Researchers discovered that a polygenic risk score, a tool commonly used in research to evaluate a person’s genetic risk for a disease, was no better than written reports at predicting the outcome of a schizophrenia patient’s disease over time. The findings raise serious concerns about the use of polygenic risk scores in clinical settings, and they also suggest that a doctor’s written report may be an untapped source of predictive information.
Researchers at Mount Sinai’s Icahn School of Medicine combed through the genetic and medical records of over 8,000 schizophrenia patients using cutting-edge computer programs. They discovered that a polygenic risk score, a tool commonly used in research to assess a person’s genetic risk for a disease, was no better than written reports at predicting the outcome of a patient’s disease over time.
“Treating schizophrenia patients is a heartbreaking experience. Trying to predict whether a patient’s condition will worsen or improve is one of the most difficult aspects of patient care. If we could do that, we might be able to alleviate the pain that the patients and their loved ones are experiencing” said Alexander W. Charney, MD, PhD, Assistant Professor in the Departments of Psychiatry and Genetics and Genomic Sciences at Icahn Mount Sinai and senior author of the Nature Medicine study.
Treating schizophrenia patients is a heartbreaking experience. Trying to predict whether a patient’s condition will worsen or improve is one of the most difficult aspects of patient care. If we could do that, we might be able to alleviate the pain that the patients and their loved ones are experiencing.Alexander W. Charney
“Our findings show that, for the most deeply characterized mental illnesses at the genetic level, the current state of genetics research cannot yet solve this problem.”
Schizophrenia, which affects approximately 20 million people worldwide, is a life-limiting mental disorder that alters the way a person thinks, acts, and perceives reality. Symptoms typically appear in the late teens to early thirties and can last a lifetime. While some patients may respond well to treatment, others do not.
Despite the fact that it is a highly inherited disease, the majority of cases cannot be traced back to a single gene. Instead, scientists discovered that the risk of developing schizophrenia is influenced by a complex combination of normal genetic variants, none of which contribute significantly to risk but account for a large proportion of cases. Currently, nearly 300 of these variants have been linked to schizophrenia.
The polygenic risk score is a popular method for summarizing a person’s genetic component of disease risk. Many large studies over the last decade have found that the risk scores of schizophrenia patients are significantly higher than those of healthy controls. Studies on other disorders, such as hypertension and diabetes, have yielded similar results.
“The polygenic risk score is calculated by adding all of the traits associated with a complex disorder. It was initially intended to be a descriptive tool. Scientists have recently proposed that it could be an effective tool for precision medicine, in which a person’s genetics are used to diagnose disease and predict outcomes “said Isotta Landi, PhD, a postdoctoral fellow in Dr. Charney’s lab and the study’s lead author. “We wanted to rigorously test whether the polygenic risk score could also be used as a predictive tool in this study.”
The researchers first compared the genetic and medical records of 762 schizophrenia patients stored in Mount Sinai Health System’s BioMeTM BioBank program. They specifically tested whether a patient’s polygenic risk score for schizophrenia could predict six poor outcomes for each patient any better than information derived from doctor-written medical reports.
Dr. Landi collaborated with others to create advanced computer programs that calculate polygenic risk scores from a patient’s genetic data and extract information from written reports using natural language processing tools.
They discovered that higher polygenic risk scores were significantly associated with two of the outcomes: aggressive behavior and the need for hospitalization. The scores, however, were no better at predicting these outcomes than the information derived from the written reports, and combining the two had no effect on predictability.
These findings were supported by follow-up experiments. For example, when the researchers tried to predict outcomes only in people with the highest polygenic risk scores, they found no difference in the results. Finally, when they examined the genetic and medical records of 7,779 patients from the Genomic Psychiatry Cohort, a large National Institutes of Health-funded project, they discovered the same pattern. Once again, polygenic risk scores did not improve clinical data’s ability to predict poor outcomes.
“Our findings suggest that more work is needed to fully realize the potential of genetics to improve the treatment of schizophrenia patients,” Dr. Charney said. “The findings also suggest that detailed medical reports written by doctors may contain far more valuable and predictive information than we previously thought.”