
tidru
g-r
esis
tant
;M
SF
,M
edec
ins
San
sF
ront
iere
s;X
DR
,ex
tens
ivel
yd
rug
-res
ista
nt.
Copyright © Lippincott Williams & Wilkins. Unauth
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
New and improved tuberculosis diagnostics Pai et al. 7
Ta
ble
3W
orl
dH
ea
lth
Org
an
iza
tio
np
oli
cy
pro
ce
ss
for
tub
erc
ulo
sis
Maj
or
step
sD
escr
iptio
no
fth
ep
roce
ss
Iden
tifyi
ngth
ene
edfo
ra
polic
ych
ang
eT
hene
edto
form
ulat
ene
wo
rre
vise
dp
olic
ies
may
aris
efr
om
WH
O’s
ong
oin
gm
oni
torin
go
fte
chni
cal
dev
elo
pm
ents
or
fro
min
tere
sted
par
ties
sub
mitt
ing
req
uest
san
dsu
pp
ort
ing
do
cum
enta
tion
for
po
licy
or
gui
del
ine
dev
elo
pm
ent.
WH
Ore
ceiv
esin
form
atio
nab
out
ane
wte
chno
log
yo
rap
pro
ach
via
man
ych
anne
ls,
with
the
mo
std
irect
lines
com
ing
fro
mna
tiona
lT
Bp
rog
ram
san
dre
sear
cher
sth
emse
lves
.T
oco
nsid
era
glo
bal
polic
ych
ang
e,W
HO
mus
tha
veso
lidev
iden
ce,
incl
udin
gcl
inic
altr
ials
or
field
eval
uatio
nsin
hig
h-T
Bp
reva
lenc
ese
ttin
gs.
Rev
iew
ing
the
evid
ence
(incl
udin
gsy
stem
atic
revi
ews)
WH
Om
ayca
rry
out
or
com
mis
sion
are
view
of
the
do
cum
enta
tion
of
tech
nolo
gy’
scl
inic
alo
rp
rog
ram
mat
icp
erfo
rman
ce,
incl
udin
gne
wly
pub
lishe
dan
d‘g
rey’
rese
arch
or
revi
ews,
‘pro
of-
of-
prin
cip
le’
rep
ort
s,la
rge-
scal
efie
ldtr
ials
,an
dd
emo
nstr
atio
np
roje
cts
ind
iffer
ent
reso
urce
sett
ing
s.S
tand
ard
ized
eval
uatio
ncr
iteria
have
bee
nan
dar
eb
eing
dev
elo
ped
by
the
New
Dia
gno
stic
s,N
ewD
rug
s,an
dN
ewV
acci
nes
Wo
rkin
gG
roup
so
fth
eS
top
TB
Par
tner
ship
.C
onv
enin
gan
exp
ert
pan
elIf
the
evid
ence
bas
eis
com
pel
ling
,W
HO
will
conv
ene
anex
tern
alp
anel
of
exp
erts
,ex
clud
ing
all
orig
inal
prin
cip
alin
vest
igat
ors
fro
mth
est
udie
s.T
hep
anel
will
revi
ewth
eev
iden
ce(u
sing
the
GR
AD
Eap
pro
ach)
and
mak
ea
reco
mm
end
atio
no
rp
rop
ose
dra
ftp
olic
ies
or
gui
del
ines
toW
HO
’sS
trat
egic
and
Tec
hnic
alA
dvi
sory
Gro
upfo
rT
uber
culo
sis
(ST
AG
-TB
).A
sses
sing
dra
ftp
olic
ies
and
gui
del
ines
ST
AG
-TB
pro
vid
eso
bje
ctiv
e,o
ngo
ing
tech
nica
l,an
dst
rate
gic
advi
ceto
WH
Ore
late
dto
TB
care
and
cont
rol.
STA
G-T
B’s
ob
ject
ives
are
top
rovi
de
the
Dire
cto
r-G
ener
al,
thro
ugh
the
Sto
pT
BD
epar
tmen
t,an
ind
epen
den
tev
alua
tion
of
the
stra
teg
ic,
scie
ntifi
c,an
dte
chni
cal
asp
ects
of
WH
O’s
TB
activ
ities
,re
view
pro
gre
ssan
dch
alle
nges
inW
HO
’sT
B-r
elat
edco
refu
nctio
ns,
revi
ewan
dm
ake
reco
mm
end
atio
nso
nco
mm
ittee
san
dw
ork
ing
gro
ups,
and
mak
ere
com
men
dat
ions
on
WH
O’s
TB
activ
ityp
riorit
ies.
STA
G-T
Bre
view
sth
ep
olic
yd
raft
san
dsu
pp
ort
ing
do
cum
enta
tion
dur
ing
itsan
nual
mee
ting
.S
TA
G-T
Bm
ayen
dors
eth
ep
olic
yre
com
men
dat
ion
with
or
with
out
revi
sio
ns,
req
uest
add
itio
nalin
form
atio
nan
dre
-rev
iew
the
evid
ence
insu
bse
que
ntye
ars,
or
reje
ctth
ere
com
men
dat
ion.
Fo
rmul
atin
gan
dd
isse
min
atin
gp
olic
yN
ewW
HO
po
licie
san
dg
uid
elin
esw
illb
ed
isse
min
ated
thro
ugh
diff
eren
tch
anne
lsto
Mem
ber
Sta
tes,
incl
udin
gth
roug
hth
eW
orld
Hea
lthA
ssem
bly
,W
HO
web
site
,lis
tse
rves
,an
djo
urna
lp
ublic
atio
ns.
WH
Oal
sod
isse
min
ates
itsre
com
men
dat
ions
too
ther
agen
cies
and
dono
rsen
gag
edin
TB
cont
rol
activ
ities
.
GR
AD
E,
Gra
din
go
fR
eco
mm
end
atio
nsA
sses
smen
t,D
evel
op
men
tan
dE
valu
atio
n;T
B,
tub
ercu
losi
s.W
orld
Hea
lthO
rgan
izat
ion:
mo
ving
rese
arch
find
ing
sin
tone
wW
HO
po
licie
s[5
1� ]
.
all new and revised WHO policies and guidelines, includ-
ing policies on diagnostics [61]. For example, recent
WHO policies on TB infection control [62] and the
revised TB treatment guidelines [63] used the GRADE
approach.
Grading of Recommendations Assessment,Development, and Evaluation for diagnostictests: strengths and limitationsThe GRADE approach provides a clear separation of
quality of evidence and strength of recommendations
[58��]. In judgments about quality of evidence, GRADE
considers six factors: study design, methodological qua-
lity, directness of evidence (patient-important outcomes
and generalizability), inconsistency of results, impreci-
sion of results (imprecise or sparse data), and publication
bias [58��]. Thus, quality of evidence reflects our confi-
dence that estimates of benefits and downsides from a
diagnostic test or strategy generated from research are
correct. Quality of evidence is graded as follows:
(1) H
ori
igh quality: further research is very unlikely to
change our confidence in the estimate of effect.
(2) M
oderate quality: further research is likely to have animportant impact on our confidence in the estimate of
effect and may change the estimate.
(3) L
ow quality: further research is very likely to have animportant impact on our confidence in the estimate of
effect and is likely to change the estimate.
