Accuracy and clinical utility of near-point-of-care blood tests for predicting incident tuberculosis in exposed contacts in high burden settings: a multi-country observational cohort study

Accuracy and clinical utility of near-point-of-care blood tests for predicting incident tuberculosis in exposed contacts in high burden settings: a multi-country observational cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Accuracy and clinical utility of near-point-of-care blood tests for predicting incident tuberculosis in exposed contacts in high burden settings: a multi-country observational cohort study Shima Abdulgader, Arthur Chiwaya, Marc Banuls, Willy Ssengooba, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9126754/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Background: The scale-up of tuberculosis preventative treatment is a global health priority yet constrained by our inability to identify which exposed contacts should be prioritised. We evaluated the diagnostic accuracy and clinical utility of new and established tests, including the first deployable host mRNA assay, done near point-of-care to diagnose incident tuberculosis in contacts in Mozambique, South Africa, and Uganda Methods : Contacts microbiologically-negative for tuberculosis or without symptoms were followed for 12 months. Xpert MTB-Host Response (Xpert MTB-HR), haemoglobin, and CRP was done by a minimally trained healthcare worker at M0 and M6 using finger-prick blood. Tuberculosis disease was identified at months 0, 6 and 12 by symptom- and chest X-ray-screening (microbiological testing if symptomatic or able to expectorate sputum or CXR-positive; CXR M12 only). Predictive accuracy and decision curve analyses were done, with microbiological confirmation serving as the primary reference standard. Results: Among 3,031 contacts, 66 incident cases occurred. At a 75% sensitivity threshold (the minimum WHO-recommended sensitivity), Xpert MTB-HR and haemoglobin had specificities of 55% (95% confidence interval 53-56) and 25% (24-26), respectively. CRP’s highest sensitivity with non-zero specificity was 52% (38-65) at 71% (69-72) specificity. At 75% specificity (the minimum WHO-recommended specificity), sensitivities were 61% (48-74), 37% (25-51) and 41% (28-55), respectively. Xpert MTB-HR and CRP in parallel (either positive) had highest sensitivity [76% (62–87)] and specificity of 59% (58-61), and the best clinical benefit for a number-willing-to-treat of 20-50. Conclusion: No tests individually met WHO sensitivity and specificity criteria but Xpert MTB-HR came closest. This work resets expectations for host RNA tests. Multi-marker strategies, including personalised risk scores, should be pursued. Health sciences/Diseases/Infectious diseases/Tuberculosis Biological sciences/Microbiology/Infectious-disease diagnostics Health sciences/Medical research/Biomarkers/Predictive markers Tuberculosis Prediction Contacts Diagnostic Accuracy Full Text Additional Declarations Yes there is potential Competing Interest. We received in-kind donations of GeneXpert platforms and RUO Xpert MTB-HR cartridges from Cepheid, Hb801 analyzers and cuvettes from HemoCue, and LumiraDx POC platforms and CRP test strips from LumiraDx. Test donors had no role in study design, data collection, analysis, or interpretation of results. AP-N is a listed inventor on patent ZA2018/03854A, “Biomarkers for prospective determination of risk for development of active tuberculosis”, and patent ZA2020/05364A, “A three-protein proteomic biomarker for prospective determination of risk for development of active tuberculosis“, both of which are related to this project. These patents are held by the University of Cape Town, and neither have been commercialized. The authors declare no financial relationships with any organization or entity that could be perceived as having a financial interest or conflict related to the subject matter or materials discussed in this manuscript, apart from those disclosed. Supplementary Files SupplementPreFIT12March2026.docx Supplement to: Accuracy and clinical utility of near-point-of-care blood tests for predicting incident tuberculosis in exposed contacts: a multi-country observational cohort study Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9126754","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":607046259,"identity":"ecc1512d-54a2-47c8-8dd6-d910bf5edfa0","order_by":0,"name":"Shima Abdulgader","email":"","orcid":"","institution":"Stellenbosch University","correspondingAuthor":false,"prefix":"","firstName":"Shima","middleName":"","lastName":"Abdulgader","suffix":""},{"id":607046260,"identity":"101e3350-de68-4742-bed5-ceb18b198ad1","order_by":1,"name":"Arthur Chiwaya","email":"","orcid":"","institution":"Stellenbosch University","correspondingAuthor":false,"prefix":"","firstName":"Arthur","middleName":"","lastName":"Chiwaya","suffix":""},{"id":607046261,"identity":"f770b19a-d309-47fa-b604-29d5c43aca5c","order_by":2,"name":"Marc