Clinical utilization of multiple antibodies of Mycobacterium tuberculosis for serodiagnosis evaluation of tuberculosis: a retrospective observational cohort study

AbstractObjectives We aimed to investigate clinical uncertainties by characterizing the accuracy and utility of commercially available antibodies of Mycobacterium tuberculosis in the diagnostic assessment of suspected tuberculosis in high-burden countries.Methods We conducted a retrospective, descriptive, cohort study among participants aged ≥ 18 years with suspected tuberculosis in Nanning, Guangxi, and China. Participants were tested for M. tuberculosis infection using commercially available antibodies against Mycobacterum tuberculosis. Specificity, sensitivity, negative and positive predictive values, and negative and positive likelihood ratios of the tests were determined. Sputum specimens and bronchoalveolar lavage fluid were sent for mycobacterial culture, Xpert MTB/RIF assay, and cell-free M. tuberculosis DNA or RNA assay. Blood samples were used for IGRAs, T-cell counts (CD3 + CD4+ and CD3 + CD8+), and antibodies to tuberculosis test.Results Of the 1857 participants enrolled in this study, 1772 were included in the analyses, among which, 1311 were diagnosed with active tuberculosis. The specificity of antibody against 16kD for active tuberculosis was 92.7% (95% confidence interval [CI]: 89.3–95.4) with a positive likelihood ratio for active tuberculosis cases of 3.1 (95% CI: 2.1–4.7), which was higher than that of antibody to Rv1636 (90.5% [95% CI: 86.6–93.5]), antibody to 38kD (89.5% [95% CI: 85.5–92.7]), antibody against CFP-10 (82.6% [95% CI: 77.9–86.7]), and antibody against LAM (79.3% [95% CI: 74.3–83.7]). Sensitivity ranged from 15.8% (95% CI: 13.9–17.9) for antibody against Rv1636 to 32.9% (95% CI: 30.4–35.6) for antibody to LAM.Conclusions Commercially available antibodies against to Mycobacterium tuberculosis do not have sufficient sensitivity for the diagnostic evaluation of active tuberculosis. However, antibody against Rv1636 and 16kD may have sufficiently high specificities, high positive likelihood ratios, and correspondingly high positive predictive values to facilitate the rule-in of active tuberculosis

Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model

Abstract Background We previously performed targeted sequencing of autism risk genes in probands from the Autism Clinical and Genetic Resources in China (ACGC) (phase I). Here, we expand this analysis to a larger cohort of patients (ACGC phase II) to better understand the prevalence, inheritance, and genotype–phenotype correlations of likely gene-disrupting (LGD) mutations for autism candidate genes originally identified in cohorts of European descent. Methods We sequenced 187 autism candidate genes in an additional 784 probands and 85 genes in 599 probands using single-molecule molecular inversion probes. We tested the inheritance of potentially pathogenic mutations, performed a meta-analysis of phase I and phase II data and combined our results with existing exome sequence data to investigate the phenotypes of carrier parents and patients with multiple hits in different autism risk genes. Results We validated recurrent, LGD, de novo mutations (DNMs) in 13 genes. We identified a potential novel risk gene (ZNF292), one novel gene with recurrent LGD DNMs (RALGAPB), as well as genes associated with macrocephaly (GIGYF2 and WDFY3). We identified the transmission of private LGD mutations in genes predominantly associated with DNMs and showed that parental carriers tended to share milder autism-related phenotypes. Patients that carried DNMs in two or more candidate genes show more severe phenotypes. Conclusions We identify new risk genes and transmission of deleterious mutations in genes primarily associated with DNMs. The fact that parental carriers show milder phenotypes and patients with multiple hits are more severe supports a multifactorial model of risk