(4) V
ery low quality: any estimate of effect is veryuncertain.
In the GRADE approach, well designed studies of diag-
nostic accuracy (cross-sectional or cohort studies on
patients with diagnostic uncertainty and use of appro-
priate reference standard) can provide high-quality evi-
dence on test accuracy. However, these studies may
provide only low-quality evidence for guideline devel-
opment because of uncertainty about the link between
test accuracy and outcomes important to patients (dis-
cussed below).
The strength of a recommendation refers to the extent to
which one can be confident that adherence to the recom-
mendation will do more good than harm [58��]. There are
four factors to consider: balance between desirable and
undesirable effects; quality of evidence; values and pre-
ferences; and costs (resource allocation). GRADE classi-
fies recommendations as strong (most informed patients
would choose this option) or weak (patients’ choices will
vary according to their values and preferences and not all
patients would choose this option).
The GRADE process was initially developed for treat-
ment interventions and, therefore, tends to be focused on
zed reproduction of this article is prohibited.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
8 Infectious diseases
Ta
ble
4H
igh
lig
hts
of
rece
nt
WH
Op
oli
cie
sa
nd
sta
tem
en
tso
ntu
be
rcu
losis
dia
gn
osti
cs
Yea
rp
olic
yw
asm
ade
Pur
po
seo
fte
stin
gD
iag
nost
icte
sto
rap
pro
ach
WH
Ore
com
men
dat
ions
20
07
Cas
ed
etec
tion
and
dru
g-s
usce
ptib
ility
test
ing
(DS
T)
Liq
uid
med
iafo
rcu
lture
and
DS
TW
HO
reco
mm
end
s,as
ast
ep-w
ise
app
roac
h:T
heus
eo
fliq
uid
med
ium
for
cultu
rean
dD
ST
inm
idd
le-in
com
ean
dlo
w-in
com
eco
untr
ies.
The
rap
idsp
ecie
sid
entifi
catio
nto
add
ress
the
need
sfo
rcu
lture
and
DS
T.
Tak
ing
into
cons
ider
atio
nth
atliq
uid
syst
ems
will
be
imp
lem
ente
din
ap
hase
dm
anne
r,in
teg
rate
din
toa
coun
try-
spec
ific
com
pre
hens
ive
pla
nfo
rla
bo
rato
ryca
pac
ityst
reng
then
ing
.2
00
7C
ase
det
ectio
nD
efini
tion
of
ane
wsp
utum
smea
r-p
osi
tive
TB
case
The
revi
sed
defi
nitio
no
fa
new
sput
umsm
ear-
po
sitiv
ep
ulm
ona
ryT
Bca
seis
bas
edo
nth
ep
rese
nce
of
atle
ast
one
acid
fast
bac
illi
(AF
Bþ
)in
atle
ast
one
sput
umsa
mp
lein
coun
trie
sw
itha
wel
lfu
nctio
ning
exte
rnal
qua
lity
assu
ranc
e(E
QA
)sy
stem
.2
00
7C
ase
det
ectio
nR
educ
tion
of
num
ber
of
smea
rsfo
rth
ed
iag
nosi
so
fp
ulm
ona
ryT
B
WH
Ore
com
men
ds
the
num
ber
of
spec
imen
sto
be
exam
ined
for
scre
enin
go
fT
Bca
ses
can
be
red
uced
fro
mth
ree
totw
o,
inp
lace
sw
here
aw
ellfu
nctio
ning
EQ
Asy
stem
exis
ts,
whe
reth
ew
ork
load
isve
ryhi
gh
and
hum
anre
sour
ces
are
limite
d.
20
08
DS
TM
ole
cula
rlin
ep
rob
eas
says
for
rap
idsc
reen
ing
of
pat
ient
sat
risk
of
MD
R-T
B
The
use
of
line
pro
be
assa
ysis
reco
mm
end
edb
yW
HO
,w
ithth
efo
llow
ing
gui
din
gp
rinci
ple
s:A
do
ptio
no
flin
ep
rob
eas
says
for
rap
idd
etec
tion
of
MD
R-T
Bsh
oul
db
ed
ecid
edb
yM
inis
trie
so
fH
ealth
with
inth
eco
ntex
to
fco
untr
yp
lans
for
app
rop
riate
man
agem
ent
of
MD
R-T
Bp
atie
nts,
incl
udin
gth
ed
evel
op
men
to
fco
untr
y-sp
ecifi
csc
reen
ing
alg
orit
hms
and
timel
yac
cess
toq
ualit
y-as
sure
dse
cond
-line
anti-
TB
dru
gs.
Line
pro
be
assa
yp
erfo
rman
cech
arac
teris
tics
have
bee
nad
equa
tely
valid
ated
ind
irect
test
ing
of
sput
umsm
ear-
po
sitiv
esp
ecim
ens
and
on
iso
late
so
fM
ycobac
terium
tuber
culo
sis
com
ple
xg
row
nfr
om
smea
r-ne
gat
ive
and
smea
r-p
osi
tive
spec
imen
s.D
irect
use
of
line
pro
be
assa
yso
nsm
ear-
neg
ativ
ecl
inic
alsp
ecim
ens
isno
tre
com
men
ded
.T
heus
eo
fco
mm
erci
allin
ep
rob
eas
says
,ra
ther
than
in-h
ous
eas
says
,is
reco
mm
end
edto
ensu
rere
liab
ility
and
rep
rod
ucib
ility
of
resu
lts,
asin
-ho
use
assa
ysha
veno
tb
een
adeq
uate
lyva
lidat
edo
rus
edo
utsi
de
limite
dre
sear
chse
ttin
gs.
Ad
op
tion
of
line
pro
be
assa
ysd
oes
not
elim
inat
eth
ene
edfo
rco
nven
tiona
lcu
lture
and
DS
Tca
pab
ility
;cu
lture
rem
ains
nece
ssar
yfo
rd
efini
tive
dia
gno
sis
of
TB
insm
ear-
neg
ativ
ep
atie
nts,
whe
reas
conv
entio
nalD
ST
isre
qui
red
tod
iag
nose
exte
nsiv
ely
dru
g-r
esis
tant
TB
(XD
R-T
B).
As
curr
ent
line
pro
be
assa
yso
nly
det
ect
resi
stan
ceto
rifam
pic
inan
d/o
ris
oni
azid
,co
untr
ies
with
do
cum
ente
do
rsu
spec
ted
case
so
fX
DR
-TB
shoul
des
tab
lish
or
exp
and
conv
entio
nal
cultu
rean
dD
ST
cap
acity
for
qua
lity-
assu
red
susc
eptib
ility
test
ing
of
seco
nd-li
ned
rug
s,b
ased
on
curr
ent
WH
Op
olic
yg
uid
ance
.2
00
9C
ase
det
ectio
nLE
D-b
ased
mic
rosc
op
yW
HO
reco
mm
end
sth
atco
nven
tiona
lflu
ore
scen
cem
icro
sco
py
be
rep
lace
db
yLE
Dm
icro
sco
py
inal
lse
ttin
gs
and
that
LED
mic
rosc
op
yb
ep
hase
din
asan
alte
rnat
ive
for
conv
entio
nalZ
Nm
icro
sco
py
inb
oth
hig
h-vo
lum
ean
dlo
w-v
olu
me
lab
ora
torie
s.T
hesw
itch
toLE
Dm
icro
sco
py
shoul
db
eca
rrie
do
utth
roug
ha
care
fully
pha
sed
imp
lem
enta
tion
pla
n,us
ing
LED
tech
nolo
gie
sth
atm
eet
WH
Osp
ecifi
catio
ns.
