R2D2TB Network: Rapid Research in Diagnostics Development for TB Network
Study Details
Study Description
Brief Summary
To reduce the burden of TB worldwide through more accurate, faster, simpler, and less expensive diagnosis of TB Every year, more than 3 million people with TB remain undiagnosed and 1 million die. Better diagnostics are essential to reducing the enormous burden of TB worldwide. The Rapid Research in Diagnostics Development for TB Network (R2D2 TB Network) brings together experts in TB care, technology assessment, diagnostics development, laboratory medicine, epidemiology, health economics and mathematical modeling with highly experienced clinical study sites in 10 countries
Condition or Disease | Intervention/Treatment | Phase |
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Detailed Description
The Rapid Research in Diagnostics Development for TB Network (R2D2 TB Network) study seeks to identify and rigorously assess promising early stage tuberculosis (TB) triage, diagnostic and drug resistance tests (hereafter referred to as "novel tests") in clinical studies conducted in settings of intended use. Rapid diagnosis, identification of drug resistance and effective treatment are critical for improving patient outcomes and reducing TB transmission. However, analysis of care cascades and prevalence surveys indicate that 40-60% of patients with TB are not initiated on effective treatment.1,2 The different types of tests required to reduce this "diagnostic gap" have been described in the form of target product profiles (TPPs). The highest- priority TPPs are for: 1) a point-of-care, non-sputum biomarker-based test to facilitate rapid TB diagnosis using easily accessible samples (a biomarker-based diagnostic test) and 2) a simple, low-cost test that can be used by front-line health workers to rule-out TB (a triage test). The R2D2 TB Network study will evaluate the sensitivity and specificity of novel triage and diagnostic tests against a reference standard including sputum/urine Gene Xpert® MTB/RIF (Mycobacterium tuberculosis/Rifampin) Ultra and sputum mycobacterial culture. The sensitivity and specificity of rapid drug susceptibility tests (rDST) will be compared against a reference standard including culture-based phenotypic DST and whole genome sequencing (WGS) of mycobacterial DNA. In addition, the usability of novel tests will be assessed through direct observations and surveys of routine health workers.
The novel TB triage, diagnostic and drug resistance tests that the investigators currently plan to evaluate are shown in Table 1. The countries/study sites in which each novel test will be evaluated are shown in Table 2. This master study protocol will be updated to include additional novel tests as they are identified or to remove novel tests when their evaluation is complete. Additional prototype TB triage, diagnostic and drug resistance tests, including assays that address multiple pathogens in parallel with TB will be evaluated in subsequent project years.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Evaluation of various novel TB triage and diagnostic tests. For the novel TB triage and diagnostic tests, the investigators will conduct large-scale evaluation of design-locked tests in a cohort of adults with presumed TB, with nested feasibility/pilot studies of early and late prototype tests. The investigators aim to enroll 1500 patients, including 300 people living with HIV and 300 people with diabetes, for evaluation of various novel TB triage and diagnostic tests. |
Diagnostic Test: FLOW-TB Next-generation LAM
A next-generation urine lipoarabinomannan (LAM) assay (Salus Discovery, Madison, USA)
Diagnostic Test: TAM-TB
T-cell Activation Marker (TAM)-TB (Beckman Coulter, Brea, USA), a novel immunodiagnostic test that characterizes expression of an activation marker (CD38) and a maturation marker (CD27) on M. tuberculosis-specific CD4 (cluster of differentiation 4) T cells to discriminate active disease from latent infection or no infection
Diagnostic Test: Host Response Cartridge
Xpert TB Host-Response (Cepheid, Sunnyvale, USA), a cartridge-based whole blood gene expression assay
Diagnostic Test: IChroma POC CRP
iChroma POC CRP (Boditech, South Korea), a point-of-care (POC) assay for measuring C-reactive protein (CRP)
Diagnostic Test: Breath sensor
A breath sensor (Bio-Rad, Hercules, USA)
Diagnostic Test: Automated CXR (chest X-ray)
CAD for Good (EPCON), an open-source computer-aided diagnosis (CAD) tool for chest x-ray interpretation
Diagnostic Test: Next-generation LAM
