Transcriptomic Biomarkers for Tuberculosis: Validation of NPC2 as a Single mRNA Biomarker to Diagnose TB, Predict Disease Progression, and Monitor Treatment Response
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethics Statements
2.2. Terminology
2.3. Inclusion Criteria for Eligible Published Datasets
2.4. Acquisition and Normalization of Datasets
2.5. Statistical Analysis
3. Results
3.1. Cross-Sectional Studies: Group Comparisons and ROC Analysis
3.1.1. TB Detection
Studies Comparing with Control and LTBI
Identification of TB in Individuals Presenting with Respiratory Symptoms
Differentiation from Other Pulmonary Diseases
3.2. Prospective Studies: Group Comparisons and ROC Analysis
3.2.1. Disease Progression
3.2.2. Correlation with Completion of Anti-TB Treatment
3.3. NPC2 Accuracy: Sensitivity and Specificity Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Study | Publication Year | Study Country | Method | Diagnostic Groups | Public ID | Reference | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
Control | S-NTB | LTBI | TB | TBtt | OD | ||||||
Cross-sectional | 2016 2019 | Brazil | RNAseq | 14 d | - | 21 e | 8 f | - | - | GSE84076 GSE131174 | [10] [11] |
2019 | Haiti | RNAseq | 14 | - | 41 | 22 | - | - | Not deposited | [20,21] | |
2017 | India | RNAseq | - | - | 28 | 16 | - | - | GSE101705 | [26] | |
2012 | UK | Microarray | 52 | - | - | 11 | - | 39 c | GSE42826 | [23] | |
2020 | SA | RNAseq | - | 127 | - | 54 | - | - | E-MTAB-8290 | [6] | |
2017 | Pan A | RNAseq | 208 a | - | - | 64 b | - | - | GSE94438 | [24] | |
Prospective | 2014 | China | Microarray | 6 | - | - | 6 | 9 | - | GSE54992 | [25] |
2016 | SA | RNAseq | 7 | - | - | - | 49 | - | GSE89403 | [7] |
Study | Platform | Age Group | Study Site | TB Incidence ¥ | Study Period (Month/Year) | Specimen | Reference Negative (n) | Reference Positive (n) | AUROC (95% CI) | ||
---|---|---|---|---|---|---|---|---|---|---|---|
DOCK9 | EPHA4 | NPC2 | |||||||||
de Araujo et al | RNAseq | Adults | Brazil | 45 | 03/2010–08/2013 | Whole blood | Control (14) | TB (6) | 0.86 | 0.89 | 0.94 |
(0.70 to 1.0) | (0.76 to 1.0) | (0.81 to 1.0) | |||||||||
LTBI (21) | 0.86 | 0.91 | 0.94 | ||||||||
(0.71 to 1.0) | (0.80 to 1.0) | (0.83 to 1.0) | |||||||||
Haiti | RNAseq | Adults | Haiti | 176 | 02/2016–08/2020 | Whole blood | Control (14) | TB (22) | 0.96 | 0.97 | 0.91 |
(0.89 to 1.0) | (0.92 to 1.0) | (0.79 to 1.0) | |||||||||
IGRApos (41) | 0.95 | 0.96 | 0.89 | ||||||||
(0.89 to 1.0) | (0.92 to 1.0) | (0.80 to 0.98) | |||||||||
GSE101705 | RNAseq | Adults | India | 199 | NA | Whole blood | LTBI (28) | TB (16) | 0.92 | 0.93 | 0.98 |
(0.84 to 1.0) | (0.85 to 1.0) | (0.93 to 1.0) | |||||||||
GSE42826 | Microarray | Adults | United Kingdom | 8 | 09/2009–03/2012 | Whole blood | Control (52) | TB (11) | 0.93 | 0.90 | 0.99 |
(0.84 to 1.0) | (0.79 to 1.0) | (0.97 to 1.0) | |||||||||
aSARC (16) | 0.51 | 0.69 | 0.66 | ||||||||
(0.29 to 0.74) | (0.47 to 0.90) | (0.45 to 0.87) | |||||||||
naSARC (9) | 0.61 | 0.80 | 0.87 | ||||||||
(0.31 to 0.91) | (0.60 to 1.0) | (0.71 to 1.0) | |||||||||
LC (8) | 0.88 | 0.75 | 0.86 | ||||||||
(0.71 to 1.0) | (0.53 to 0.97) | (0.65 to 1.0) | |||||||||