20
09
DS
TN
onc
om
mer
cial
cultu
rean
dD
ST
met
hod
sW
HO
reco
mm
end
sth
atse
lect
edno
ncom
mer
cial
cultu
rean
dD
ST
met
hod
sb
eus
edas
anin
terim
solu
tion
inre
sour
ce-c
ons
trai
ned
sett
ing
s,in
refe
renc
ela
bo
rato
ries,
or
tho
sew
ithsu
ffici
ent
cultu
reca
pac
ity,
whi
leca
pac
ityfo
rg
eno
typ
ican
d/o
rau
tom
ated
liqui
dcu
lture
and
DS
Tar
eb
eing
dev
elo
ped
.W
ithd
ueco
nsid
erat
ion
of
the
abo
veis
sues
,W
HO
end
ors
esth
ese
lect
ive
use
of
one
or
mo
reo
fth
efo
llow
ing
nonc
om
mer
cial
cultu
rean
dD
ST
met
hod
s:M
icro
sco
pic
ally
ob
serv
edd
rug
susc
eptib
ility
(MO
DS
),fo
rra
pid
scre
enin
go
fp
atie
nts
susp
ecte
do
fha
ving
MD
R-T
B,
und
ercl
early
defi
ned
pro
gra
mm
atic
and
op
erat
ion
cond
itio
ns,
and
onc
esp
ecia
tion
conc
erns
have
bee
nad
equa
tely
add
ress
edw
itho
utco
mp
rom
isin
gb
io-s
afet
y;T
heni
trat
ere
duc
tase
assa
y(N
RA
),fo
rsc
reen
ing
of
pat
ient
ssu
spec
ted
of
havi
ngM
DR
-TB
,un
der
clea
rlyd
efine
dp
rog
ram
mat
ican
do
per
atio
nco
nditi
ons
,an
dac
kno
wle
dg
ing
that
time
tod
etec
tion
of
MD
Rin
ind
irect
app
licat
ion
woul
dno
tb
efa
ster
(but
less
exp
ensi
ve)
than
conv
entio
nal
DS
Tm
etho
ds
usin
gco
mm
erci
alliq
uid
cultu
reo
rlin
ep
rob
eas
says
;C
olo
rimet
ricre
do
xin
dic
ato
r(C
RI)
met
hod
s,as
ind
irect
test
so
nM
.tu
ber
culo
sis
iso
late
sfr
om
pat
ient
ssu
spec
ted
of
havi
ngM
DR
-TB
,un
der
clea
rlyd
efine
dp
rog
ram
mat
ican
do
per
atio
nco
nditi
ons
,an
dac
know
led
gin
gth
attim
eto
det
ectio
no
fM
DR
wo
uld
not
be
fast
er(b
utle
ssex
pen
sive
)th
anco
nven
tiona
lD
ST
met
hod
sus
ing
com
mer
cial
liqui
dcu
lture
or
line
pro
be
assa
ys.
LED
,lig
ht-e
mitt
ing
dio
de;
MD
R-T
B,
mul
tidru
g-r
esis
tant
tub
ercu
losi
s.F
rom
the
Wo
rldH
ealth
Org
aniz
atio
n[5
1� ,
53
–5
6].
C
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
New and improved tuberculosis diagnostics Pai et al. 9
randomized controlled trials (RCTs). It has been adapted
for diagnostic tests and strategies [64��,65], though this
area is a work in progress and can be improved based
on user’s feedback. The first time the GRADE approach
was applied to TB diagnostics by the WHO was in
September 2009 for use in developing guidelines for
improving sputum smear microscopy and using noncom-
mercial culture methods for rapid detection of TB drug
resistance. From these experiences, we have found the
GRADE approach to have several strengths as well as
some limitations.
On the positive side, GRADE offers a systematic, objec-
tive, and transparent process and requires the explicit use
of systematic reviews and evidence summaries. GRADE
forces us to consider several elements, including quality
of evidence, cost, values and preferences, and trade-offs
between good and bad consequences. One challenge in
using GRADE is learning the process itself, as systematic
reviewers, policy makers, and TB experts are not necess-
arily trained in the GRADE approach. We expect this
challenge to be overcome as more people receive training
and use GRADE. Another challenge recognizes situ-
ations in which patient outcomes may not reflect the
accuracy or benefit of a diagnostic test/approach because
treatment is unavailable (e.g. improved microscopy in
facilities where stock-outs of anti-TB drugs occur fre-
quently). Additional limitations and challenges for diag-
nostic policies are summarized in Table 5. A recent
review by Kavanagh [66] provides an interesting pers-
pective on GRADE, especially on the issue of whether
GRADE itself is reliable and has been proven to be valid.
By the nature of the GRADE process being based on
evidence, it is intrinsically reliant on the availability and
quality of the evidence base itself. As we have discussed
above, challenges remain to ensure both the quality of
primary diagnostic evaluations and the availability of the
necessary types of data in systematic reviews. This is
brought into clear focus when using the GRADE process,
as a lack of objective studies on a topic opens the door to
the substitution of expert opinion for evidence. Although
expert experiences cannot be discounted, they may often
not be generalizable and are subject to being influenced
by personal agendas and anecdotal experiences. Experts
in TB often rate the same evidence inconsistently,
depending on their prior experience with a test, and this
can result in poor interrater agreement on GRADE
elements. For example, TB researchers who work exten-
sively in resource-poor settings are often skeptical of high-
tech tools and tend to undervalue them because of the
perceived limited applicability in developing countries.
Conflicts of interest (COI) among guideline panel mem-
bers and industry involvement in guideline processes are
other issues of concern, especially when commercial tests
opyright © Lippincott Williams & Wilkins. Unauth
and products are involved. There is some evidence that
industry involvement is fairly common with TB diagnos-
tic research, with about 40–50% of TB diagnostic studies
reporting some degree of industry involvement or sup-
port [26,39]. A recent survey of IGRA guidelines and
statements from various countries found that only a small
minority had explicit COI disclosures [67]. Some organ-
izations have recognized the need to address the issue of
COI. For example, the American Thoracic Society (ATS)
published its COI policy for guideline development in
2009 [68]. This policy now recommends procedures such
as self-declaration of COI; review of potential parti-
cipants’ COI; disclosure of COI to project participants;
refusal or excusal from certain decisions or recommen-
dations when appropriate; and disclosure of COI to users
of documents or attendees of conferences. All agencies
and bodies involved in guideline development should
follow this example.
COI, however, are not restricted to commercial products.
Diagnostic tests developers can be academics with no
industry involvement. Because of their heavy intellectual
investment in new test development and better under-
standing of the test, they tend to have strong opinions on
how policies should be formulated and this can pose
conflicts during the guideline development process.
