Identification of reduced host transcriptomic signatures for tuberculosis and digital PCR-based validation and quantification

Gliddon, Harriet D.; Kaforou, Myrsini; Alikian, Mary; Habgood-Coote, Dominic; Zhou, Chenxi; Oni, Tolu; Anderson, Suzanne T.; Brent, Andrew; Crampin, Amelia C.; Eley, Brian; Kern, Florian; Langford, Paul; Ottenhoff, Tom H. M.; Hibberd, Martin L.; French, Neil; Wright, Victoria; Dockrell, Hazel M.; Coin, Lachlan; Wilkinson, Robert J.; Levin, Michael

doi:10.1101/583674

Cited by 8 publications

(15 citation statements)

References 41 publications

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“…Baseline characteristics of the study participants are shown in Supplementary Table 1 Of the 17 identified signatures ( Table 2), two were discovered from paediatric populations 28,29 . Four signature discovery datasets included HIV-infected and -uninfected participants 11,13,29,30 , one was discovered in an exclusively HIV-infected population for the purpose of active case finding 31 , while the remainder were discovered in HIV-negative populations. Four signatures were discovered with the intention of diagnosis of incipient TB [16][17][18] , with the remaining 13 discovered for diagnosis of active TB disease.…”

Section: Systematic Review Process and Summaries Of Included Datasetsmentioning

confidence: 99%

“…The eight signatures that achieved equivalent performance were discovered with the primary intention of diagnosis of incipient TB [16][17][18] , or differentiating active TB from people who are healthy or with LTBI 12,13,30,37 .…”

Section: Eight Signatures Have Equivalent Diagnostic Accuracy For Incmentioning

confidence: 99%

“…Discovery populations for these eight signatures included adults or adolescents from the UK or Southern Africa 12,13,[16][17][18]30 , or a meta-analysis of microarray data from multiple studies 11 , including a minimum of 37 incipient or active TB cases. All eight signatures were discovered using genome-wide approaches.…”

Section: Eight Signatures Have Equivalent Diagnostic Accuracy For Incmentioning

confidence: 99%

“…Moreover, integral to both diagnostic accuracy and impact studies is the translation of transcriptional measurements from un-scalable genome-wide approaches such RNAseq to the reproducible quantification of selected signature genes, with appropriately defined cut-offs. While this has been performed for some signatures using PCR-based platforms 16,17,30,42 , no signature platforms have yet been validated for implementation in a near-patient or commercial assay.…”

Section: Future Directionsmentioning

confidence: 99%

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Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis

Turner

Venturini

et al. 2019

Preprint

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Blood transcriptional signatures may predict risk of tuberculosis (TB). We compared the performance of 17 mRNA signatures in a pooled dataset comprising 1,026 samples, including 183 samples from 127 incipient TB cases, from four studies conducted in South Africa, Ethiopia, The Gambia and the UK. We show that eight signatures (comprising 1-25 transcripts) that predominantly reflect interferon inducible gene expression, have equivalent diagnostic accuracy for incipient TB over a two-year period with areas under the receiver operating characteristic curves ranging from 0.70 (95% confidence interval 0.64-0.76) to 0.77 (0.71-0.82).The sensitivity of all eight signatures declined with increasing disease-free time interval. Using a threshold derived from two standard deviations above the mean of uninfected controls giving specificities of >90%, the eight signatures achieved sensitivities ranging 24.7-39.9% over a 24 month interval, rising to 47.1-81.0% over 3 months. Based on pre-test probability of 2%, the eight signatures achieved positive predictive value ranging from 6.8-9.4% over 24 months, rising to 11.1-14.3% over 3 months. When using biomarker thresholds maximising sensitivity and specificity with equal weighting to both, no signature met the minimum World Health Organization (WHO) Target Product Profile parameters for incipient TB biomarkers over a twoyear period. Blood transcriptional biomarkers reflect short-term risk of TB and only exceed WHO benchmarks if applied to 3-6 month intervals.