PN (6) | 0.71 | 0.68 | 0.88 | ||||||||
(0.41 to 1.0) | (0.42 to 0.94) | (0.68 to 1.0) | |||||||||
Mean (all of the above) | Control (80) | TB (55) | 0.92 | 0.92 | 0.95 | ||||||
(0.79 to 1.0) | (0.81 to 1.0) | (0.84 to 1.0) | |||||||||
LTBI (90) | 0.91 | 0.93 | 0.94 | ||||||||
(0.87 to 0.99) | (0.87 to 1.0) | (0.83 to 1.0) | |||||||||
OD (37) | 0.65 | 0.63 | 0.73 | ||||||||
(0.50 to 0.80) | (0.62to 0.79) | (0.56 to 0.90) |
Study or GEO Accession Number | Country | Comparison | Sensitivity and Specificity Analysis Adjusted to: | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Maximum Youden Index | TPP for a Community-Based Triage or Referral Test to Identify People Suspected of Having TB a | TPP for a Test for Predicting Progression from TB Infection to Active Disease a | |||||||||||
Minimum SENSITIVITY: ≥90% | Minimum SPECIFICITY: ≥70% | Minimum SENSITIVITY: ≥75 | Minimum SPECIFICITY: ≥75 | ||||||||||
Sensitivity (95% CI) | Specificity (95% CI) | Sensitivity (95% CI) | Specificity (95% CI) | Sensitivity (95% CI) | Specificity (95% CI) | Sensitivity (95% CI) | Specificity (95% CI) | Sensitivity (95% CI) | Specificity (95% CI) | ||||
Cross-sectional analyses | |||||||||||||
Control or LTBI vs TB | |||||||||||||
de Araujo et al 2016 | BR | Control (n = 14) b | vs TB (n = 6) | 87.5 (47.4–99.7) | 100 (76.8–100) | 100 (63.1–100) | 50 (23–77) | 87.5 (47.4–99.7) | 100 (76.8–100) | 87.5 (47.4–99.7) | 100 (76.8–100) | 87.5 (47.4–99.7) | 100 (76.8–100) |
LTBI (n = 21) | 75 (34.9–96.8) | 100 (83.9–100) | 100 (63.1–100) | 57.1 (34–78.2) | 87.5 (47.4–99.7) | 90.5 (69.6–98.9) | 75 (34.9–96.8) | 100 (83.9–100) | 87.5 (47.4–99.7) | 90.5 (69.6–98.8) | |||
Haiti | H | Control (n = 14) c | vs TB (n = 22) | 90.9 (70.8–98.9) | 100 (75.3–100) | 90.9 (70.8–98.9) | 100 (75.3–100) | 95.5 (77.2–99.9) | 76.9 (46.2–95) | 90.9 (70.8–98.9) | 100 (75.3–100) | 95.5 (77.2–99.9) | 76.9 (46.2–95) |
LTBI (n = 41) | 72.7 (49.8–89.3) | 90.2 (76.8–97.3) | 90.9 (70.8–98.9) | 78.1 (62.4–89.4) | 90.9 (70.8–98.9) | 70.7 (54.5–83.9) | 77.3 (54.6–92.2) | 87.8 (73.8–95.9) | 90.9 (70.8–98.9) | 78.1 (62.4–89.4) | |||
GSE101705 | I | LTBI (n = 28) | vs TB (n = 16) | 96.4 (81.7–99.9) | 100 (79.4–100) | 96.4 (81.7–99.9) | 100 (79.4–100) | 96.4 (81.7–99.9) | 100 (79.4–100) | 96.4 (81.7–99.9) | 100 (79.4–100) | 96.4 (81.7–99.9) | 75 (47.6–92.7) |
OD vs TB | |||||||||||||
GSE42826 | UK | Control (n = 52) c | vs TB (n = 11) | 100 (71.5–100) | 90.4 (79–96.8) | 90.9 (58.7–99.8) | 96.2 (86.8–99.5) | 100 (71.5–100) | 71.2 (56.9–82.9) | 81.8 (48.2–97.7) | 100 (93.2–100) | 100 (71.5–100) | 75 (61.1–86) |
aSARC (n = 16) | 81.8 (48.2–97.8) | 56.3 (29.9–80.3) | 90.9 (58.7–99.8) | 43.8 (19.8–70.1) | 45.5 (16.8–76.6) | 75 (47.6–92.8) | 81.8 (48.2–97.7) | 56.3 (29.9–80.3) | 45.5 (16.8–76.6) | 75 (47.6–92.7) | |||
naSARC (n = 9) | 72.7 (39–94) | 88.9 (51.8–99.7) | 90.9 (58.7–99.8) | 66.7 (29.9–92.5) | 81.8 (48.2–97.7) | 77.8 (40–97.2) | 81.8 (48.2–97.7) | 77.8 (40–97.2) | 81.8 (48.2–97.7) | 77.8 (40–97) | |||
LC (n = 8) | 81.8 (48.2–97.7) | 87.5 (47.4–99.7) | 90.9 (58.7–99.8) | 87.5 (47.4–99.7) | 90.9 (58.7–99.8) | 75 (34.9–96.8) | 81.8 (48.2–97.7) | 87.5 (47.4–99.7) | 90.9 (58.7–99.8) | 87.5 (47.4–99.7) | |||