A novel urine LAM assay that seeks to optimize sensitivity without compromising specificity by increasing the affinity of anti-LAM antibodies (Mologic, Thurleigh, UK)
Diagnostic Test: Oral swab Xpert Ultra
Oral swab analysis (OSA) using Xpert MTB/RIF Ultra (University of Washington, Seattle, USA and Cepheid, Sunnyvale, USA
Diagnostic Test: Xpert MTB cfDNA Cartridge
Xpert MTB cell-free DNA (Cepheid, Sunnyvale, USA), a cartridge-based assay that detects M. tuberculosis cell-free DNA (cfDNA) in the acellular fraction of plasma or urine, also known as "liquid biopsy"
Diagnostic Test: Nanodisk-MS2
NanoDisk-MS (mass spectrometer) uses antibody-conjugated nanoparticles to enrich serum peptides derived from M. tuberculosis proteins CFP-10 and ESAT-6. (NanoPin, Phoenix, USA)
Device: imPulse™ Una e-stethoscope
Infrasound-to-ultrasound e-stethoscope
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Experimental: Evaluation of novel rDST assays Clinicians at participating sites will be asked to refer adult patients with rifampin-resistance identified by routine molecular testing. The investigators aim to enroll 200 patients for evaluation of novel rDST assays. |
Diagnostic Test: Deeplex Myc-TB
an assay originally developed for NGS (next-generation sequencing) platforms that identifies mutations in 18 main MTB drug resistance-associated gene targets to detect resistance to 13 anti-TB drugs/drug classes including all first- and most second-line drugs (injectables, fluoroquinolones, bedaquiline, clofazimine, linezolid, and ethionamide
Diagnostic Test: DeepChek-TB
An assay that identifies the established high and medium confidence drug resistance targets for isoniazid, rifampin, ethambutol, injectables, fluoroquinolones, pyrazinamide, and linezolid. (GenoScreen, France)
Diagnostic Test: Nanopore-optimized targeted sequencing assay
an assay developed specifically for use with the MinION platform. It detects resistance to all first- and most second-line drugs (injectables, fluoroquinolones, ethionamide, bedaquiline, linezolid, and clofazimine). The minimal infrastructure requirements for the MinION platform make it ideally suited to generating rapid and comprehensive drug resistance profiles onsite at district-level and reference laboratories in high burden countries.(Quadram Institute and Oxford Nanopore Technologies [QI/ONT], UK)
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Outcome Measures
Primary Outcome Measures
- Sensitivity [2 years]
Number of positive results for a given index test/(Total positive + negative results for a given index test) among patients with TB using the microbiological reference standard
- Specificity [2 years]
Number of negative results for a given index test/(Total positive + negative results for a given index test) among patients without TB using the microbiological reference standard
Eligibility Criteria
Criteria
Inclusion Criteria:
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For evaluation of TB triage/diagnostic test: We will include adult outpatients (age ≥18 years) with either a cough ≥2 weeks' duration or a known TB risk factor (HIV or diabetes).
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For evaluation of rDST tests: We will include adults (age ≥18 years) who are positive for TB and RIF resistance according to routine diagnostic testing (based typically on Xpert MTB/RIF, Xpert MTB/RIF Ultra, or Hain MTBDRplus).
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For the usability assessment: We will include health workers at each clinical site who are 1) aged ≥18 years and 2) involved in routine TB testing (collecting specimens for or performing TB tests).
Exclusion Criteria:
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For evaluation of TB triage/diagnostic tests: We will exclude patients who: completed latent or active TB treatment within the past 12 months (to increase TB prevalence and reduce false-positive results, respectively); have taken any medication with anti-mycobacterial activity (including fluoroquinolones) for any reason, within 2 weeks of study entry (to reduce false-negatives); reside >20km from the study site or are unwilling to return for follow-up visits; or are unwilling to provide informed consent
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For evaluation of rDST tests: We will exclude patients who: have negative or contaminated results on all baseline (i.e., enrollment) sputum cultures; are unable to provide at least two sputum specimens of 3 mL each within one day of enrollment; or are unable or unwilling to provide informed consent.
