Mount Sinai Researchers Use AI and Lab Tests to Predict Genetic Disease Risk
AI model uses common data to gauge risk from rare genetic variants
When genetic testing reveals a rare DNA mutation, doctors and patients are frequently left in the dark about what it actually means. Now, researchers at the Icahn School of Medicine at Mount Sinai have developed a powerful new way to determine whether a patient with a mutation is likely to actually develop disease, a concept known in genetics as penetrance.
The team set out to solve this problem using artificial intelligence (AI) and routine lab tests like cholesterol, blood counts, and kidney function. Details of the findings were reported in the August 28 online issue of Science. Their new method combines machine learning with electronic health records to offer a more accurate, data-driven view of genetic risk.
Traditional genetic studies often rely on a simple yes/no diagnosis to classify patients. But many diseases, like high blood pressure, diabetes, or cancer, don’t fit neatly into binary categories. The Mount Sinai researchers trained AI models to quantify disease on a spectrum, offering more nuanced insight into how disease risk plays out in real life.
“We wanted to move beyond black-and-white answers that often leave patients and providers uncertain about what a genetic test result actually means,” says Ron Do, PhD, senior study author and the Charles Bronfman Professor in Personalized Medicine at the Icahn School of Medicine at Mount Sinai. “By using artificial intelligence and real-world lab data, such as cholesterol levels or blood counts that are already part of most medical records, we can now better estimate how likely disease will develop in an individual with a specific genetic variant. It’s a much more nuanced, scalable, and accessible way to support precision medicine, especially when dealing with rare or ambiguous findings.”
Using more than 1 million electronic health records, the researchers built AI models for 10 common diseases. They then applied these models to people known to have rare genetic variants, generating a score between 0 and 1 that reflects the likelihood of developing the disease.
A higher score, closer to 1, suggests a variant may be more likely to contribute to disease, while a lower score indicates minimal or no risk. The team calculated “ML penetrance” scores for more than 1,600 genetic variants.
Some of the results were surprising, say the investigators. Variants previously labeled as “uncertain” showed clear disease signals, while others thought to cause disease had little effect in real-world data.
“While our AI model is not meant to replace clinical judgment, it can potentially serve as an important guide, especially when test results are unclear. Doctors could in the future use the ML penetrance score to decide whether patients should receive earlier screenings or take preventive steps, or to avoid unnecessary worry or intervention if the variant is low-risk,” says lead study author Iain S. Forrest, MD, PhD, in the lab of Dr. Do at the Icahn School of Medicine at Mount Sinai. “If a patient has a rare variant associated with Lynch syndrome, for instance, and it scores high, that could trigger earlier cancer screening, but if the risk appears low, jumping to conclusions or overtreatment might be avoided.”
The team is now working to expand the model to include more diseases, a wider range of genetic changes, and more diverse populations. They also plan to track how well these predictions hold up over time, whether people with high-risk variants actually go on to develop disease, and whether early action can make a difference.
“Ultimately, our study points to a potential future where AI and routine clinical data work hand in hand to provide more personalized, actionable insights for patients and families navigating genetic test results,” says Dr. Do. “Our hope is that this becomes a scalable way to support better decisions, clearer communication, and more confidence in what genetic information really means.”
The paper is titled “Machine learning-based penetrance of genetic variants.”
The study’s authors, as listed in the journal, are Iain S. Forrest, Ha My T. Vy, Ghislain Rocheleau, Daniel M. Jordan, Ben O. Petrazzini, Girish N. Nadkarni, Judy H. Cho, Mythily Ganapathi, Kuan-Lin Huang, Wendy K. Chung, and Ron Do.
This work was supported in part by the following grants: National Institute of General Medical Sciences of the National Institutes of Health (NIH) (T32-GM007280); the National Institute of General Medical Sciences of the NIH (R35-GM124836); the National Institute of Diabetes and Digestive and Kidney Diseases (U24-DK062429); the National Human Genome Research Institute of the NIH (R01-HG010365); the National Institute of General Medical Sciences of the NIH (R35-GM138113); and the National Institute of Diabetes and Digestive and Kidney Diseases (U24-DK062429).
About Mount Sinai's Windreich Department of AI and Human Health
Led by Girish N. Nadkarni, MD, MPH—an international authority on the safe, effective, and ethical use of AI in health care—Mount Sinai’s Windreich Department of AI and Human Health is the first of its kind at a U.S. medical school, pioneering transformative advancements at the intersection of artificial intelligence and human health.
The Department is committed to leveraging AI in a responsible, effective, ethical, and safe manner to transform research, clinical care, education, and operations. By bringing together world-class AI expertise, cutting-edge infrastructure, and unparalleled computational power, the department is advancing breakthroughs in multi-scale, multimodal data integration while streamlining pathways for rapid testing and translation into practice.
The Department benefits from dynamic collaborations across Mount Sinai, including with the Hasso Plattner Institute for Digital Health at Mount Sinai—a partnership between the Hasso Plattner Institute for Digital Engineering in Potsdam, Germany, and the Mount Sinai Health System—which complements its mission by advancing data-driven approaches to improve patient care and health outcomes.
At the heart of this innovation is the renowned Icahn School of Medicine at Mount Sinai, which serves as a central hub for learning and collaboration. This unique integration enables dynamic partnerships across institutes, academic departments, hospitals, and outpatient centers, driving progress in disease prevention, improving treatments for complex illnesses, and elevating quality of life on a global scale.
In 2024, the Department's innovative NutriScan AI application, developed by the Mount Sinai Health System Clinical Data Science team in partnership with Department faculty, earned Mount Sinai Health System the prestigious Hearst Health Prize. NutriScan is designed to facilitate faster identification and treatment of malnutrition in hospitalized patients. This machine learning tool improves malnutrition diagnosis rates and resource utilization, demonstrating the impactful application of AI in health care.
For more information on Mount Sinai's Windreich Department of AI and Human Health, visit: ai.mssm.edu
About the Hasso Plattner Institute at Mount Sinai
At the Hasso Plattner Institute for Digital Health at Mount Sinai, the tools of data science, biomedical and digital engineering, and medical expertise are used to improve and extend lives. The Institute represents a collaboration between the Hasso Plattner Institute for Digital Engineering in Potsdam, Germany, and the Mount Sinai Health System.
Under the leadership of Girish Nadkarni, MD, MPH, who directs the Institute, and Professor Lothar Wieler, a globally recognized expert in public health and digital transformation, they jointly oversee the partnership, driving innovations that positively impact patient lives while transforming how people think about personal health and health systems.
The Hasso Plattner Institute for Digital Health at Mount Sinai receives generous support from the Hasso Plattner Foundation. Current research programs and machine learning efforts focus on improving the ability to diagnose and treat patients.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai
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