, a constituent journal of the Science Group,
published by the American Association for the Advancement of Science (AAAS),
The study was jointly
led by Dr. David Walt, PhD and Dr. Michael Gillette, MD, PhD. Dr. Walt is a
Core Faculty Member of the Wyss Institute, Boston and is also the Hansjörg Wyss
Professor of Biologically Inspired Engineering at Harvard Medical School,
Boston. He also holds joint appointments as Professor at Brigham and Women's
Hospital, Boston and Howard Hughes Medical Institute, Chevy Chase, Maryland,
Dr. Gillette is a Research Scientist and Senior Group Leader of the Proteomics and
Biomarker Discovery Program at the Broad Institute, Cambridge, Massachusetts.
He is also an Assistant Professor of Medicine at Harvard Medical School, Boston
and a Pulmonary/Critical Care Physician at Massachusetts General Hospital,
Boston, Massachusetts, USA.
Ingber, MD, PhD, was the senior advisor and collaborator of the study. Dr.
Ingber is the Founding Director of Wyss Institute, Boston. He also holds
several joint appointments, such as the Judah Folkman Professor of Vascular
Biology at Harvard Medical School, Boston and the Vascular Biology Program at
Boston Children's Hospital, as well as Professor of Bioengineering at Harvard's
John A. Paulson School of Engineering and Applied Sciences, Cambridge,
The first author of the paper was Dr. Rushdy Ahmad, PhD, a former Research Scientist at
the Broad Institute, Cambridge, Massachusetts. He is currently the President of
True North Bio, LLC based in Cedar Park, Texas, USA.
What is meant by 'Triage'?
The term 'triage'
means prioritization of the order of treatment
of a large number of patients based on the urgency or seriousness of the
disease. The new triage test for diagnosis of
active tuberculosis (ATB)
, developed under the leadership of the
World Health Organization (WHO), will help
patients at the highest risk of acquiring ATB
get timely treatment on
a priority basis.
Salient Features of the TB Triage Test
features of the test are highlighted below:
- It is a multiplexed blood-based test that helps in
early detection of suspected ATB patients
- It picks-up and analyzes the 'signature' emitted by the combined effect of four protein
biomarkers and an antibody targeting the TB antigen Ag85B
- The test is ultrasensitive and very fast that gives
results within 30 minutes
- It is much cheaper than currently
available TB tests, costing just USD 2 per test
- It is ideal for use as a point-of-care diagnostic
test in low-resource settings
How was the TB Triage Test Developed?
The triage test for
TB was developed by a large multidisciplinary team of researchers from several
institutes in the US. The underlying principle of this triage test involves the
detection of a 'signature'
set of biomarkers
present in blood that helps to diagnose suspected ATB patients.
The levels of 47
different blood proteins were analyzed in around 400 samples from patients in
Tanzania and the Philippines, who had been diagnosed with either ATB or a
condition 'Other than TB' (OTB) using conventional microbiologic tests. The
protein level data was analyzed using an algorithm based on machine learning.
This algorithm accurately identified the following four proteins that were
consistently elevated in the blood of ATB patients:
"Elevated levels of all four of the blood proteins we
analyzed have been identified in a range of different diseases, but only when
combined into a predictive algorithm do they have the power to distinguish ATB
from other conditions,"
- Interleukin (IL)-6
- Vascular Endothelial Growth Factor (VEGF)
The research team further validated their
algorithm by testing its ability to detect ATB in an altogether different set
of 317 blood samples from patients in Vietnam, South Africa, and Peru.
Key Findings of the Study
The machine learning-based
algorithm predicted the following:
- Presence of ATB in 86 percent of all positive
samples (Sensitivity: 86%)
- Absence of ATB in 65 percent of all negative
samples (Specificity: 65%)
- Presence of ATB in 100 percent of HIV-positive
- Absence of ATB in 84 percent of blood samples
obtained from cured ATB patients
The research team developed an
ultrasensitive immunoassay using the Simoa®
platform to further
streamline the triage test, so that it could detect very minuscule levels of the four
proteins - IL-6, IL-8, IL-18, and VEGF - even in a single drop of blood. This Simoa®
immunoassay increased the sensitivity to 87 percent and specificity to 69
"Our test demonstrated 87 percent sensitivity and 69 percent specificity,
which are very close to the WHO's minimum requirements of 90 percent
sensitivity and 70 percent specificity for an effective TB triage test,"
said Ahmad. "It also effectively
identified the ATB signature in patient samples from three different continents,
meaning it can detect many strains of the pathogen, and in both HIV-positive
and HIV-negative samples, making it widely applicable to most ATB patients."
It should be noted
that the TB triage test didn't predict ATB in 19 blood samples collected from
patients with latent TB (LTB)
, indicating that the test would be
highly useful for triaging patients who require urgent medical attention from
those who don't require immediate medical intervention.
"Not only is this
method one of the fastest and most accurate ATB triage tests available, it is
also much more amenable to deployment in low-resource communities than other
existing approaches, it works on patients with different strains of TB, and its
results are not complicated by HIV infection status,"
said Gillette. "These qualities give it the potential to be
a lifesaver by identifying patients who need a diagnostic TB test right away,
which would reduce both deaths from undiagnosed ATB and overuse of antibiotics and expensive diagnostics on
The researchers are
planning to further refine and improve the TB triage test by incorporating more
diagnostic biomarkers and multiplexing the assay procedure so that it would be
possible to detect up to ten analytes at the same time.
"The approach taken to create this triage
test - first identifying multiplexed biomarkers that provide a highly specific
signature for a disease and then designing an assay to achieve endpoints that
have been established by clinical need - represents a paradigm shift in the way
that diagnostic tests are developed, and we hope to see this test and many
others emerge from the Wyss Institute's Diagnostic Accelerator in the future
succeed where previous attempts have failed."
The research was
funded by the University of Melbourne, Australia and a Grand Challenge in
Global Health Grant from the Bill & Melinda Gates Foundation, USA. References :
- A Timely Triage Test for TB - (https://wyss.harvard.edu/news/a-timely-triage-test-for-tb/)
- A Rapid Triage Test for Active Pulmonary Tuberculosis in Adult Patients with Persistent Cough - (https://stm.sciencemag.org/content/11/515/eaaw8287)