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For the usability assessment: We will exclude staff who are unwilling to provide informed consent.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Christian Medical College DOTS Clinic | Vellore | India | ||
2 | De La Salle Medical and Health Sciences Institute Public-Private Mix DOTS clinic | Dasmariñas | Philippines | ||
3 | Brooklyn Chest Hospital | Cape Town | South Africa | ||
4 | Khayelitsha District Health Center | Cape Town | South Africa | ||
5 | Scottsdene primary care clinic | Cape Town | South Africa | ||
6 | Wallacedene primary care clinic | Cape Town | South Africa | ||
7 | Kisenyi Health Center | Kampala | Uganda | ||
8 | Kisugu Health Center | Kampala | Uganda | ||
9 | Mulago DOTS clinic | Kampala | Uganda | ||
10 | Hanoi Lung Hospital | Hanoi | Vietnam | ||
11 | National Lung Hospital | Hanoi | Vietnam |
Sponsors and Collaborators
- University of California, San Francisco
- University Hospital Heidelberg
- Christian Medical College, Vellore, India
- Vietnam National Lung Hospital
- De La Salle University Medical Center
- University of Stellenbosch
- Makerere University
- Johns Hopkins Bloomberg School of Public Health
- Harvard Medical School (HMS and HSDM)
- Stanford University
- Foundation for Innovative New Diagnostics, Switzerland
- Socios En Salud Sucursal, Peru
- Federal University of Mato Grosso
- Medical Research Council
- National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia
- Centre for Infectious Disease Research in Zambia
- National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
- Principal Investigator: Adithya Cattamanchi, MD, University of California, San Francisco
Study Documents (Full-Text)
None provided.More Information
Publications
- Ahmad Khan F, Pande T, Tessema B, Song R, Benedetti A, Pai M, Lönnroth K, Denkinger CM. Computer-aided reading of tuberculosis chest radiography: moving the research agenda forward to inform policy. Eur Respir J. 2017 Jul 13;50(1). pii: 1700953. doi: 10.1183/13993003.00953-2017. Print 2017 Jul.
- Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, Allen J, Tahirli R, Blakemore R, Rustomjee R, Milovic A, Jones M, O'Brien SM, Persing DH, Ruesch-Gerdes S, Gotuzzo E, Rodrigues C, Alland D, Perkins MD. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010 Sep 9;363(11):1005-15. doi: 10.1056/NEJMoa0907847. Epub 2010 Sep 1.
- Cho SN, Brennan PJ. Tuberculosis: diagnostics. Tuberculosis (Edinb). 2007 Aug;87 Suppl 1:S14-7. Epub 2007 Jun 20. Review.
- Colman RE, Mace A, Seifert M, Hetzel J, Mshaiel H, Suresh A, Lemmer D, Engelthaler DM, Catanzaro DG, Young AG, Denkinger CM, Rodwell TC. Whole-genome and targeted sequencing of drug-resistant Mycobacterium tuberculosis on the iSeq100 and MiSeq: A performance, ease-of-use, and cost evaluation. PLoS Med. 2019 Apr 30;16(4):e1002794. doi: 10.1371/journal.pmed.1002794. eCollection 2019 Apr. Erratum in: PLoS Med. 2019 Jun 3;16(6):e1002823.
- Colman RE, Schupp JM, Hicks ND, Smith DE, Buchhagen JL, Valafar F, Crudu V, Romancenco E, Noroc E, Jackson L, Catanzaro DG, Rodwell TC, Catanzaro A, Keim P, Engelthaler DM. Detection of Low-Level Mixed-Population Drug Resistance in Mycobacterium tuberculosis Using High Fidelity Amplicon Sequencing. PLoS One. 2015 May 13;10(5):e0126626. doi: 10.1371/journal.pone.0126626. eCollection 2015.
- Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho SN, Erokhin VV, Ershova J, Gler MT, Kazennyy BY, Kim HJ, Kliiman K, Kurbatova E, Kvasnovsky C, Leimane V, van der Walt M, Via LE, Volchenkov GV, Yagui MA, Kang H; Global PETTS Investigators, Akksilp R, Sitti W, Wattanaamornkiet W, Andreevskaya SN, Chernousova LN, Demikhova OV, Larionova EE, Smirnova TG, Vasilieva IA, Vorobyeva AV, Barry CE 3rd, Cai Y, Shamputa IC, Bayona J, Contreras C, Bonilla C, Jave O, Brand J, Lancaster J, Odendaal R, Chen MP, Diem L, Metchock B, Tan K, Taylor A, Wolfgang M, Cho E, Eum SY, Kwak HK, Lee J, Lee J, Min S, Degtyareva I, Nemtsova ES, Khorosheva T, Kyryanova EV, Egos G, Perez MT, Tupasi T, Hwang SH, Kim CK, Kim SY, Lee HJ, Kuksa L, Norvaisha I, Skenders G, Sture I, Kummik T, Kuznetsova T, Somova T, Levina K, Pariona G, Yale G, Suarez C, Valencia E, Viiklepp P. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet. 2012 Oct 20;380(9851):1406-17. doi: 10.1016/S0140-6736(12)60734-X. Epub 2012 Aug 30. Erratum in: Lancet. 2012 Oct 20;380(9851):1386.
- de Vos M, Ley SD, Wiggins KB, Derendinger B, Dippenaar A, Grobbelaar M, Reuter A, Dolby T, Burns S, Schito M, Engelthaler DM, Metcalfe J, Theron G, van Rie A, Posey J, Warren R, Cox H. Bedaquiline Microheteroresistance after Cessation of Tuberculosis Treatment. N Engl J Med. 2019 May 30;380(22):2178-2180. doi: 10.1056/NEJMc1815121.
- Farhat MR, Sultana R, Iartchouk O, Bozeman S, Galagan J, Sisk P, Stolte C, Nebenzahl-Guimaraes H, Jacobson K, Sloutsky A, Kaur D, Posey J, Kreiswirth BN, Kurepina N, Rigouts L, Streicher EM, Victor TC, Warren RM, van Soolingen D, Murray M. Genetic Determinants of Drug Resistance in Mycobacterium tuberculosis and Their Diagnostic Value. Am J Respir Crit Care Med. 2016 Sep 1;194(5):621-30. doi: 10.1164/rccm.201510-2091OC.
- Fernández-Carballo BL, Broger T, Wyss R, Banaei N, Denkinger CM. Toward the Development of a Circulating Free DNA-Based In Vitro Diagnostic Test for Infectious Diseases: a Review of Evidence for Tuberculosis. J Clin Microbiol. 2019 Mar 28;57(4). pii: e01234-18. doi: 10.1128/JCM.01234-18. Print 2019 Apr. Review.
- Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 1982 Mar;38(1):143-51.
- Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, Zeller K, Andrews J, Friedland G. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006 Nov 4;368(9547):1575-80.
- Lange C, Chesov D, Furin J, Udwadia Z, Dheda K. Revising the definition of extensively drug-resistant tuberculosis. Lancet Respir Med. 2018 Dec;6(12):893-895. doi: 10.1016/S2213-2600(18)30428-4. Epub 2018 Nov 9.
- Lee JJ, Feng L. Randomized phase II designs in cancer clinical trials: current status and future directions. J Clin Oncol. 2005 Jul 1;23(19):4450-7. Review.
- Liu C, Lyon CJ, Bu Y, Deng Z, Walters E, Li Y, Zhang L, Hesseling AC, Graviss EA, Hu Y. Clinical Evaluation of a Blood Assay to Diagnose Paucibacillary Tuberculosis via Bacterial Antigens. Clin Chem. 2018 May;64(5):791-800. doi: 10.1373/clinchem.2017.273698. Epub 2018 Jan 18.