Should test developers be included in guideline panels,
but excused from voting on recommendations? Some-
times, test developers publish systematic and narrative
reviews on their own tests (which invariably tend to be
positive) and it is unclear whether such reviews should be
included or excluded in the GRADE process. Publication
bias is an added concern, especially if industry-supported
diagnostic studies are more likely to be published when
they report positive findings. Unlike RCTs, inclusion of
unpublished diagnostic studies is difficult because of the
lack of a diagnostic trials registry.
The involvement of public–private partnerships for pro-
duct development perhaps increases the complexity.
These are often characterized by a partnership between
a nonprofit organization and a for-profit diagnostics com-
pany with confidential agreements on intellectual prop-
erty related to a co-developed diagnostic. Test devel-
opers from the nonprofit organization may have the same
intellectual investment COI as test developers in acade-
mia, but may in addition have a COI related to their
partnership with a for-profit company. These issues point
out a fundamental problem with all guidelines, a problem
that GRADE can never address – the fate of a guideline
or policy can heavily rest on the group of experts and
stakeholders included in the guideline development
committee or panel.
The application of the GRADE approach to evidence on
diagnostics is relatively new and as a result there are some
orized reproduction of this article is prohibited.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
10 Infectious diseases
Ta
ble
5C
ha
lle
ng
es
an
dli
mit
ati
on
sin
form
ula
tin
gtu
be
rcu
losis
dia
gn
osti
cp
oli
cie
s
Cha
lleng
eo
rlim
itatio
nD
escr
iptio
nan
dex
amp
les
Lim
itatio
nso
fth
eex
istin
gev
iden
ceb
ase
Maj
orit
yo
fT
Bd
iag
nost
icst
udie
sar
efo
cuse
do
nte
stac
cura
cy(s
ensi
tivity
and
spec
ifici
ty);
ther
efore
,sy
stem
atic
revi
ews
are
also
focu
sed
on
accu
racy
Tes
tac
cura
cyst
udie
sar
eo
ften
po
orly
des
igne
d,
exec
uted
,an
dre
po
rted
.Im
pac
to
fte
sts
on
pat
ient
-imp
ort
ant
out
com
esis
rare
lyav
aila
ble
.A
ccur
acy
stud
ies
are
do
wng
rad
edb
yG
RA
DE
for
‘dire
ctne
ss’
and
can
neve
rre
ceiv
ea
ratin
go
f‘h
igh-
qua
lity’
evid
ence
.E
ase
of
imp
lem
enta
tion,
reso
urce
sre
qui
red
,co
st-e
ffec
tiven
ess,
bio
safe
ty,
and
pro
gra
mm
atic
issu
esar
ecr
itica
lfo
rp
olic
y,b
utsy
stem
atic
revi
ews
may
not
pro
vid
esu
chd
ata.
Evi
den
cevs
.ex
per
to
pin
ion
Exi
stin
gev
iden
ced
oes
not
mee
tth
ene
eds
of
po
licy
mak
ers.
Out
com
esth
atex
per
tsw
ant
and
GR
AD
Ere
qui
res
are
oft
enno
tav
aila
ble
.In
such
situ
atio
ns,
exp
ert
op
inio
nte
nds
tod
om
inat
ean
dex
per
tsd
ono
tal
way
sag
ree;
exp
ert
op
inio
nsar
eo
ften
bas
edo
nth
eir
ow
nun
ique
exp
erie
nces
and
anec
do
tes,
whi
chm
ayno
tne
cess
arily
be
gen
eral
izab
leo
rva
lid.
Diffi
culti
esin
lear
ning
and
usin
gth
eG
RA
DE
syst
emS
yste
mat
icre
view
ers,
po
licy
mak
ers,
and
TB
exp
erts
are
not
nece
ssar
ilytr
aine
din
GR
AD
E.
Gra
din
gm
ayb
ed
one
inco
nsis
tent
lyac
ross
test
sb
yd
iffer
ent
syst
emat
icre
view
ers;
sam
eev
iden
ceca
nb
ein
terp
rete
dan
dra
ted
diff
eren
tly;
GR
AD
Era
ting
sm
ayb
ere
vise
dpost
hoc,
dep
end
ing
on
whi
chte
sts
the
exp
erts
wan
tto
reco
mm
end
.S
om
ete
sts
are
activ
ely
‘cha
mp
ione
d’,
whe
reas
oth
ers
are
not
and
this
can
resu
ltin
unev
end
ecis
ions
Co
nflic
tso
fin
tere
stan
din
volv
emen
to
fte
std
evel
op
ers
Par
ticip
atio
no
fte
std
evel
op
ers
and
ind
ustr
yre
pre
sent
ativ
esin
the
po
licy
pro
cess
intr
od
uces
confl
icts
of
inte
rest
.T
here
isno
cons
ensu
so
nw
heth
erte
std
evel
op
ers
and
tho
sein
vest
edin
spec
ific
tech
nolo
gie
sb
eal
low
edto
do
syst
emat
icre
view
san
dp
artic
ipat
ein
gui
del
ine
pan
elm
eetin
gs.
The
reca
nb
ete
nsio
nb
etw
een
com
mer
cial
and
nonc
om
mer
cial
test
s;ty
pe
and
qua
lity
of
evid
ence
mig
htd
iffer
for
com
mer
cial
vs.
nonc
om
mer
cial
test
s,an
dco
mm
erci
alp
rod
ucts
mig
htb
em
ore
activ
ely
cham
pio
ned
by
tho
sew
ithin
dus
try
invo
lvem
ent.
Pat
ient
-imp
ort
ant
out
com
esP
atie
nto
utco
mes
may
not
refle
ctth
eac
cura
cyo
rb
enefi
to
fa
dia
gno
stic
test
/ap
pro
ach
inse
ttin
gs
with
wea
ko
vera
llhe
alth
infr
astr
uctu
re(e
.g.
rap
ido
rim
pro
ved
mic
rosc
op
yin
faci
litie
sw
here
sto
ck-o
uts
of
anti-
TB
dru
gs
occ
urfr
eque
ntly
).T
hep
oss
ible
tens
ion
(fo
rT
Bd
iag
nosi
san
dco
ntro
l)b
etw
een
the
imp
ort
ance
of
ind
ivid
ualp
atie
nto
utco
mes
and
pub
liche
alth
out
com
es(e
.g.
the
notio
nth
atfa
lse-
neg
ativ
esp
utum
smea
rre
sults
may
po
sea
gre
ater
pub
liche
alth
risk
than
fals
e-p
osi
tive
resu
lts).
Fo
rte
sts
used
atth
ece
ntra
l/re
fere
nce
lab
ora
tory
leve
l,p
atie
nt-o
utco
me
dat
am
ayno
tb
ea
go
od
ind
exo
fa
test
’sim
pac
t;th
ete
st’s
imp
act
isco
nfo
und
edb
yse
vera
lo
ther
fact
ors
such
assp
ecim
entr
ansp
ort
,tim
eto
get
resu
ltsb
ack
toth
ecl
inic
ians
,w
eak
heal
thca
resy
stem
s,et
c.Im
pac
to
np
atie
nto
utco
mes
isaf
fect
edno
tju
stb
yth
ete
st,
but
the
who
lep
acka
ge,
incl
udin
gtr
eatm
ent,
heal
thca
resy
stem
effic
ienc
y,et
c.It
can
be
diffi
cult
tose
par
ate
out
the
test
’sim
pac
t,an
dha
rd/e
xpen
sive
tost
udy
the
who
lep
acka
ge
or
stra
teg
y(w
hich
can
be
time-
cons
umin
gan
dex
pen
sive
).D
iag
nost
icR
CT
sar
era
rely
avai
lab
lean
dve
ryha
rdto
do
(eth
ics,
cost
,et
c.)
