Dataset Information

Diagnostic performance of host protein signatures as a triage test for active pulmonary TB.

ABSTRACT: The current four-symptom screen recommended by the World Health Organization (WHO) is widely used as screen to initiate diagnostic testing for active pulmonary tuberculosis (TB), yet the performance is poor especially when TB prevalence is low. In contrast, more sensitive molecular tests are less suitable for placement at primary care level in low-resource settings. In order to meet the WHO End TB targets, new diagnostic approaches are urgently needed to find the missing undiagnosed cases. Proteomics-derived blood host biomarkers have been explored because protein detection technologies are suitable for the point-of-care setting and could meet cost targets. This study aimed to find a biomarker signature that fulfills WHO's target product profile (TPP) for a TB screening. Twelve blood-based protein biomarkers from three sample populations (Vietnam, Peru, and South Africa) were analyzed individually and in combinations via advanced statistical methods and machine learning algorithms. The combination of I-309, SYWC and kallistatin showed the most promising results to discern active TB throughout the data sets meeting the TPP for a triage test in adults from two countries (Peru and South Africa). The top-performing individual markers identified at the global level (I-309 and SYWC) were also among the best-performing markers at country level in South Africa and Vietnam. This analysis clearly shows that a host protein biomarker assay is feasible in adults for certain geographical regions based on one or two biomarkers with a performance that meets minimal WHO TPP criteria.

SUBMITTER: Koeppel L

PROVIDER: S-EPMC10654108 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Diagnostic performance of host protein signatures as a triage test for active pulmonary TB.

Koeppel Lisa L Denkinger Claudia M CM Wyss Romain R Broger Tobias T Chegou Novel N NN Dunty Jill M JM Scott Kerry K Cáceres Tatiana T Dutoit Elloise E Ugarte-Gil Cesar C Nicol Mark M Gotuzzo Eduardo E Corstjens Paul L A M PLAM Geluk Annemieke A Sutherland Jayne J Sigal George B GB Moreau Emmanuel E Albertini Audrey A Mantsoki Anna A Ongarello Stefano S Walzl Gerhard G Fernandez Suarez Marta M

Journal of clinical microbiology 20230919 10

The current four-symptom screen recommended by the World Health Organization (WHO) is widely used as screen to initiate diagnostic testing for active pulmonary tuberculosis (TB), yet the performance is poor especially when TB prevalence is low. In contrast, more sensitive molecular tests are less suitable for placement at primary care level in low-resource settings. In order to meet the WHO End TB targets, new diagnostic approaches are urgently needed to find the missing undiagnosed cases. Prote ...[more]

PMID: 37724874

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Project description:The development of a non-sputum-based, point-of-care diagnostic test for tuberculosis (TB) is a priority in the global effort to combat this disease, particularly in resource-constrained settings. Previous studies have identified host biomarker signatures which showed potential, but there is a need to validate and refine these for development as a test. We recruited 1,403 adults presenting with symptoms suggestive of pulmonary TB at primary healthcare clinics in six countries from West, East and Southern Africa. Of the study cohort, 326 were diagnosed with TB and 787 with other respiratory diseases, from whom we randomly selected 1005 participants. Using Luminex® technology, we measured the levels of 20 host biomarkers in serum samples which we used to evaluate the diagnostic accuracy of previously identified and novel bio-signatures. Our previously identified seven-marker bio-signature did not perform well (sensitivity: 89%, specificity: 60%). We also identified an optimal, two-marker bio-signature with a sensitivity of 94% and specificity of 69% in patients with no history of previous TB. This signature performed slightly better than C-reactive protein (CRP) alone. The cut-off value for a positive diagnosis differed for human immuno-deficiency virus (HIV)-positive and -negative individuals. Notably, we also found that no signature was able to diagnose TB adequately in patients with a prior history of the disease. We have identified a two-marker, pan-African bio-signature which is more robust than CRP alone and meets the World Health Organization (WHO) target product profile requirements for a triage test in both HIV-negative and HIV-positive individuals. This signature could be incorporated into a point-of-care device, greatly reducing the necessity for expensive confirmatory diagnostics and potentially reducing the number of cases currently lost to follow-up. It might also potentially be useful with individuals unable to provide sputum or with paucibacillary disease. We suggest that the performance of TB diagnostic signatures can be improved by incorporating the HIV-status of the patient. We further suggest that only patients who have never had TB be subjected to a triage test and that those with a history of previous TB be evaluated using more direct diagnostic techniques.

