Diagnostic Accuracy of Tuberculosis Screening Tests in a Prospective Multinational Cohort: Chest Radiography With Computer-Aided Detection, Xpert Tuberculosis Host Response, and C-Reactive Protein
Authors: Crowder Rebecca , Thangakunam Balamugesh , Andama Alfred , Christopher Devasahayam J , Dalay Victoria , Nwamba Welile , Kik Sandra V , Van Nguyen Dong , Nguyen Nhung Viet , Phillips Patrick P J , Ruhwald Morten , Theron Grant , Worodria William , Yu Charles , Nahid Payam , Cattamanchi Adithya , Gupta-Wright Ankur , Denkinger Claudia M ,   for the R2D2 TB Network, Elango Shanmugasundaram , Emmanuel Jerusha , Ernest Vinita , Gajendran Priyadarshini , John Flavita , Karthikeyan Bharath , Mangal Divya , Sankar Swetha , Sekar Rajasekar , Sekar Reena , Shankar Deepa , Shibiya Mary , Vijayasree Sai , Almonte Jared , Alonzo Kevin Joshua , Angcaya Mary Faith , Bascuña Joseph Edwin L , Basilio Ramon P , Cariaga Asella Ruvijean , Castillon Gabriella , Dayawon Karlo , Destura Raul , Esguerra Jezreel , Garcia Eleonor , Gelina Darecil , Goleña Joseph Aldwin , Golla Maria Marissa , Gutierrez Emmanuelle , Ilagan Gidalthi Jonathan , Lim Dodge R , Maranan Jaiem , Marcelo Danaida , Masangcay Leonedy , Mendoza Jenkin , Pabruada Angelita , Perlas Laarean , Reyes Annalyn , Reyes Roeus Vincent Arjay G , Reyes Lorenzo , Sanchez-Pogosa Maria Guileane , Tonquin Maricef , Abdulgadar Shima , Botha Cammy , Derendinger Brigitta , Fortuin Jane , Gonya Siphosethu , Hatile Chumani , Hendrikse Megan , Lawn Charlotte , Mathoorah Disha , Mbu Desiree Lem , Ntetha Zintle , Okunola Anna , Palmer Zaida , Seti Fikiswa , Van Der Walt Charmaine , Yekani Lusanda , Asege Lucy , Bukirwa Alice , Katumba David , Kisakye Esther , Mangeni Wilson , Mukwatamundu Job , Mwebe Sandra , Nakaweesa Annet , Nakaye Martha , Nalugwa Talemwa , Nassuna Irene , Nekesa Irene , Nyawere Justine , Ssonko John Baptist , Dang Hai , Dinh Luong , Do Hang , Do Tam , Do Thuong , Dao Dung , Doan Ha , Doan Thien , Ha Huy , Lai Oanh , Le Hien , Le Nguyet , Nguyen Anh , Nguyen Hanh , Nguyen Hoa , Nguyen Hoang , Nguyen Thanh , Nguyen Yen , Phan Ha , Pham Nam , Pham Thuong , Trinh Trang , Vu Phuong , Vu Trung , Castro Robert , Cattamanchi Adithya , Cook Catherine , Huddart Sophie , Jaganath Devan , Kato-Maeda Midori , Mochizuki Tessa , Nathavitharana Ruvandhi , Nahid Payam , Nolan Kevin , Shah Kinari , Sudarsan Swati , Yoon Christina , Castro Noriega Maria del Mar , Pfurtscheller Theresa , Yerlikaya Seda , Arentz Matthew , Frey Nathalie 
Published: November 2024

Abstract

Background
Accessible, accurate screening tests are necessary to advance tuberculosis case finding and early detection in high-burden countries.

Methods
We prospectively screened adults with ≥2 weeks of cough at primary health centers in the Philippines, Vietnam, South Africa, Uganda, and India. Participants underwent chest radiography, Cepheid Xpert TB Host Response (Xpert HR) testing, and point-of-care C-reactive protein (CRP) testing (Boditech). Chest radiographs were processed using CAD4TB v7, a computer-aided detection (CAD) algorithm. We assessed diagnostic accuracy against a microbiologic reference standard (sputum Xpert Ultra, culture). Optimal cutoff points were chosen to maximize specificity at 90% sensitivity. Two-test screening algorithms were considered, using (1) sequential negative serial screening (with positive defined as positive on either test) and (2) sequential positive serial screening (with positive defined as positive on both tests).

Results
Between July 2021 and August 2022, a total of 1392 participants with presumptive tuberculosis had valid index tests and reference standard results, and 303 (22%) had confirmed tuberculosis. In head-to-head comparisons, CAD4TB v7 showed the highest specificity at 90% sensitivity (70.3% vs 65.1% for Xpert HR [95% confidence interval for absolute difference in specificity, 1.6%–8.9%] and vs 49.7% for CRP [17.0%–24.3%]). Three 2-test screening algorithms met World Health Organization target product profile 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).

Conclusions
CAD4TB achieves target product profile targets and outperforms Xpert HR and CRP. Combining screening tests further increased accuracy.
Clinical Trials Registration. NCT04923958