Inad
diti
on
top
atie
ntva
lues
and
pre
fere
nces
,ne
edto
ackn
ow
led
ge
pre
fere
nces
and
valu
eso
fla
bo
rato
ryte
chno
log
ists
and
test
user
s.If
RC
Ts
and
pat
ient
-imp
ort
ant
out
com
esar
ere
qui
red
for
nonc
om
mer
cial
test
s,th
isw
illb
ese
vere
lylim
ited
by
acce
ssto
fund
sre
qui
red
top
erfo
rmth
ese
larg
e-sc
ale
eval
uatio
ns.
Sys
tem
atic
revi
ewm
etho
ds
No
stan
dar
diz
edm
etho
do
log
yto
sear
chfo
ran
do
bje
ctiv
ely
synt
hesi
zeev
iden
ceo
no
per
atio
nal
imp
lem
enta
tion
issu
es,
cost
sto
heal
thse
rvic
es,
cost
sto
pat
ient
s,an
dp
atie
ntp
ersp
ectiv
eso
nne
wd
iag
nost
icte
sts
and
app
roac
hes.
Nar
rativ
eev
iden
ceo
nth
eab
ove
issu
esm
ayb
eex
clud
edfr
om
sear
chst
rate
gie
sd
urin
gsy
stem
atic
revi
ews
of
stud
ies
on
dia
gno
stic
accu
racy
.R
esul
tsfr
om
qua
litat
ive
and
soci
o-e
cono
mic
stud
ies
may
not
have
bee
nca
ptu
red
inth
esy
stem
atic
revi
ews
on
dia
gno
stic
accu
racy
of
the
diff
eren
tap
pro
ache
s.S
yste
mat
icre
view
sca
nm
ake
anef
fort
tolo
ok
for,
incl
ude,
and
des
crib
eo
utco
mes
oth
erth
anse
nsiti
vity
and
spec
ifici
ty,
but
oft
end
ono
tb
ecau
seth
eych
oo
seto
focu
sin
stea
do
nea
sily
met
a-an
alyz
able
out
com
es.
Po
licy
mak
ers
sho
uld
have
ath
oro
ugh
und
erst
and
ing
of
allth
eim
po
rtan
to
utco
mes
(incl
udin
go
utco
mes
that
are
imp
ort
ant
top
atie
nts)
they
hop
eto
incl
ude
inth
eir
po
licy
del
iber
atio
nsb
efo
reco
mm
issi
oni
ngsy
stem
atic
revi
ews.
By
exp
licitl
yo
utlin
ing
the
test
char
acte
ristic
sth
atw
illin
fluen
ceth
eir
dec
isio
nsin
adva
nce,
gui
del
ine
pan
els
can
ensu
reev
iden
ceis
asco
mp
lete
and
ob
ject
ive
asp
oss
ible
.T
his
app
roac
hw
illm
inim
ize
evid
ence
gap
s,m
akin
gth
ep
roce
ssle
sssu
scep
tible
toex
per
to
pin
ion.
Wei
ght
ing
the
imp
ort
ance
of
test
char
acte
ristic
sin
adva
nce
can
also
help
toav
oid
red
efini
ngan
dre
inte
rpre
ting
evid
ence
post
hoc
tosu
itin
div
idua
ld
esire
sto
reco
mm
end
or
not
reco
mm
end
.
GR
AD
E,
Gra
din
go
fR
eco
mm
end
atio
nsA
sses
smen
t,D
evel
op
men
tan
dE
valu
atio
n;R
CT
,ra
ndo
miz
edco
ntro
lled
tria
l;T
B,
tub
ercu
losi
s.
C
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
New and improved tuberculosis diagnostics Pai et al. 11
difficulties specific to diagnostics, which may be alle-
viated in time. For example, forcing diagnostic evidence
into the RCT framework can be nonintuitive to labora-
tory researchers who typically conduct diagnostic evalu-
ations. Certainly, the lack of experience using GRADE
on the part of systematic reviewers and policy makers
currently can lead to inconsistent interpretation of criteria
and the revision of ratings posthoc in order to create
GRADE profiles consistent with predetermined opinions
regarding diagnostics that should be recommended. The
transition from traditional policy making, which was
made primarily based on expert opinion, to the use of
more standardized, objective methods is likely to be
a struggle for all organizations whether it is clearly
acknowledged and dealt with or not.
The absence of diagnostic RCTs and data regarding
patient-important outcomes and preferences in the field
of TB diagnostics is a major hindrance to their assess-
ments using GRADE, which currently places much
weight on these aspects of patient care. As noted above,
studies providing estimates of accuracy alone are down-
graded for their lack of ‘direct’ evidence and thus cannot
achieve a rating of ‘high-quality’ evidence. Although it
can be agreed that higher levels of evidence need to be
encouraged when assessing diagnostics, there are many
practical barriers to extrapolating between the use of a
diagnostic and the clinical outcomes of patients. Any
number of deficiencies in the health system can impact
a patient outcome, some of which may prevent the full
recognition of benefits clearly provided by a diagnostic.
At the same time, many user-important outcomes (as
described above), which are of great importance to the
feasibility of implementing diagnostics, are not easily
captured in the GRADE process.
Diagnostic RCTs are almost nonexistent in TB. Even if
they were feasible, there are concerns about their design,
interpretation, and ethics [69]. Diagnostic RCTs do not
just evaluate a test; they evaluate a strategy or package
that includes testing followed by some intervention as
a follow-up to the test result [44]. In this context, it is
not easy to disentangle the efficacy of the test from
the efficacy of the follow-up treatment or intervention.
Furthermore, it is not easy to capture patient-important
outcomes when ethical considerations prevent clinical
decision-making on the basis of a trial product. Evidence
from RCTs in highly controlled trial settings may not
reflect the real-world conditions in which diagnostics
have to be ultimately deployed. Lastly, diagnostic RCTs
can take much longer than conventional diagnostic accu-
racy studies and this can delay the introduction of new
policies.
The lack of stringent regulation and licensing of diag-
nostics certainly contributes to the lack of standardized,
opyright © Lippincott Williams & Wilkins. Unauth
high-quality evidence available for the use of decision
and policy makers. Additionally, this leads to the need for
diagnostic policy processes to not only assess ‘added
benefit’ of one test over another, but often to make
the first objective assessment of a test’s performance.
The imposition of well defined, high standards at the
stage of regulatory approval would help guide devel-
opers and researchers in their assessments of new
diagnostics and provide impetus for the publication of
appropriate and needed evidence. Compared to the
therapeutics arena wherein strict regulation is imposed
before a product is licensed for use, diagnostics require
very limited data before they can be used to make patient
care decisions. For example, despite a large body of
evidence showing poor accuracy of commercial serologi-
cal, antibody detection tests for TB, several commercial
serological tests are on the market and used frequently
in developing countries with weak regulatory systems
[16,17,70,71]. Poorly performing diagnostics continue to
remain on the market despite poor performance in the
published literature and there are no mechanisms to
‘withdraw’ or ‘ban’ a bad diagnostic.