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Section: Systematic Review Process and Summaries Of Included Datasetsmentioning

confidence: 99%

Section: Eight Signatures Have Equivalent Diagnostic Accuracy For Incmentioning

confidence: 99%

Section: Eight Signatures Have Equivalent Diagnostic Accuracy For Incmentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

See 2 more Smart Citations

Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis

Turner

Venturini

et al. 2019

Preprint

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“…As shown in Table 1 and Figure 1, the TB infection gene signature derived from different studies, represents associations with host innate immune responses such as B cell receptors, T cell receptors, Toll‐like receptors, and interferon (IFN) pathways 17–25 . Some other studies (Table 1) have also revealed a significant role of the NF‐κB pathway gene signature in TB pathogenesis 21,26 .…”

Section: Gene Signatures and Pathways Shared Between Tb And Ramentioning

confidence: 95%

Tuberculosis comorbidity with rheumatoid arthritis: Gene signatures, associated biomarkers, and screening

et al. 2020

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Rheumatoid arthritis (RA) is known to be related to an elevated risk of infections because of its pathobiology and the use of immunosuppressive therapies. Reactivation of latent tuberculosis (TB) infection is a serious issue in patients with RA, especially after receiving anti-TNFs therapy. TNF blocking reinforces the TB granuloma formation and maintenance and the growth of Mycobacterium tuberculosis (Mtb). After intercurrent of TB infection, the standard recommendation is that the treatment with TNF inhibitors to be withheld despite its impressive effect on suppression of inflammation until the infection has resolved. Knowing pathways and mechanisms that are common between two diseases might help to find the mechanistic basis of this comorbidity, as well as provide us a new approach to apply them as therapeutic targets or diagnostic biomarkers. Also, screening for latent TB before initiation of an anti-TNF therapy can minimize complications. This review summarizes the shared gene signature between TB and RA and discusses the biomarkers for early detection of this infection, and screening procedures as well.

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Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis

Turner

Venturini

et al. 2020

The Lancet Respiratory Medicine

160

154

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Background Multiple blood transcriptional signatures have been proposed for identification of active and incipient tuberculosis. We aimed to compare the performance of systematically identified candidate signatures for incipient tuberculosis and to benchmark these against WHO targets. MethodsWe did a systematic review and individual participant data meta-analysis. We searched Medline and Embase for candidate whole blood mRNA signatures discovered with the primary objective of diagnosis of active or incipient tuberculosis, compared with controls who were healthy or had latent tuberculosis infection. We tested the performance of eligible signatures in whole blood transcriptomic datasets, in which sampling before tuberculosis diagnosis was done and time to disease was available. Culture-confirmed and clinically or radiologically diagnosed pulmonary or extrapulmonary tuberculosis cases were included. Non-progressor (individuals who remained tuberculosis-free during follow-up) samples with less than 6 months of follow-up from the date of sample collection were excluded, as were participants with prevalent tuberculosis and those who received preventive therapy. Scores were calculated for candidate signatures for each participant in the pooled dataset. Receiver operating characteristic curves, sensitivities, and specificities were examined using prespecified intervals to tuberculosis (<3 months, <6 months, <1 year, and <2 years) from sample collection. This study is registered with PROSPERO, number CRD42019135618. ResultsWe tested 17 candidate mRNA signatures in a pooled dataset from four eligible studies comprising 1126 samples. This dataset included 183 samples from 127 incipient tuberculosis cases in South Africa, Ethiopia, The Gambia, and the UK. Eight signatures (comprising 1-25 transcripts) that predominantly reflect interferon and tumour necrosis factor-inducible gene expression, had equivalent diagnostic accuracy for incipient tuberculosis over a 2-year period with areas under the receiver operating characteristic curves ranging from 0•70 (95% CI 0•64-0•76) to 0•77 (0•71-0•82). The sensitivity of all eight signatures declined with increasing disease-free time interval. Using a threshold derived from two SDs above the mean of uninfected controls to prioritise specificity and positive-predictive value, the eight signatures achieved sensitivities of 24•7-39•9% over 24 months and of 47•1-81•0% over 3 months, with corresponding specificities of more than 90%. Based on pre-test probability of 2%, the eight signatures achieved positive-predictive values ranging from 6•8-9•4% over 24 months and 11•2-14•4% over 3 months. When using biomarker thresholds maximising sensitivity and specificity with equal weighting to both, no signature met the minimum WHO target product profile parameters for incipient tuberculosis biomarkers over a 2-year period.Interpretation Blood transcriptional biomarkers reflect short-term risk of tuberculosis and only exceed WHO benchmarks if applied to 3-6-month intervals. Serial testing among caref...

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Identification of reduced host transcriptomic signatures for tuberculosis and digital PCR-based validation and quantification

Cited by 8 publications

References 41 publications

Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis

Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis

Tuberculosis comorbidity with rheumatoid arthritis: Gene signatures, associated biomarkers, and screening

Concise whole blood transcriptional signatures for incipient tuberculosis: a systematic review and patient-level pooled meta-analysis

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