Several gene expression signatures have potential application in blood tests for predicting the onset of active tuberculosis (TB) from three to six months in advance, though challenges remain, according to a comparative review published online January 10 in Lancet Respiratory Medicine.
The review evaluated whole blood mRNA signatures that have been proposed for identifying the onset of TB. The authors used a patient-level pooled dataset of four studies that included 1,126 samples from 905 patients, with 183 samples from 127 cases of incipient tuberculosis, which is defined as the asymptomatic phase of disease. The dataset included cases from African countries -- South Africa, Ethiopia, and Gambia -- and the U.K.
A total of 17 candidate mRNA signatures were tested and the results were compared. BATF2 achieved the best performance for identifying incipient tuberculosis over a two-year period, with an area under the curve of 0.74. Seven other multigene signatures had equivalent performance, including Zak16, Suliman2 and Kaforou25.
"The sensitivity of all eight signatures declined with increasing disease-free time interval," wrote co-author Dr. Mahdad Noursadeghi, a professor of infectious disease at University College London, and colleagues.
The World Health Organization (WHO) would like to see sensitivity of at least 75% and specificity of at least 75% two years prior to disease onset as a minimum standard for tests identifying incipient tuberculosis. Ideally, however, the organization prefers at least 90% for both sensitivity and specificity. The early detection of asymptomatic disease enables preventive treatment and is a cornerstone of WHO public health strategy for tackling TB.
"Tests that identify the incipient phase, between latent infection and active disease, might lead to improved positive predictive value for incident tuberculosis, while still offering an opportunity to prevent tuberculosisrelated morbidity and mortality and reduce onward transmission," the authors wrote.
None of the signatures evaluated met the minimum two-year standard, the authors reported. Rather, the blood transcriptional markers reflect short-term risk of TB and "only exceed WHO benchmarks if applied to [three- to six-month] intervals."
"Serial testing among carefully selected target groups might be required for optimal implementation of these biomarkers," Noursadeghi and colleagues concluded.
The three- to six-month interval for screening is not feasible on the population level, and even keeping the focus on high-risk groups would be challenging in high-transmission, low-resource settings. However, the authors believe serial blood transcriptional testing may have a role in low-transmission, high-resource settings -- for example, in testing new migrants from countries where TB is more prevalent.
The cost of testing is a future challenge in translating research into usable tests, the group acknowledged, noting that the WHO has set target price levels of $2 for nonsputum triage tests and $100 for detecting incipient disease.
"The fact that a number of different signatures show equivalent performance enables greater freedom for commercial development of this approach by overcoming restricted access to specific signatures protected by intellectual property rights and encouraging competition to drive down costs," the authors concluded.