It needs to be recognized that by the nature of systematic
reviews (upon which the GRADE process is reliant), the
questions which are asked are of paramount importance
[72]. Search criteria, selection processes, and presentation
of evidence will all depend on the exact questions posed.
If policy makers have a clear understanding of the issues
that are important for implementation of a given diag-
nostic in advance, then evidence can be objectively
collected to inform decisions and assessments on both
quantitative and qualitative aspects. However, if only
issues of test accuracy and technical performance are
covered by systematic reviews, then gaps pertaining to
other aspects of performance may need to be filled
through less objective expert opinion.
All things considered, policy making is a big challenge in
TB, as it is in other areas of medicine. Although GRADE
has its limitations and can definitely be improved and
adapted for TB diagnostics, we believe it is a major
advance over the conventional policy making process.
Challenges in translating policies into impactAvailability of new tools does not necessarily ensure their
adoption and implementation. Translation of policy into
practice requires better understanding of barriers to
implementation and methods to overcome such barriers.
The impact of new tests will depend largely on the extent
of their introduction and acceptance into the global
public sector. This will itself depend in part on policy
decisions made by international technical agencies such
as WHO, by donors, and ultimately by national TB
programs. This area has been extensively reviewed by
orized reproduction of this article is prohibited.
C
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
12 Infectious diseases
the Stop TB Partnership’s Task Force on Retooling and
has led to the creation of a roadmap to guide global,
regional, and country-based activities as well as guide-
lines for engaging stakeholders in retooling and the
introduction of specific TB diagnostics [73–75]. The
work of the time-limited and now disbanded Task Force
on Retooling has been mainstreamed into routine TB
control activities led by the DOTS Expansion Working
Group and its Subgroup on Introducing New Tools and
Approaches (INAT).
The major obstacles to diagnostic retooling for TB con-
trol are undoubtedly the poor laboratory infrastructure
and weak healthcare delivery systems present in many
disease-endemic countries [76]. This has been recog-
nized for many years. Although vastly increased funds
are being invested in diagnostics retooling through
national investments and funding agencies, there is still
little guidance available to countries on what new diag-
nostic tools, or combinations of these tools, should be
implemented in their particular epidemiological/health
systems settings, what laboratory capability or capacity
should be built to support this implementation, or how
this should be done. A roadmap for strengthening TB
laboratories that is abreast with recent developments and
addresses these issues is urgently needed [77]. Beyond
introducing new diagnostics and strengthening labora-
tories, challenges will remain in the development of
accessible, equitable, and high-quality diagnostic ser-
vices based on them and ensuring that healthcare deliv-
ery systems are strengthened so that better diagnostic
services translate into better care [78]. In many countries,
the private healthcare sector is the dominant source of
healthcare. Lack of private sector involvement in TB
control is a major weakness in existing programs.
ConclusionAfter decades of neglect and poor progress, there is now
great excitement about the development and introduc-
tion of new diagnostics for TB. The diagnostics pipeline
has rapidly expanded and several new tools and strategies
have received WHO endorsement for implementation at
the country level. There are major gaps in the existing
pipeline and the evidence base is predominantly made up
of research studies of test accuracy. Future TB diagnostic
research needs to focus on clinically meaningful out-
comes and also consider obstacles to implementation.
The GRADE system has brought greater transparency
and evidence-based approaches to policy making, though
GRADE for diagnostics is still a work in progress. Future
TB policies and guidelines will need to be transparent,
evidence-based, and free of COI. Today, despite many
years of intensive effort to remedy the situation, weak
laboratories remain the major immediate obstacle to
translating policy into practice in low-income and
opyright © Lippincott Williams & Wilkins. Unautho
middle-income countries. With the engagement of all
key stakeholders, these challenges can be addressed to
translate all the scientific progress into public health
impact.
AcknowledgementsM.P. is a recipient of a New Investigator Award from the CanadianInstitutes of Health Research (CIHR). J.M. is a recipient of a QuebecRespiratory Health Training Program (QRHTP) Fellowship. Thesefunding sources had no role in the preparation of this manuscript, northe decision to submit the manuscript for publication.
The authors have no financial involvement with any organization or entitywith a financial interest in or financial conflict with the subject matter ormaterials discussed in the manuscript apart from those disclosed. M.P.serves as an external consultant for the Foundation for Innovative NewDiagnostics (FIND). FIND is a nonprofit agency that works with severalindustry partners in developing and evaluating new diagnostics forneglected infectious diseases. M.P. serves as a co-chair of the Stop TBPartnership’s New Diagnostics Working Group (NDWG) and A.R.serves as the secretary of the NDWG. K.S. serves as co-chair of theEvidence Synthesis subgroup of the NDWG.
References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:� of special interest�� of outstanding interest
Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (pp. 000–000).
1
�Pai M, Minion J, Sohn H, et al. Novel and improved technologies for tubercu-losis diagnosis: progress and challenges. Clin Chest Med 2009; 30:701–716.
This paper reviews the existing evidence base on TB diagnostics, describes theprogress of new technologies, and ends with a review of cost-effectiveness andmodeling studies on the potential effect of new diagnostics in TB control.
2 Perkins MD, Cunningham J. Facing the crisis: improving the diagnosis oftuberculosis in the HIV era. J Infect Dis 2007; 196 (Suppl 1):S15–S27.
3
�World Health Organization & Stop TB Partnership. New laboratory diagnostictools for tuberculosis control. Geneva: World Health Organization; 2008.
Detailed review of the existing TB diagnostics pipeline.
4 Pai M, O’Brien R. New diagnostics for latent and active tuberculosis: state of theart and future prospects. Semin Respir Crit Care Med 2008; 29:560–568.
5
�Pai M, Ramsay A, O’Brien R. Comprehensive new resource for evidence-based TB diagnosis. Expert Rev Mol Diagn 2009; 9:637–639.
This study describes the development of a new website resource on ‘evidence-based TB diagnosis’.
6
�Pai M, Ramsay A, O’Brien R. Evidence-based tuberculosis diagnosis. PLoSMed 2008; 5:e156.
A survey of all the systematic reviews on TB diagnostic tests and the contributionmade by systematic reviews for informing clinical practice and policy.
7 Steingart KR, Henry M, Ng V, et al. Fluorescence versus conventional sputumsmear microscopy for tuberculosis: a systematic review. Lancet Infect Dis2006; 6:570–581.
8 Steingart KR, Ng V, Henry M, et al. Sputum processing methods to improvethe sensitivity of smear microscopy for tuberculosis: a systematic review.Lancet Infect Dis 2006; 6:664–674.
9 Mase SR, Ramsay A, Ng V, et al. Yield of serial sputum specimen examinationsin the diagnosis of pulmonary tuberculosis: a systematic review. Int J TubercLung Dis 2007; 11:485–495.
10 Greco S, Girardi E, Navarra S, Saltini C. The current evidence on diagnosticaccuracy of commercial based nucleic acid amplification tests for the diag-nosis of pulmonary tuberculosis. Thorax 2006; 61:783–790.
