Diagnostic Test Accuracy in Childhood Pulmonary Tuberculosis: A Bayesian Latent Class Analysis

American Journal of Epidemiology © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: Vol. 184, No. 9 DOI: 10.1093/aje/kww094 Advance Access publication: October 13, 2016 Practice of Epidemiology Diagnostic Test Accuracy in Childhood Pulmonary Tuberculosis: A Bayesian Latent Class Analysis * Correspondence to Dr. Samuel G. Schumacher, FIND, Campus Biotech, Building B2, Level 0, 9 Chemin des Mines 1202 Geneva, Switzerland (e-mail: ); or Dr. Maarten van Smeden, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands (e-mail: ). Initially submitted November 5, 2015; accepted for publication February 25, 2016. Evaluation of tests for the diagnosis of childhood pulmonary tuberculosis (CPTB) is complicated by the absence of an accurate reference test. We present a Bayesian latent class analysis in which we evaluated the accuracy of 5 diagnostic tests for CPTB. We used data from a study of 749 hospitalized South African children suspected to have CPTB from 2009 to 2014. The following tests were used: mycobacterial culture, smear microscopy, Xpert MTB/RIF (Cepheid Inc.), tuberculin skin test (TST), and chest radiography. We estimated the prevalence of CPTB to be 27% (95% credible interval (CrI): 21, 35). The sensitivities of culture, Xpert, and smear microscopy were estimated to be 60% (95% CrI: 46, 76), 49% (95% CrI: 38, 62), and 22% (95% CrI: 16, 30), respectively; specificities of these tests were estimated in accordance with prior information and were close to 100%. Chest radiography was estimated to have a sensitivity of 64% (95% CrI: 55, 73) and a specificity of 78% (95% CrI: 73, 83). Sensitivity of the TST was estimated to be 75% (95% CrI: 61, 84), and it decreased substantially among children who were malnourished and infected with human immunodeficiency virus (56%). The specificity of the TST was 69% (95% CrI: 63%, 76%). Furthermore, it was estimated that 46% (95% CrI: 42, 49) of CPTB-negative cases and 93% (95% CrI: 82; 98) of CPTB-positive cases received antituberculosis treatment, which indicates substantial overtreatment and limited undertreatment. childhood pulmonary tuberculosis; diagnosis; latent class analysis; overtreatment; sensitivity; specificity Abbreviations: CPTB, childhood pulmonary tuberculosis; CrI, credible interval; HIV, human immunodeficiency virus; PTB, pulmonary tuberculosis; TST, tuberculin skin test. culture is currently considered the best available reference standard, its sensitivity for detecting CPTB is acknowledged to be imperfect (3, 4, 10). The culture reference standard thus inevitably leads to true CPTB case patients being misclassified as being negative for CPTB. If these misclassifications by the reference standard are ignored, then the assessment of the test accuracy can be biased (11–14). To address the problem of the lack of an accurate reference standard, multivariable diagnostic algorithms for CPTB have been proposed to combine information from multiple imperfect diagnostic tests (including tests for tuberculosis infection and clinical data) in a systematic manner. Although more Tuberculosis in children is an important global health problem. There are an estimated 0.5 to 1 million new cases each year (1, 2), with childhood pulmonary tuberculosis (CPTB) being the most common form. One of the major challenges in diagnosing CPTB is the lack of sensitive diagnostic tests (3–6). In clinical practice, the diagnosis of CPTB therefore relies on a combination of imperfect tests, which gives rise to unknown degrees of under- or overtreatment (7, 8). In recent years, new tests for CPTB have been developed, and their accuracy has been evaluated using mycobacterial culture as a reference standard (4, 9). Although 690 Am J Epidemiol. 2016;184(9):690–700 Samuel G. Schumacher*, Maarten van Smeden*, Nandini Dendukuri, Lawrence Joseph, Mark P. Nicol, Madhukar Pai, and Heather J. Zar Test Accuracy in Childhood Pulmonary Tuberculosis 691 METHODS Data were obtained from a study of hospitalized South African children who were suspected to have CPTB (9). Details on the design of the study are available from the original publications (9, 20). Briefly, between February 2009 and June 2014, children were consecutively enrolled when they presented to a hospital in Cape Town, South Africa, with signs or symptoms suggestive of pulmonary tuberculosis (PTB). Inclusion criteria were: 1) cough and at least 1 additional factor suggestive of CPTB (9, 20); 2) age younger than 15 years; and 3) a parent or legal guardian who provided informed consent. Children were excluded if: 1) they had received tuberculosis treatment or prophylaxis for more than 72 hours or 2) their place of residence precluded follow-up. Patient characteristics are shown in Table 1. In total, 749 children were included in our analysis. Written informed consent for enrollment in the study was obtained from a parent or legal guardian. The Research Ethics Committee of the Faculty of Health Sciences, University of Cape Town, approved the study. Renewed approval for the current analysis was not required because anonymized data were used. Study procedures Up to 3 induced sputum samples per child were each tested with 3 different microbiological tests: liquid culture (mycobacterial growth indicator, BACTEC MGIT, Becton Dickinson Microbiology Systems, Cockeysville, Maryland; hereafter referred to as culture), a molecular nucleic acid amplification test (Xpert MTB/RIF, Cepheid Inc., Sunnyvale, California; hereafter referred to as Xpert), and sputum smear microscopy. A TST was administered and read according to standard procedures by measuring transverse induration in response to purified protein derivative (2TU, PPD RT23, Staten Serum Institute, Denmark, Copenhagen). Based on a standardized reporting format, radiographs of the chest were judged as “consistent with CPTB” or “not consistent with CPTB” by 2 independent readers who were Am J Epidemiol. 2016;184(9):690–700 Table 1. Characteristics of 749 Children Suspected to Have Pulmonary Tuberculosis, South Africa, 2009–2014 Characteristic Median (IQR) Female sex Age, months No. 347 22 (12 to 50) Infected with HIV % 46 1–120a 154 21 211 28 Liquid culture 122 16 Xpert MTB/RIF 106 14 Weight, kg 10 (8 to 14) Weight, z scoreb Malnutrition c −1.1 (−2.2 to 0.2) Diagnostic test positive Microscopy 42 6 Radiography 249 33 TST 321 43 Household tuberculosis contact 409 55 Treated for PTB 436 58 Abbreviations: HIV, human immunodeficiency virus; IQR, interquartile range; PTB, pulmonary tuberculosis; TST, tuberculin skin test. a Value is expressed as median (range). b Weight for age z score, calculated according to World Health Organization Child Growth Standards (21). c Malnutrition was defined as having a weight-for- (...truncated)