Spectrum CTSA pilot project improves clinical prediction of severe dengue progression

Dengue virus (DENV) is an ongoing threat to global and child health as there are currently no effective vaccines or approved antivirals. About five to 20 percent of symptomatic dengue patients per year ­– three to six million people – experience progression to severe dengue (SD) infection, yet there are no effective clinical biomarkers to predict which patients will develop this life- threatening complication.

But Stanford researchers, funded in 2015 by a Spectrum CTSA pilot grant and mentored through the SPARK program, have discovered an 8-gene set that is predictive of the progression from DENV to SD. This discovery is now being translated into the development of a paradigm-shifting molecular prognostic assay that can help define the level of care for specific patients, thereby reducing morbidity and mortality.

The team, led by Associate Professor of Medicine Purvesh Khatri and Associate Professor of Medicine (Infectious Diseases) and of Microbiology and Immunology Shirit Einav, used public datasets to identify eight differentially expressed genes (DEGs) that diverged early in the disease course between non-severe patients and SD progressors. From this gene set, they built an XGBoost model with greater generalizability than linear models.

After the SPARK pilot ended, the research continued. “We validated the 8-gene set in an independent, prospectively enrolled cohort of over 400 dengue patients in Colombia,” explains Dr. Einav. Model performance, alone or combined with clinical features, was evaluated using whole blood samples collected upon presentation. The locked 8-gene XGBoost model, trained on heterogeneous dengue datasets, accurately predicted progression to SD in the Colombia cohort, including in the early febrile stage. It substantially improved prediction of SD compared to clinical warning signs and provided additional prognostic power even after accounting for clinical parameters.  

“The assay can also be used to guide the design of therapeutic clinical trials and future treatment decisions once anti-DENV therapies, such as those we are developing, are approved,” adds Dr. Einav.

Dr. Benjamin Pinsky from Stanford collaborated with Drs. Einav and Khatri on this project. The team’s discoveries were published in Genome Medicine in March 2022. The project is ongoing, with most basic research completed and development of the actual diagnostic in progress.