Project description:Background Artificial Intelligence (AI) systems have demonstrated potential in detecting tuberculosis (TB) associated abnormalities from chest X-ray (CXR) images. Thus, they might provide a solution to radiologist shortages in high TB burden countries. However, the cost of implementing computer-aided detection (CAD) software has thus far been understudied. In this study, we performed a costing analysis of CAD software when used as a screening or triage test for pulmonary TB, estimated the incremental cost compared to a radiologist reading of different throughput scenarios, and predicted the cost for the national scale-up plan in Pakistan. Methods For the study, we focused on CAD software reviewed by the World Health Organization (CAD4TB, Lunit INSIGHT CXR, qXR) or listed in the Global Drug Facility diagnostics catalogue (CAD4TB, InferRead). Costing information was obtained from the CAD software developers. CAD4TB and InferRead use a perpetual license pricing model, while Lunit and qXR are priced per license for restricted number of scans. A major implementer in Pakistan provided costing information for human resource and software training. The per-screen cost was estimated for each CAD software and for radiologist for 1) active case finding, and 2) facility based CXR testing scenarios with throughputs ranging from 50,000–100,000 scans. Moreover, we estimated the scale-up cost for CAD or radiologist CXR reading in Pakistan based on the National Strategic Plan, considering that to reach 80% diagnostic coverage, 50% of TB patients would need to be found through facility-based triage and 30% through active case finding (ACF). Results The per-screen cost for CAD4TB (0.25 USD– 2.33 USD) and InferRead (0.19 USD– 2.78 USD) was lower than that of a radiologist (0.70 USD– 0.93 USD) for high throughput scenarios studied. In comparison, the per-screen cost for Lunit (0.94 USD– 1.69 USD) and qXR (0.95 USD—1.9 USD) were only comparable with that of the radiologists in the highest throughput scenario in ACF. To achieve 80 percent diagnostic coverage at scale in Pakistan, the projected additional cost of deploying CAD software to complement the current infrastructure over a four-year period were estimated at 2.65–19.23 million USD, whereas Human readers, would cost an additional 23.97 million USD. Conclusions Our findings suggest that using CAD software could enable large-scale screening programs in high TB-burden countries and be less costly than radiologist. To achieve minimum cost, the target number of screens in a specific screening strategy should be carefully considered when selecting CAD software, along with the offered pricing structure and other aspects such as performance and operational features. Integrating CAD software in implementation strategies for case finding could be an economical way to attain the intended programmatic goals.

Project description:BackgroundAccessible, accurate screening tests are necessary to advance tuberculosis (TB) case finding and early detection in high-burden countries. We compared the diagnostic accuracy of available TB triage tests.MethodsWe prospectively screened consecutive adults with ≥2 weeks of cough presenting to primary health centers in the Philippines, Vietnam, South Africa, Uganda, and India. All participants received the index tests: chest-X-ray (CXR), venous or capillary Cepheid Xpert TB Host Response (HR) testing, and point-of-care C-reactive protein (CRP) testing (Boditech iChroma II). CXR images were processed using computer-aided detection (CAD) algorithms. We assessed diagnostic accuracy against a microbiologic reference standard (sputum Xpert Ultra, culture). Optimal cut-points were chosen to achieve sensitivity ≥90% and maximize specificity. Two-test screening algorithms were considered, using two approaches: 1) sequential negative serial screening in which the second screening test is conducted only if the first is negative and positive is defined as positive on either test and 2) sequential positive serial screening, in which the second screening test is conducted only if the first is positive and positive is defined as positive on both tests.ResultsBetween July 2021 and August 2022, 1,392 participants with presumptive TB had valid results on index tests and the reference standard, and 303 (22%) had confirmed TB. In head-to-head comparisons, CAD4TB v7 showed the highest specificity when using a cut-point that achieves 90% sensitivity (70.3% vs. 65.1% for Xpert HR, difference 95% CI 1.6 to 8.9; 49.7% for CRP, difference 95% CI 17.0 to 24.3). Among the possible two-test screening algorithms, three met WHO target product profile (TPP) minimum accuracy thresholds and had higher accuracy than any test alone. At 90% sensitivity, the specificity was 79.6% for Xpert HR-CAD4TB [sequential negative], 75.9% for CRP-CAD4TB [sequential negative], and 73.7% for Xpert HR-CAD4TB [sequential positive].ConclusionsCAD4TB achieves TPP targets and outperforms Xpert HR and CRP. Combining screening tests further increased accuracy. Cost and feasibility of two-test screening algorithms should be explored.RegistrationNCT04923958.

Dataset Information

Diagnostic performance of host protein signatures as a triage test for active pulmonary TB.

Publications

Diagnostic performance of host protein signatures as a triage test for active pulmonary TB.

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