11 Ling DI, Flores LL, Riley LW, Pai M. Commercial nucleic-acid amplificationtests for diagnosis of pulmonary tuberculosis in respiratory specimens: meta-analysis and meta-regression. PLoS One 2008; 3:e1536.
12 Dinnes J, Deeks J, Kunst H, et al. A systematic review of rapid diagnostic testsfor the detection of tuberculosis infection. Health Technol Assess 2007;11:1–196.
rized reproduction of this article is prohibited.
C
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
New and improved tuberculosis diagnostics Pai et al. 13
13 Pai M, Flores LL, Hubbard A, et al. Nucleic acid amplification tests in thediagnosis of tuberculous pleuritis: a systematic review and meta-analysis.BMC Infect Dis 2004; 4:6.
14 Pai M, Flores LL, Pai N, et al. Diagnostic accuracy of nucleic acid amplificationtests for tuberculous meningitis: a systematic review and meta-analysis.Lancet Infect Dis 2003; 3:633–643.
15 Daley P, Thomas S, Pai M. Nucleic acid amplification tests for the diagnosis oftuberculous lymphadenitis: a systematic review. Int J Tuberc Lung Dis 2007;11:1166–1176.
16 Steingart KR, Henry M, Laal S, et al. A systematic review of commercialserological antibody detection tests for the diagnosis of extra-pulmonarytuberculosis. Thorax 2007; 62:911–918.
17 Steingart KR, Henry M, Laal S, et al. Commercial serological antibodydetection tests for the diagnosis of pulmonary tuberculosis: a systematicreview. PLoS Med 2007; 4:e202.
18 Steingart KR, Dendukuri N, Henry M, et al. Performance of purified antigensfor serodiagnosis of pulmonary tuberculosis: a meta-analysis. Clin VaccineImmunol 2009; 16:260–276.
19 Greco S, Girardi E, Masciangelo R, et al. Adenosine deaminase and interferongamma measurements for the diagnosis of tuberculous pleurisy: a meta-analysis. Int J Tuberc Lung Dis 2003; 7:777–786.
20 Liang QL, Shi HZ, Wang K, et al. Diagnostic accuracy of adenosine deami-nase in tuberculous pleurisy: a meta-analysis. Respir Med 2008; 102:744–754.
21 Jiang J, Shi HZ, Liang QL. Diagnostic value of interferon-g in tuberculouspleurisy: a meta-analysis. Chest 2007; 131:1133–1141.
22 Kalantri S, Pai M, Pascopella L, et al. Bacteriophage-based tests for thedetection of Mycobacterium tuberculosis in clinical specimens: a systematicreview and meta-analysis. BMC Infect Dis 2005; 5:59.
23 Cruciani M, Scarparo C, Malena M, et al. Meta-analysis of BACTEC MGIT 960and BACTEC 460 TB, with or without solid media, for detection of myco-bacteria. J Clin Microbiol 2004; 42:2321–2325.
24 Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skintests: what is the absolute effect of BCG and nontuberculous mycobacteria?Int J Tuberc Lung Dis 2006; 10:1192–1204.
25 Wang L, Turner MO, Elwood RK, et al. A meta-analysis of the effect of BacilleCalmette Guerin vaccination on tuberculin skin test measurements. Thorax2002; 57:804–809.
26 Pai M, Zwerling A, Menzies D. T-cell based assays for the diagnosis of latenttuberculosis infection: an update. Ann Intern Med 2008; 149:177–184.
27 Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis oflatent tuberculosis infection: areas of uncertainty and recommendations forresearch. Ann Intern Med 2007; 146:340–354.
28 Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiag-nosis of tuberculosis: a systematic review. Lancet Infect Dis 2004; 4:761–776.
29 van Zyl-Smit RN, Zwerling A, Dheda K, Pai M. Within-subject variability ofinterferon-g assay results for tuberculosis and boosting effect of tuberculinskin testing: a systematic review. PLoS One 2009; 4:e8517.
30 Pai M, Kalantri S, Pascopella L, et al. Bacteriophage-based assays for therapid detection of rifampicin resistance in Mycobacterium tuberculosis: ameta-analysis. J Infect 2005; 51:175–187.
31 Minion J, Pai M. Bacteriophage assays for rifampin resistance detection inMycobacterium tuberculosis: updated meta-analysis. Presented at the WorldHealth Organization Expert Group Meeting on Non-commercial CultureMethods and Mycobacteriophage-based Assays for Rapid Screening ofPatients at Risk of Drug-Resistant Tuberculosis. September 8–9, 2009,Geneva, Switzerland.
32 Ling DI, Zwerling A, Pai M. GenoType MTBDR assays for the diagnosisof multidrug-resistant tuberculosis: a meta-analysis. Eur Respir J 2008;32:1165–1174.
33 Morgan M, Kalantri S, Flores L, Pai M. A commercial line probe assay for therapid detection of rifampicin resistance in Mycobacterium tuberculosis: asystematic review and meta-analysis. BMC Infect Dis 2005; 5:62.
34 Bwanga F, Hoffner S, Haile M, Joloba ML. Direct susceptibility testing for multidrug resistant tuberculosis: a meta-analysis. BMC Infect Dis 2009; 9:67.
35 Martin A, Portaels F, Palomino JC. Colorimetric redox-indicator methods forthe rapid detection of multidrug resistance in Mycobacterium tuberculosis: asystematic review and meta-analysis. J Antimicrob Chemother 2007; 59:175–183.
36 Martin A, Panaiotov S, Portaels F, et al. The nitrate reductase assay for therapid detection of isoniazid and rifampicin resistance in Mycobacteriumtuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother2008; 62:56–64.
opyright © Lippincott Williams & Wilkins. Unauth
37 Minion J, Leung E, Menzies D, Pai M. Microscopic-Observation DrugSusceptibility (MODS) and Thin Layer Agar (TLA) assays for the detectionof drug resistant tuberculosis: a systematic review. Presented at the WorldHealth Organization Expert Group Meeting on Non-commercial CultureMethods and Mycobacteriophage-based Assays for Rapid Screening ofPatients at Risk of Drug-Resistant Tuberculosis. September 8–9, 2009,Geneva, Switzerland.
38 Pai M, O’Brien R. Tuberculosis diagnostics trials: do they lack methodologicalrigor? Expert Rev Mol Diagn 2006; 6:509–514.
39 Fontela PS, Pai NP, Schiller I, et al. Quality and reporting of diagnosticaccuracy studies in TB, HIV and malaria: evaluation using QUADAS andSTARD standards. PLoS One 2009; 4:e7753.
40 Banoo S, Bell D, Bossuyt P, et al. Evaluation of diagnostic tests for infectiousdiseases: general principles. Nat Rev Microbiol 2006; 4 (9 Suppl):S21–S31.
41 Bossuyt PM, Reitsma JB, Bruns DE, et al. Towards complete and accuratereporting of studies of diagnostic accuracy: the STARD initiative. Ann InternMed 2003; 138:40–44.
42
��Stop TB Partnership’s New Diagnostics Working Group and World HealthOrganization. Pathways to better diagnostics for tuberculosis: a blueprint forthe development of TB diagnostics. Geneva: World Health Organization;2009.
Comprehensive, well referenced blueprint to guide researchers, clinicians, industrypartners, academics, and TB controllers in all sectors in all aspects of TBdiagnostics development, from concept to evaluation, implementation, scale-up,delivery, and impact.
