NEW YORK – Using electronic health record (EHR) data for nearly 2 million individuals, a Vanderbilt University Medical Center-led team tracked shifts in clinical genetic test applications, uptake, methods, and findings over two decades.
"By comprehensively curating genetic testing from the EHRs, we were able to characterize its use and value across medical specialties and over time," first and corresponding author Lisa Bastarache, a biomedical informatics and digital genomic medicine researcher at the VUMC, and her colleagues wrote in the American Journal of Human Genetics on Wednesday.
For their study, researchers from VUMC and Concert Genetics brought together EHR data for more than 1.8 million individuals treated at VUMC from 2002 to 2022, identifying 104,392 genetic tests performed for 77,033 individuals. Nearly 86 percent of those tests were performed with diagnoses in mind, though 9.6 percent represented carrier screening tests and 4.4 percent of the tests were done to test for familial variants.
With these data, the investigators saw an overall uptick in the use of clinical genetic tests over time, coupled with a corresponding rise in diagnoses and the identification of variants of uncertain significance.
More than 6 percent of EHRs from 2022 contained clinical genetic test results, for example, compared to just 1 percent of EHRs reviewed from 2002. Genetic testing was particularly common in contemporary EHRs from patients who visited a specialist, where testing was observed in 1 in 8 patients.
"[T]wenty years ago genetic testing was quite niche, and was given to only a small fraction of patients, most of whom were affected by serious and life-limiting conditions like cystic fibrosis," Bastarache said in an email, noting that clinical genetic testing is now used "across essentially all areas of medicine."
Along with the identification of genetic risk variants in 18,476 individuals, the clinical genetic tests considered led to diagnoses in 19,032 cases, including 533 patients with multiple diagnoses. Those diagnoses involved more than 7,500 conditions ranging from Down syndrome, Duchenne muscular dystrophy, cystic fibrosis, or Huntington disease to relatively rare conditions found in just one individual.
"In 2002, only 51 different conditions were diagnosed with genetic testing," Bastarache noted. "That number grew to 509 by 2022."
In general, the genetic tests selected became more comprehensive over time, including a shift from single-gene to multi-gene panel testing.
"Our findings were broadly consistent with previous studies," the authors reported, "showing an increase in clinical genetic testing over the last 20 years, a trend toward more comprehensive testing, a corresponding increase in the total number and diversity of diagnoses, and an increased number of inconclusive test results."
More than one-quarter of the clinical genetic tests were done using multi-gene panel sequencing, while single-gene and single-variant tests, respectively, accounted for 23.1 percent and 17.3 percent of the tests performed. Another 14.1 percent of tests were done using chromosomal microarrays, while karyotype tests made up 9.7 percent of tests and 7.1 percent focused on repeat-expansions.
Just 1.3 percent of the clinical tests were done with exome or whole-genome sequencing, the team reported, noting that 1.1 percent of clinical genetic tests included methylation testing.
With the help of data from the genetic test and EHR data, the researchers also performed phenome-wide analyses to tally the "genetically attributable fraction" (GAF) of clinical phenotypes of interest, flagging 74 phenotypes or conditions with at least 5 percent GAF.
The investigators cautioned that the current analyses centered specifically on germline genetic tests done at one academic medical center with a "substantial clinical genetic footprint," which may have more experience, focus, and expertise in clinical genetics and related EHR records than those found at other sites.
Despite the uptick in clinical genetic tests done over time, the team noted there are still obstacles to standardizing the ways clinical genetic tests are recorded in EHRs, with a significant subset of test results documented in a narrative manner rather than being recorded in a consistent, structured format.
In contrast, Bastarache explained, the current study "shows the value of structuring genetic test results in the EHR."
"Currently, the vast majority of genetic tests are linked to EHRs as PDFs, which are not machine readable," she explained. "If these data were stored in a computable format in the EHR, we would gain a better sense of how testing is being used across a health system and likely find areas where testing practices could be improved."
In addition, the inclusion of more structured clinical genetic testing data in health records is expected to boost investigators' ability to investigate genetic contributors to rare disease in the future, by making it easier to identify rare disease patients and their genetic test results in EHRs.
With that in mind, members of the VUCM team hope to come up with automated health record data extraction methods to improve rare disease diagnoses and refine what is known about genotype-phenotype relationships, Bastarache noted. They are currently developing methods to interrogate clinical genetic databases for clues to the range of clinical presentations possible for conditions such as cystic fibrosis, Marfan syndrome, or sickle cell anemia.
"Given the rapid accrual of clinical genetic tests and diagnoses in our health systems, we are at the beginning of what I believe will be a new wave of research that looks at rare diseases at the population level," she said, "leading to tangible improvements in the diagnosis and care of patients affected by genetic disorders."