Banuls","email":"","orcid":"https://orcid.org/0000-0001-9455-0051","institution":"Fundación Privada Instituto de Salud Global Barcelona (ISGlobal)","correspondingAuthor":false,"prefix":"","firstName":"Marc","middleName":"","lastName":"Banuls","suffix":""},{"id":607046262,"identity":"da7d74aa-7028-4a51-8bc3-1e9303e067ba","order_by":3,"name":"Willy Ssengooba","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"Willy","middleName":"","lastName":"Ssengooba","suffix":""},{"id":607046263,"identity":"2d350efe-a092-4e6b-b5ec-4e028ffe6723","order_by":4,"name":"Dinis Nguenha","email":"","orcid":"","institution":"Centro de Investigação em Saúde de Manhiça (CISM)","correspondingAuthor":false,"prefix":"","firstName":"Dinis","middleName":"","lastName":"Nguenha","suffix":""},{"id":607046264,"identity":"d450d096-bedd-4ff9-be25-a65cab9cb1ef","order_by":5,"name":"James Sserubiri","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"James","middleName":"","lastName":"Sserubiri","suffix":""},{"id":607046265,"identity":"e9d44262-0219-4110-bcbb-9b513c77ff3d","order_by":6,"name":"Patricia Manjate","email":"","orcid":"","institution":"Centro de Investigação em Saúde de Manhiça (CISM)","correspondingAuthor":false,"prefix":"","firstName":"Patricia","middleName":"","lastName":"Manjate","suffix":""},{"id":607046266,"identity":"e7eac44e-cea3-4987-93e1-446963daa9fc","order_by":7,"name":"Catarina Bazima","email":"","orcid":"","institution":"Centro de Investigação em Saúde de Manhiça (CISM)","correspondingAuthor":false,"prefix":"","firstName":"Catarina","middleName":"","lastName":"Bazima","suffix":""},{"id":607046267,"identity":"d4b60ae8-7709-40a3-bd87-c663bd5a6502","order_by":8,"name":"Vinzeigh Leukes","email":"","orcid":"","institution":"FIND","correspondingAuthor":false,"prefix":"","firstName":"Vinzeigh","middleName":"","lastName":"Leukes","suffix":""},{"id":607046268,"identity":"f31aa4b4-72d7-46fb-b702-1b472b5b1e8c","order_by":9,"name":"Adam Penn-Nicholson","email":"","orcid":"","institution":"FIND","correspondingAuthor":false,"prefix":"","firstName":"Adam","middleName":"","lastName":"Penn-Nicholson","suffix":""},{"id":607046269,"identity":"2329e50b-4d7f-4e81-aaf8-f4f111410baa","order_by":10,"name":"Achilles Katamba","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"Achilles","middleName":"","lastName":"Katamba","suffix":""},{"id":607046270,"identity":"b5ad02d2-f964-4bd1-9c79-5d945fa01ee8","order_by":11,"name":"Moses Joloba","email":"","orcid":"","institution":"Makerere University","correspondingAuthor":false,"prefix":"","firstName":"Moses","middleName":"","lastName":"Joloba","suffix":""},{"id":607046271,"identity":"d8972a74-ba3b-46bf-b05d-51dfaf494b09","order_by":12,"name":"Alberto García-Basteiro","email":"","orcid":"https://orcid.org/0000-0002-2038-5505","institution":"ISGlobal, Hospital Clínic, Universitat de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Alberto","middleName":"","lastName":"García-Basteiro","suffix":""},{"id":607046258,"identity":"5f7016f7-1ba4-4128-b94c-ef5cacc884f5","order_by":13,"name":"Grant Theron","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYFACHjApR4IONogWY9K1JDYQrUM+vvfg44qKO+nzZ+QeYPhRw2DPT0iz4TG+ZMMzZ57lbriRl8DYc4yBWeIAIS1tPGaSjW2HczdI5Bgw8DYwsDEQocX8J1BLuvyMHAPGvw0MPPKEtMiz8ZgxArUkMNzIMWAG2iJhQEiLAVuOsWTDmcOGG868MTgsc0zCwJCgLc1nDD82VByWl2/PMXz4psbGXo6gLcgKgGwJAupBtjQQVjMKRsEoGAUjHQAAUv47y4fMmMEAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-9216-2415","institution":"Stellenbosch University","correspondingAuthor":true,"prefix":"","firstName":"Grant","middleName":"","lastName":"Theron","suffix":""},{"id":607046272,"identity":"fe482935-8d1f-4b30-8a7a-bb160bd6f2c3","order_by":14,"name":"Frank Cobelens","email":"","orcid":"https://orcid.org/0000-0002-4367-1133","institution":"University of Amsterdam, Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands","correspondingAuthor":false,"prefix":"","firstName":"Frank","middleName":"","lastName":"Cobelens","suffix":""}],"badges":[],"createdAt":"2026-03-15 07:08:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9126754/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9126754/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105851083,"identity":"43d1a8d6-6ac7-4a42-8b60-7f56e347748e","added_by":"auto","created_at":"2026-03-31 19:40:17","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":938921,"visible":true,"origin":"","legend":"","description":"","filename":"TheaccuracyofPOCtestsforTBpredictioninHHCs12March2026.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9126754/v1_covered_6e45667f-2345-42be-94f3-8719c0bae941.pdf"},{"id":105808114,"identity":"d92b504a-3e1d-41e0-b7a0-5d2695730da7","added_by":"auto","created_at":"2026-03-31 10:54:50","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1443118,"visible":true,"origin":"","legend":"Supplement to: Accuracy and clinical utility of near-point-of-care blood tests for predicting incident tuberculosis in exposed contacts: a multi-country observational cohort study","description":"","filename":"SupplementPreFIT12March2026.docx","url":"https://assets-eu.researchsquare.com/files/rs-9126754/v1/3d9e987ae910b9457e2550c2.