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University of Houston Cullen College of Engineering


Professor Develops Screening Test to Help Save Lives of Children in Sub-Saharan Africa

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Elena Watts
Sergey Shevkoplyas

Casual conversations around the dinner table belonging to a biomedical engineer and a health economist are as interesting as one might expect – and potentially just as productive.

Sergey Shevkoplyas, UH Cullen College associate professor of biomedical engineering, at the urging of his wife, Natalia Zhivan, UH clinical assistant professor of economics, found the time and resources to develop an inexpensive paper-based screening test for sickle cell disease, SCD, despite notoriously limited funding available for such research.

In the United States, an estimated 100,000 individuals live with SCD, and about 1,000 children are born with the inherited blood disorder each year, according to the Sickle Cell Disease Association of America website. More than 2 million Americans carry benign sickle cell trait, SCT, which means they do not experience symptoms of the disease but can pass either the trait or the disease to their children. Approximately 5 percent of the world’s population carry the trait, and almost 300,000 children worldwide are born with the disease each year.

The majority of SCD patients in the U.S. are African American. Zhivan was surprised by the drastic difference between the level of funding per capita historically available for SCD research and the level furnished for research for similar diseases that affect other populations. For example, cystic fibrosis, a genetic disease of similar life-shortening severity, affects three times fewer Americans than SCD but has attracted more than three times the funding per patient. Cystic fibrosis, which causes breathing and digestive problems, most frequently affects Caucasians of northern European descent. More funding ultimately leads to more therapeutic options and better quality of life for patients.

“My wife looks at the impact of social economic disparities on health care outcomes, and she was frankly appalled by the difference in funding levels,” Shevkoplyas said. “She said, ‘You’re an engineer, go engineer something.’”

Shevkoplyas was a tenure-track assistant professor when he first discussed the funding disparities with Zhivan, so he was extremely hesitant to pursue the matter at first.

“Getting into sickle cell research seemed like career suicide for a starting assistant professor precisely because there’s so little research funding available for it,” Shevkoplyas said. “But my wife always had a very low tolerance for any type of inequity, and she would not let it go … I figured I would give it a try.”

After many more thoughtful discussions with his wife, his clinical collaborators and his students, Shevkoplyas reasoned that he could make the most immediate impact by developing a very inexpensive diagnostic tool for the disease.

Low-cost screening could help save millions of lives

Universal screening of all newborns for SCD is required in the United States, and early interventions make childhood mortality almost nonexistent. However, the majority of children with SCD go undiagnosed in sub-Saharan Africa because existing diagnostic technology is too costly and complex. Consequently, at least half of the affected infants do not survive beyond age 5. With proper diagnoses, patient-family education, vaccinations and inexpensive antibiotic and vitamin regimens, this outcome is avoidable.

Large-scale universal screening from 2010 to 2050 could save the lives of approximately 10 million infants born with SCD globally, according to a report at the 2013 Annual Sickle Cell Disease Convention. Of those newborns, 85 percent are expected to be born in sub-Saharan Africa.

The existing diagnostic gold standards such as hemoglobin electrophoresis, (HE), high performance liquid chromatography (HPLC), and isoelectric focusing electrophoresis (IEF), are highly accurate but too complex and expensive for widespread use in developing countries.

Existing non-quantitative hemoglobin solubility assays are more economical but far less accurate than the gold standards, work only for adults and cannot distinguish between trait and disease. With these assays, clinicians attempt to visually recognize cloudiness created by clumps of sickle hemoglobin that form when blood is mixed with the hemoglobin solubility buffer.

Consequently, Shevkoplyas’ goal was to develop a low-cost diagnostic test as simple as hemoglobin solubility assays, but as accurate as conventional gold standard methods.

“The incidence of SCD at birth is only a few percent even in the most severely affected countries.  Thus, conventional screening programs currently spend most of their limited resources on highly accurate and expensive testing of healthy children,” Shevkoplyas said.  “If all our low-cost paper-based screening test would do is separate children with sickle trait or disease from those without evidence of either, we could drastically reduce the number of expensive tests performed and enable local governments to use the savings for expanding the reach of SCD screening programs.”

Inspiration appears in least obvious places

Inspiration for the paper-based test came to Shevkoplyas one afternoon as he gazed at an intricate pattern of overlapping stains produced by coffee on a paper napkin he used as a coaster. He remembered an article he had read in the journal Nature that explained the physics behind the dark edges that surround the lighter interiors of the stains. Tiny suspended particles that give coffee its blackish-brown color are transported differentially based on characteristics such as shape and size. Shevkoplyas pondered the idea of using the same principles as the basis for a very inexpensive SCD diagnostic test.

At a molecular level, removal of oxygen from sickle hemoglobin causes it to clump while normal hemoglobin remains dissolved. The clumps of sickle hemoglobin would be transported through paper differently than the molecules of normal hemoglobin because of their different sizes.  So, theoretically, a drop of blood with sickle hemoglobin and a drop of blood without would produce two different coffee-ring-like patterns.