- Luabeya AK, Wood RC, Shenje J, Filander E, Ontong C, Mabwe S, Africa H, Nguyen FK, Olson A, Weigel KM, Jones-Engel L, Hatherill M, Cangelosi GA. Noninvasive Detection of Tuberculosis by Oral Swab Analysis. J Clin Microbiol. 2019 Feb 27;57(3). pii: e01847-18. doi: 10.1128/JCM.01847-18. Print 2019 Mar.
- Makhado NA, Matabane E, Faccin M, Pinçon C, Jouet A, Boutachkourt F, Goeminne L, Gaudin C, Maphalala G, Beckert P, Niemann S, Delvenne JC, Delmée M, Razwiedani L, Nchabeleng M, Supply P, de Jong BC, André E. Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests: an observational study. Lancet Infect Dis. 2018 Dec;18(12):1350-1359. doi: 10.1016/S1473-3099(18)30496-1. Epub 2018 Oct 18.
- Masjedi MR, Farnia P, Sorooch S, Pooramiri MV, Mansoori SD, Zarifi AZ, Akbarvelayati A, Hoffner S. Extensively drug-resistant tuberculosis: 2 years of surveillance in Iran. Clin Infect Dis. 2006 Oct 1;43(7):841-7. Epub 2006 Aug 21.
- Mesman AW, Calderon R, Soto M, Coit J, Aliaga J, Mendoza M, Franke MF. Mycobacterium tuberculosis detection from oral swabs with Xpert MTB/RIF ULTRA: a pilot study. BMC Res Notes. 2019 Jun 20;12(1):349. doi: 10.1186/s13104-019-4385-y.
- Metcalfe JZ, Streicher E, Theron G, Colman RE, Penaloza R, Allender C, Lemmer D, Warren RM, Engelthaler DM. Mycobacterium tuberculosis Subculture Results in Loss of Potentially Clinically Relevant Heteroresistance. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e00888-17. doi: 10.1128/AAC.00888-17. Print 2017 Nov.
- Nakhleh MK, Jeries R, Gharra A, Binder A, Broza YY, Pascoe M, Dheda K, Haick H. Detecting active pulmonary tuberculosis with a breath test using nanomaterial-based sensors. Eur Respir J. 2014 May;43(5):1522-5. doi: 10.1183/09031936.00019114.
- Organization WH. High-priority target product profiles for new tuberculosis diagnostics: report of a consensus meeting. Geneva, Switzerland: WHO Press; 2014. p. 98.
- Paris L, Magni R, Zaidi F, Araujo R, Saini N, Harpole M, Coronel J, Kirwan DE, Steinberg H, Gilman RH, Petricoin EF 3rd, Nisini R, Luchini A, Liotta L. Urine lipoarabinomannan glycan in HIV-negative patients with pulmonary tuberculosis correlates with disease severity. Sci Transl Med. 2017 Dec 13;9(420). pii: eaal2807. doi: 10.1126/scitranslmed.aal2807.
- Portevin D, Moukambi F, Clowes P, Bauer A, Chachage M, Ntinginya NE, Mfinanga E, Said K, Haraka F, Rachow A, Saathoff E, Mpina M, Jugheli L, Lwilla F, Marais BJ, Hoelscher M, Daubenberger C, Reither K, Geldmacher C. Assessment of the novel T-cell activation marker-tuberculosis assay for diagnosis of active tuberculosis in children: a prospective proof-of-concept study. Lancet Infect Dis. 2014 Oct;14(10):931-8. doi: 10.1016/S1473-3099(14)70884-9. Epub 2014 Aug 31.
- Prasad R, Singh A, Balasubramanian V, Gupta N. Extensively drug-resistant tuberculosis in India: Current evidence on diagnosis & management. Indian J Med Res. 2017 Mar;145(3):271-293. doi: 10.4103/ijmr.IJMR_177_16. Review.
- Schmidt S. Bringing cheap and accurate tuberculosis tests to Africa. University of Wisconsin - News. 2018.