43 Bossuyt PM, McCaffery K. Additional patient outcomes and pathways inevaluations of testing. Med Decis Making 2009; 29:E30–E38.
44 Lord SJ, Irwig L, Bossuyt PM. Using the principles of randomizedcontrolled trial design to guide test evaluation. Med Decis Making 2009;29:E1–E12.
45 Keeler E, Perkins MD, Small P, et al. Reducing the global burden of tubercu-losis: the contribution of improved diagnostics. Nature 2006; 444 (Suppl 1):49–57.
46
�Abu-Raddad LJ, Sabatelli L, Achterberg JT, et al. Epidemiological benefits ofmore-effective tuberculosis vaccines, drugs, and diagnostics. Proc Natl AcadSci U S A 2009; 106:13980–13985.
Recent modeling study on potential impact and epidemiological benefits of newTB diagnostic tools.
47 Getahun H, Harrington M, O’Brien R, Nunn P. Diagnosis of smear-negativepulmonary tuberculosis in people with HIV infection or AIDS in resource-constrained settings: informing urgent policy changes. Lancet 2007; 369:2042–2049.
48 Marais BJ, Pai M. New approaches and emerging technologies in thediagnosis of childhood tuberculosis. Paediatr Respir Rev 2007; 8:124–133.
49 Barry CE 3rd, Boshoff HI, Dartois V, et al. The spectrum of latent tuberculosis:rethinking the biology and intervention strategies. Nat Rev Microbiol 2009;7:845–855.
50 Pai M. Spectrum of latent tuberculosis: existing tests cannot resolve theunderlying phenotypes. Nat Rev Microbiol 2010 Jan 19 [Epub ahead of print].
51
�World Health Organization. Moving research findings into new WHO policies.http://www.who.int/tb/dots/laboratory/policy/en/index4.html. Geneva: WorldHealth Organization; 2008.
This WHO document describes the new process for policies on tuberculosis.
52
�Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM. Systematic reviews ofdiagnostic test accuracy. Ann Intern Med 2008; 149:889–897.
This study describes the Cochrane Collaboration methodologies and approachesfor diagnostic test accuracy meta-analyses.
53 World Health Organization. The use of liquid medium for culture and DST.http://www.who.int/tb/dots/laboratory/policy/en/index3.html. Geneva: WorldHealth Organization; 2007.
54 World Health Organization. Reduction of number of smears for the diagnosisof pulmonary TB [cited 27 January 2010]. http://www.who.int/tb/dots/labora-tory/policy/en/index2.html
55 World Health Organization. Definition of a new sputum smear-positive TBcase [cited 27 January 2010]. http://www.who.int/tb/dots/laboratory/policy/en/index1.html
56 World Health Organization. Policy statement. Molecular line probe assays forrapid screening of patients at risk of multidrug-resistant tuberculosis (MDR-TB) [cited 27 January 2010]. http://www.who.int/tb/dots/laboratory/policy/en/index4.html
57 World Health Organization. Report of the 9th Meeting of the Strategic andTechnical Advisory Group on Tuberculosis (STAG-TB). Geneva: WorldHealth Organization; 2009 http://www.who.int/tb/advisory_bodies/stag/en/index.html
orized reproduction of this article is prohibited.
C
CE: Tripti; MCP/440; Total nos of Pages: 14;
MCP 440
14 Infectious diseases
58
��Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus onrating quality of evidence and strength of recommendations. BMJ 2008;336:924–926.
This study provides a comprehensive introduction to the GRADE approach fordeveloping policy recommendations.
59 Oxman AD, Lavis JN, Fretheim A. Use of evidence in WHO recommendations.Lancet 2007; 369:1883–1889.
60 Schunemann HJ, Oxman AD, Brozek J, et al. GRADE: assessing the quality ofevidence for diagnostic recommendations. Evid Based Med 2008; 13:162–163.
61 World Health Organization. Guidelines for WHO Guidelines. Geneva: WorldHealth Organization; 2003.
62 World Health Organization. WHO policy on TB infection control in health-care facilities, congregate settings and households. Geneva: World HealthOrganization; 2010.
63 World Health Organization. Treatment of tuberculosis. 4th ed. Geneva: WorldHealth Organization; 2009.
64
��Schunemann HJ, Oxman AD, Brozek J, et al. Grading quality of evidence andstrength of recommendations for diagnostic tests and strategies. BMJ 2008;336:1106–1110.
This report outlines the GRADE approach to diagnostic tests and strategies.
65 Brozek JL, Akl EA, Jaeschke R, et al. Grading quality of evidence and strengthof recommendations in clinical practice guidelines: Part 2 of 3. The GRADEapproach to grading quality of evidence about diagnostic tests and strategies.Allergy 2009; 64:1109–1116.
66 Kavanagh BP. The GRADE system for rating clinical guidelines. PLoS Med2009; 6:e1000094.
67 Pai M. Guidelines on IGRAs: concordant or discordant? 2nd Global Sympo-sium on IGRAs. Dubrovnik, Croatia; 2009.
opyright © Lippincott Williams & Wilkins. Unautho
68 Schunemann HJ, Osborne M, Moss J, et al. An official American ThoracicSociety Policy statement: managing conflict of interest in professional socie-ties. Am J Respir Crit Care Med 2009; 180:564–580.
69 Biesheuvel CJ, Grobbee DE, Moons KG. Distraction from randomization indiagnostic research. Ann Epidemiol 2006; 16:540–544.
70 Steingart KR, Ramsay A, Pai M. Commercial serological tests for the diag-nosis of tuberculosis: do they work? Future Microbiol 2007; 2:355–359.
71 World Health Organization & UNICEF/UNDP/World Bank/WHO SpecialProgramme for Research and Training in Tropical Diseases. Laboratory-basedevaluation of 19 commercially-available rapid diagnostic tests for tuberculo-sis. Geneva: World Health Organization; 2008.
72 Pai M, McCulloch M, Enanoria W, Colford JM Jr. Systematic reviews ofdiagnostic test evaluations: what’s behind the scenes? ACP J Club 2004;141:A11–A13.
73 World Health Organization. New technologies for tuberculosis control: aframework for their adoption, introduction and implementation [WHO/HTM/STB/2007.40]. Geneva: World Health Organization; 2007.
74 Stop TB Partnership Retooling Task Force. Engaging stakeholders for retool-ing TB control. Geneva: World Health Organization; 2008.
75 Stop TB Partnership Retooling Task Force. Checklist of key actions for theuse of liquid culture and drug susceptibility testing. Geneva: World HealthOrganization; 2008.
76 Ridderhof JC, van Deun A, Kam KM, et al. Roles of laboratories and laboratorysystems in effective tuberculosis programmes. Bull World Health Organ2007; 85:354–359.
77 World Health Organization. Strategic approach to the strengthening oflaboratory services for tuberculosis control: 2006–2009. Geneva: WorldHealth Organization; 2006.
78 Yagui M, Perales MT, Asencios L, et al. Timely diagnosis of MDR-TB underprogram conditions: is rapid drug susceptibility testing sufficient? Int J TubercLung Dis 2006; 10:838–843.
rized reproduction of this article is prohibited.