Shevkoplyas tasked his students with testing this theory by comparing normal blood to blood with SCT and SCD. For each of the three groups, they added blood to chemicals in test tubes, shook the tubes for a few minutes and dropped the concoctions on napkin-like paper. They observed the formation of dramatically different patterns, easily detectable by the naked eye, which indicated whether the blood contained the trait, the disease or neither.

“The results were vivid and scary-accurate,” Shevkoplyas said. “There was absolutely no question.”

Shevkoplyas and his students also discovered they could quantify the results by using image analysis to measure relative brightness of the center and the periphery of the bloodstain. They spiked blood samples with different proportions of sickle hemoglobin and found correlations between quantities added and colors observed. The quantitative accuracy of the paper-based test was within about 7 percent of the values measured by hemoglobin electrophoresis (HE), one of the diagnostic gold standards.

“The quantitative paper-based test is not as precise as hemoglobin electrophoresis, but it is much faster and, according to our clinical collaborators, it’s good enough to be clinically useful,” Shevkoplyas said.

Clinical studies move medical technology closer to African children at risk

In 2014, one of Shevkoplyas’ graduate students, Nathaniel Piety, and his clinical collaborator from Texas Children’s Hospital, Alex George, traveled to Angola, Africa for two weeks to initiate the first-ever clinical study of the utility and diagnostic accuracy of the paper-based test. Piety trained two healthcare workers at the sickle cell newborn screening laboratory in Angola to perform the paper-based test. In a few subsequent months, the healthcare workers were able to screen more than 700 mothers and their newborns for SCD using the paper-based test and IEF, one of the diagnostic gold standards. The paper-based test was able to correctly identify every one of the 10 infants born with SCD, and all false-negatives were infants with sickle trait.

“That is an amazing level of performance for what is essentially a napkin test,” Shevkoplyas said. “The healthcare workers in Angola loved it because it is so simple, fast and works even when electricity is out.”

The sickle cell newborn screening laboratory where Shevkoplyas and his colleagues validated the paper-based test is a part of the Angola Sickle Cell Initiative, a collaboration between Texas Children’s Hospital, Baylor College of Medicine, the Ministry of Health of Angola, and Chevron.  The screening laboratory has successfully operated for several years, diagnosing thousands of affected infants.

Yet, comprehensive newborn screening by centralized clinical laboratories may be impractical in Africa because many births occur outside of hospitals, in homes, in remote villages. Shevkoplyas and his team are adapting their research to screen African children for SCD when they visit field hospitals for the first time. Parents begin arriving with their children when manifestations of SCD appear, typically around the age of 6 months when the level of sickle hemoglobin in their blood reaches adult levels.

Diagnostic tool also helps SCD patients at home

The paper-based test is much easier to perform than the current diagnostic techniques, which is particularly important in Africa. Yet, the test can also positively affect SCD patients in the United States. For example, a monthly blood transfusion, which is a common therapy for many SCD patients, requires clinicians to measure the level of sickle hemoglobin to optimize treatment.

Shevkoplyas’ simple diagnostic tool could eliminate the need to send the specimen to a lab for analysis, an often-lengthy process necessary with current quantitative methods, and consequently, the need for multiple visits. Instead, clinicians could perform the paper-based test and the transfusion during the same appointment because the results are available immediately.

“Taking a child with SCD to the hospital for transfusion therapy currently means a parent must often miss two or more days of work per month – one day for the blood test and a second day for the transfusion,” Shevkoplyas said. “This adds a lot of undue stress on the families and makes an already difficult situation even worse.”

Funding from NIH helps advance towards commercialization

Halcyon Biomedical Incorporated, a startup company co-founded by Shevkoplyas in part to commercialize the paper-based test, submitted a grant proposal based on the results of his preliminary research, which he achieved without funding, to the National Institutes of Health, NIH. In 2014, the NIH awarded Halcyon Biomedical with a two-year, $450,000 Small Business Innovation Research grant to continue his pursuit.

“I think the NIH chose to make this a small business grant rather than a research grant because they believe, and rightfully so, that technology must be commercialized to make a sustainable impact on the health and well-being of patients,” Shevkoplyas said. “The NIH reviewers evaluated our proposal and placed it in the ‘exceptional to outstanding range’ – a direct quote from the summary statement. They gave our proposal an impact score of 15, which is so high it’s almost unheard of.”

Shevkoplyas and his colleagues have recently applied for follow-up funding from the NIH to complete a clinical trial of the diagnostic test at several clinical sites in sub-Saharan Africa, including Angola, Mali, Nigeria, Zambia and Tanzania.

“Biomedical research is great fun, but most of the time the only thing we can show for our hard work is a publication in a peer-reviewed journal,” Shevkoplyas said. “With this project, my colleagues and I have a unique opportunity to make a real impact. I personally don’t have any choice but to see this project all the way through. My wife told me to.”




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