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nWe received in-kind donations of GeneXpert platforms and RUO Xpert MTB-HR cartridges from Cepheid, Hb801 analyzers and cuvettes from HemoCue, and LumiraDx POC platforms and CRP test strips from LumiraDx. Test donors had no role in study design, data collection, analysis, or interpretation of results. AP-N is a listed inventor on patent ZA2018/03854A, “Biomarkers for prospective determination of risk for development of active tuberculosis”, and patent ZA2020/05364A, “A three-protein proteomic biomarker for prospective determination of risk for development of active tuberculosis“, both of which are related to this project. These patents are held by the University of Cape Town, and neither have been commercialized. The authors declare no financial relationships with any organization or entity that could be perceived as having a\r\nfinancial interest or conflict related to the subject matter or materials discussed in this manuscript, apart from those disclosed.","formattedTitle":"Accuracy and clinical utility of near-point-of-care blood tests for predicting incident tuberculosis in exposed contacts in high burden settings: a multi-country observational cohort study","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Tuberculosis, Prediction, Contacts, Diagnostic Accuracy","lastPublishedDoi":"10.21203/rs.3.rs-9126754/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9126754/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe scale-up of tuberculosis preventative treatment is a global health priority yet constrained by our inability to identify which exposed contacts should be prioritised. We evaluated the diagnostic accuracy and clinical utility of new and established tests, including the first deployable host mRNA assay, done near point-of-care to diagnose incident tuberculosis in contacts in Mozambique, South Africa, and Uganda\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Contacts microbiologically-negative for tuberculosis or without symptoms were followed for 12 months. Xpert MTB-Host Response (Xpert MTB-HR), haemoglobin, and CRP was done by a minimally trained healthcare worker at M0 and M6 using finger-prick blood. Tuberculosis disease was identified at months 0, 6 and 12 by symptom- and chest X-ray-screening (microbiological testing if symptomatic or able to expectorate sputum or CXR-positive; CXR M12 only). Predictive accuracy and decision curve analyses were done, with microbiological confirmation serving as the primary reference standard.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong 3,031 contacts, 66 incident cases occurred. At a 75% sensitivity threshold (the minimum WHO-recommended sensitivity), Xpert MTB-HR and haemoglobin had specificities of 55% (95% confidence interval 53-56) and 25% (24-26), respectively. CRP’s highest sensitivity with non-zero specificity was 52% (38-65) at 71% (69-72) specificity. At 75% specificity (the minimum WHO-recommended specificity), sensitivities were 61% (48-74), 37% (25-51) and 41% (28-55), respectively. Xpert MTB-HR and CRP in parallel (either positive) had highest sensitivity [76% (62–87)] and specificity of 59% (58-61), and the best clinical benefit for a number-willing-to-treat of 20-50.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eNo tests individually met WHO sensitivity and specificity criteria but Xpert MTB-HR came closest. This work resets expectations for host RNA tests. Multi-marker strategies, including personalised risk scores, should be pursued.\u003c/p\u003e","manuscriptTitle":"Accuracy and clinical utility of near-point-of-care blood tests for predicting incident tuberculosis in exposed contacts in high burden settings: a multi-country observational cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-31 10:53:20","doi":"10.21203/rs.3.rs-9126754/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nm","sideBox":"Learn more about [Nature Medicine](http://www.nature.com/nm/)","snPcode":"","submissionUrl":"","title":"Nature Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"47d6b47d-2877-474d-a5f7-2a8b8e62a82a","owner":[],"postedDate":"March 31st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64594680,"name":"Health sciences/Diseases/Infectious diseases/Tuberculosis"},{"id":64594681,"name":"Biological sciences/Microbiology/Infectious-disease diagnostics"},{"id":64594682,"name":"Health sciences/Medical research/Biomarkers/Predictive markers"}],"tags":[],"updatedAt":"2026-04-28T16:46:00+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-31 10:53:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9126754","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9126754","identity":"rs-9126754","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}