PN (n = 6) | 90.9 (58.7–99.8) | 83.3 (35.9–99.6) | 90.9 (58.7–99.8) | 83.3 (35.9–99.6) | 90.9 (58.7–99.8) | 83.3 (35.9–99.6) | 81.8 (48.2–97.7) | 87.5 (47.4–99.7) | 90.9 (58.7–99.8) | 83.3 (35.9–99.6) | |||
Mean | |||||||||||||
All of the above | Control (n = 80) c | TB (n = 55) | 92.8 (76.8–100) | 96.8 (83–100) | 93.9 (80.9–100) | 82.1 (12.9–100) | 94.3 (78.6–100) | 82.7 (44.8–100) | 86.7 (75.3–98.2) | 100 (100–100) | 94.3 (78.6–100) | 84 (49.4–100) | |
LTBI (n = 90) | 81.4 (48.9–100) | 96.7 (82.7–100) | 95.8 (84.4–100) | 78.4 (25.1–100) | 91.6 (80.4–100) | 87.1 (49.9–100) | 82.9 (53.7–100) | 95.9 (78.4–100) | 91.6 (80.4–100) | 81.2 (60.8–100) | |||
OD (n = 39) | 81.8 (70–93.6) | 79 (54.6–100) | 90.9 (90.9–90.9) | 70.3 (38.8–100) | 77.3 (42.9–100) | 77.8 (71.6–84) | NA | NA | NA | NA | |||
Symptomatic respiratory | |||||||||||||
E-MTAB-8290 | SA | S-NTB (n = 127) | TB (n = 54) | 61.1 (46.9–74.1) | 67.8 (58.9–75.7) | 90.7 (79.7–96.9) | 26 (18.6–34.5) | 57.4 (43.2–70.8) | 70 (61.3–77.9) | 75.9 (62.4–86.5) | 49.6 (40.6–58.6) | 64.81 (50.6–77.3) | 91.3 (85.0–95.6) |
Prospective analyses | |||||||||||||
GSE94438 | PA | Control (n = 208) | vs TB(≤3 m) (n = 13) | 92.3 (64–99.8) | 83.2 (77.4–88) | 92.3 (64–99.8) | 83.2 (77.4–88) | 100 (75.3–100) | 74.5 (68–80.39) | 76.9 (46.2–95) | 87.5 (82.2–91.7) | 92.3 (64–99.8) | 75 (68.5–80.7) |
Control (n = 208) | vs TB(4–6m) (n = 34) | 76.5 (58.8–89.3) | 53.9 (46.8–60.8) | 91.2 (76.3–98.1) | 23.1 (17.5–29.4) | 52.9 (35.1–70.2) | 70.2 (63.5–76.3) | 76.5 (58.8–89.3) | 53.9 (46.8–60.8) | 50 (32.4–67.6) | 75 (68.5–80.7) | ||
Control (n = 208) | vs TB(7–12m) (n = 19) | 57.9 (33.5–79.8) | 90.4 (85.5–94) | 94.7 (74–99.9) | 31.3 (25–38) | 63.2 (38.4–83.7) | 76 (69.6–81.6) | 79 (54.4–94) | 61.1 (54.7–67.7) | 63.2 (38.4–83.7) | 75 (68.5–80.7) | ||
Control (n = 208) | vs TB(13–18m) (n = 32) | 84.4 (67.2–94.7) | 44.7 (37.8–51.7) | 90.6 (75–98) | 30.3 (24.1–379) | 40.6 (23.7–59.4) | 70.2 (63.5–76.3) | 75 (56.6–88.5) | 50 (43–57) | 34.4 (18.6–53.2) | 75 (68.5–80.7) |
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de Araujo, L.S.; Ribeiro-Alves, M.; Wipperman, M.F.; Vorkas, C.K.; Pessler, F.; Saad, M.H.F. Transcriptomic Biomarkers for Tuberculosis: Validation of NPC2 as a Single mRNA Biomarker to Diagnose TB, Predict Disease Progression, and Monitor Treatment Response. Cells 2021, 10, 2704. https://doi.org/10.3390/cells10102704
de Araujo LS, Ribeiro-Alves M, Wipperman MF, Vorkas CK, Pessler F, Saad MHF. Transcriptomic Biomarkers for Tuberculosis: Validation of NPC2 as a Single mRNA Biomarker to Diagnose TB, Predict Disease Progression, and Monitor Treatment Response. Cells. 2021; 10(10):2704. https://doi.org/10.3390/cells10102704
Chicago/Turabian Stylede Araujo, Leonardo S., Marcelo Ribeiro-Alves, Matthew F. Wipperman, Charles Kyriakos Vorkas, Frank Pessler, and Maria Helena Féres Saad. 2021. "Transcriptomic Biomarkers for Tuberculosis: Validation of NPC2 as a Single mRNA Biomarker to Diagnose TB, Predict Disease Progression, and Monitor Treatment Response" Cells 10, no. 10: 2704. https://doi.org/10.3390/cells10102704