- Shin SS, Modongo C, Baik Y, Allender C, Lemmer D, Colman RE, Engelthaler DM, Warren RM, Zetola NM. Mixed Mycobacterium tuberculosis-Strain Infections Are Associated With Poor Treatment Outcomes Among Patients With Newly Diagnosed Tuberculosis, Independent of Pretreatment Heteroresistance. J Infect Dis. 2018 Nov 5;218(12):1974-1982. doi: 10.1093/infdis/jiy480.
- Subbaraman R, Nathavitharana RR, Satyanarayana S, Pai M, Thomas BE, Chadha VK, Rade K, Swaminathan S, Mayer KH. The Tuberculosis Cascade of Care in India's Public Sector: A Systematic Review and Meta-analysis. PLoS Med. 2016 Oct 25;13(10):e1002149. doi: 10.1371/journal.pmed.1002149. eCollection 2016 Oct. Review.
- Systematic Screening for Active Tuberculosis: Principles and Recommendations. Geneva: World Health Organization; 2013.
- UNITAID. TB Diagnostics Market in Select High-Burden Countries: Current Market and Future Opportunities for Novel Diagnostics. Geneva, Switzerland, 2015.
- Walker TM, Kohl TA, Omar SV, Hedge J, Del Ojo Elias C, Bradley P, Iqbal Z, Feuerriegel S, Niehaus KE, Wilson DJ, Clifton DA, Kapatai G, Ip CLC, Bowden R, Drobniewski FA, Allix-Béguec C, Gaudin C, Parkhill J, Diel R, Supply P, Crook DW, Smith EG, Walker AS, Ismail N, Niemann S, Peto TEA; Modernizing Medical Microbiology (MMM) Informatics Group. Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study. Lancet Infect Dis. 2015 Oct;15(10):1193-1202. doi: 10.1016/S1473-3099(15)00062-6. Epub 2015 Jun 23. Erratum in: Lancet Infect Dis. 2017 Nov 21;:.
- Walusimbi S, Bwanga F, De Costa A, Haile M, Joloba M, Hoffner S. Meta-analysis to compare the accuracy of GeneXpert, MODS and the WHO 2007 algorithm for diagnosis of smear-negative pulmonary tuberculosis. BMC Infect Dis. 2013 Oct 30;13:507. doi: 10.1186/1471-2334-13-507.
- Wood A, Barizuddin S, Darr CM, Mathai CJ, Ball A, Minch K, Somoskovi A, Hamasur B, Connelly JT, Weigl B, Andama A, Cattamanchi A, Gangopadhyay K, Bok S, Gangopadhyay S. Ultrasensitive detection of lipoarabinomannan with plasmonic grating biosensors in clinical samples of HIV negative patients with tuberculosis. PLoS One. 2019 Mar 26;14(3):e0214161. doi: 10.1371/journal.pone.0214161. eCollection 2019.
- World Health Organization. Drug-resistant TB. https://www.who.int/tb/areas-of-work/drug-resistant-tb/en/.
- World Health Organization. Global tuberculosis report Geneva, Switzerland: World Health Organization, 2015.
- World Health Organization. High-priority target product profiles for new tuberculosis diagnostics: report of a consensus meeting. Geneva, Switzerland, 2014.
- Xpert MTB/RIF Implementation Manual: Technical and Operational 'How-To'; Practical Considerations. Geneva: World Health Organization; 2014.
- Yoon C, Dowdy DW, Esmail H, MacPherson P, Schumacher SG. Screening for tuberculosis: time to move beyond symptoms. Lancet Respir Med. 2019 Mar;7(3):202-204. doi: 10.1016/S2213-2600(19)30039-6.
- Yoon C, Semitala FC, Atuhumuza E, Katende J, Mwebe S, Asege L, Armstrong DT, Andama AO, Dowdy DW, Davis JL, Huang L, Kamya M, Cattamanchi A. Point-of-care C-reactive protein-based tuberculosis screening for people living with HIV: a diagnostic accuracy study. Lancet Infect Dis. 2017 Dec;17(12):1285-1292. doi: 10.1016/S1473-3099(17)30488-7. Epub 2017 Aug 25.
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