a novel tb diagnostic algorithm using automated microscopy
Post on 04-Feb-2022
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A novel TB diagnostic algorithm using
automated microscopy achieves
high sensitivity while reducing the volume
of Xpert MTB/RIF testing
N Ismail
SV Omar, J Lewis, D Dowdy, D Clark,
M v/d Meulen, S Kennedy, G Churchyard
Background
• “For better or worse microscopy is here to stay
…”
– Could we improve this test?
• GXP has proven to an excellent diagnostic tool
but uptake has been limited
– Could we use a screening strategy to reduce the
number of test while maintaining performance
and thus increase uptake?
Automated Microscopy• TBDx® is a computer-aided detection (CAD) system
to automatically detect and count TB AFB on
digitized fields of view using “signature mapping”
Further improvements ….
Aims
• Evaluate the diagnostic
performance of the
improved TBDx as a stand
alone tool
• Evaluate the diagnostic
performance a novel
diagnostics algorithm
combining TBDx with the
GXP
Methods
• Setting: NTBRL, Johannesburg, South Africa
• Samples: Consecutive sputum from patients with symptoms of TB and not on treatment
• Gold standards:
– Culture:
• MGIT 960
– Auramine Smear Microscopy
• Microscopy : technician with >40years experience
• Confirmatory microscopy: technologist >40years experience
– All pos and ~ 10% random negative
Specimen processing
decontamination, centrifugation,
and standardization
Standardized pellet (2ml)
0.5 mL 200 µL remnant
Culture and DST Slide smears Stored 2-8oC
Produced, heated and fixed
then stained
Routine microscopy
TBDx GXP for all TBDx pos
& GXP ~10% TBDx neg
Economic methods
(prelim)
Cost Assumptions:
Smear: $2.25 (Shah et al)
TBDx: Smear + $2.99
(possible high-volume price)
GXP: $17.18 (Vassall et al)
Treatment for TB: $610
(WHO notification from SA)
Compare Algorithms:
TBDx positive -> treat (GXP
for RIF if desired)
TBDx scanty -> confirm with
GXP
TBDx negative -> no
treatment
Laboratory Methods
Results
• 1006 samples were directly comparable
(smear/culture/GXP)
– 204 were excluded; contamination, missing results
or NTMs
• Positivity rate: 10.6%
• Scanty: 36%
• ≥1+: 65%
The ROC curve (smear vs TBDx)
TBDx vs Culture
• Sensitivity and specificity of smear and TBDx (with different cut-offs) compared to gold standard of culture.
0%
20%
40%
60%
80%
100%
sme
ar
1+
2+
3+
4+
5+
6+
7+
8+
9+
TBDx cut-off
sensitivity
specificity
TBDx vs Culture
0%
20%
40%
60%
80%
100%
no
rma
l
sca
nty
1
sca
nty
2
sca
nty
3
sca
nty
4
sca
nty
5
sca
nty
7
sca
nty
8
sca
nty
9 P+
P+
+
P+
++
730 158 26 7 8 1 4 2 1 14 26 29
% c
ult
ure
po
siti
ve
fo
r M
TB
TBDx result (and number with result below)
TBDx > GXP
TBDX, TBDx(scanty)>GXP
sensitivity specificity PPV NPV
number of GXP
needed
(n=1,006)
smear 68.2% 99.2% 91.3% 96.3% 0
1+ 77.6% 98.8% 88.3% 97.4% 207
2+ 72.9% 99.3% 92.9% 96.9% 49
3+ 68.2% 99.3% 92.4% 96.3% 23
4+ 66.4% 99.3% 92.2% 96.1% 16
5+ 64.5% 99.3% 92.0% 95.9% 8
6+ 64.5% 99.3% 92.0% 95.9% 7
7+ 64.5% 99.3% 92.0% 95.9% 7
8+ 63.6% 99.6% 94.4% 95.8% 3
9+ 62.6% 99.7% 95.7% 95.7% 1
Preliminary Economic Evaluation(1006 patients tested)
Algorithm Confirmed TB
Cases
Diagnosed
(n = 107)
Culture
Negative,
Test Pos.
GXP
Tests*
Diagnostic
Costs
Treatment
Costs**
Total Costs Incr. Cost
Smear 73 (68%) 7 0 $2,300 $48,800 $51,100 ref
TBDx (S2) 78 (73%) 4 49/118 $6,100 $50,000 $56,100 $5,000
TBDx (S1) 83 (78%) 9 207/276 $8,800 $56,100 $64,900 $13,800
GXP 93 (87%)*** 27*** 1006 $17,300 $73,200 $90,500 $39,400
* The second number includes testing of positive results for RIF testing
** Excludes additional costs of treating MDR-TB
*** Estimated, as not all samples were tested with TBDx
Conclusion
• TBDx as a stand alone test provides equivalent sensitivity and specificity to a microscopy standard of >80years of experience
• TBDx provides a useful screening tool to GXP and could achieve high sensitivity
– 77% with 75% less GXP testing
– 73% with 90% less GXP testing
• Limitations of the study:
– used digested and decontaminated sediments
– high microscopy standard and low prevalence cohort
RecommendationDemonstration studies in different settings to confirm our
findings. Potential applications …
1. Can afford GXP on all
– Use Technology for Treatment monitoring
2. Limited budget for GXP
– Rif Resistance not a concern• Automated microscopy followed by GXP in scanty cases
– Rif resistance is a concern• Automated microscopy followed by GXP in all cases
3. No budget for GXP
– Automated microscopy or
– Automated microscopy confirmations at central locations
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