Precision Medicine: the Arrival of Genomics to the Clinic is the Beginning of a Longer Journey

It has been a year since the announcement of the new US Precision Medicine Initiative. As new funding is awarded to investigators across the country, the pace of assembling the cohort of a million or more individuals will accelerate. This cohort will link information from genomic, behavioral, social, environmental, and health outcomes to discover and evaluate new biomarkers and interventions for disease prevention and treatment. Genomic data is a central component of this initiative, propelled by scientific discoveries in genomic variations that are potentially important in multiple diseases across the life span.

To get an inkling of the kind of information that could be obtained from such a cohort in the future, we turn to the recently published study in JAMA, in which Van Driest and colleagues explore the potential clinical impact of suspected “pathogenic” variations in 2 ion channel genes previously associated with fatal cardiac conditions such as sudden death. The analysis was conducted in populations not selected for cardiac problems using information contained in electronic medical records (EMR). In many regards, this study foreshadows the potential applications of the Precision Medicine Initiative cohort data.

Van Driest et al found 223 individuals (11% of the cohort, about 2200 individuals) harbored 1 or more rare variants in the 2 genes. 42 rare variants in 63 individuals were determined by at least 1 of the 4 reference sources (3 laboratories, and the ClinVar variant database) to be pathogenic or likely pathogenic. Despite having a median of 18 years of EMR data for the study population the authors found no association among the presence of these variants and diagnostic codes or EKG evidence of conduction defects. In addition, they found that the level of agreement among the 3 laboratories and ClinVar in assigning pathogenicity was very low.

Though this is a single study in a relatively small population, examining only 2 genes associated with a few uncommon conditions, these findings may have important implications that generalize to precision medicine and population health. For one, they show that linkage of genome sequencing with health data using EMRs can be implemented successfully to study the clinical validity of genetic variations in large populations. Moreover, these data show that we need to be rigorous in our evidence-based approach to labeling genetic variation as pathogenic or not, especially when it comes to healthy individuals. Establishing clinical validity will be important in characterizing risks of disease and clinical outcomes before results are returned to participants of these studies. Not surprisingly, the low agreement found in this study in labeling pathogenicity among reference laboratories and Clinvar reflects the lack of empirical data needed to characterize disease risks in unselected populations. Finally, establishing clinical utility of genomic information will require more studies ahead to characterize the risks and benefits of communicating and acting on this information with patients.

As we temper our excitement about precision medicine, it is important to realize that the arrival of large scale genomic data to the clinic is only the beginning of a longer journey that involves careful characterization of health impact, validation of the utility of making use of testing, and evaluation of the effects of genomics implementation in order to benefits patients, families and populations. As Sekar Kathiresan, a genomics researcher, from Massachusetts General Hospital recently stated: “To have genomics impact clinical medicine, we need to be able to accurately interpret the genome, to properly describe the phenotypic impact of any given variation…Right now, we are like my second-grader who can pronounce the words but often doesn’t understand meaning. Hopefully, with new tools like the NIH’s Precision Medicine Initiative, we will develop into advanced genome readers who understand spelling, pronunciation, and clinical meaning.”