With next generation sequencing (NGS), we are now able to provide genetic tests that are more comprehensive, faster, and less expensive per base than ever before. But, this doesn’t mean that NGS is low-cost. As laboratories get into the NGS game, they quickly realize that the technology is expensive, there are multiple new complexities encountered, and there may be issues surrounding reimbursement and regulations. These factors may cause many to question if it’s worth offering this type of testing at all. The short answer is: maybe! Before setting up an NGS testing program, laboratories should consider which types of tests would provide value to their internal and external clients, and balance this with an awareness of the resource-heavy nature of NGS.
There are several different clinical uses for NGS with much of the testing falling into three major categories: gene panels for oncology (somatic), gene panels for inherited disorders (germline), and whole exome/genome sequencing (WES/WGS) for diagnostic odyssey/rare disorders. The latter two are not as dependent on rapid turnaround time (with the exception of rapid genome sequencing for critically ill newborns), and therefore they may not be as critical to implement for in-house testing purposes. However, somatic panels usually require quick turnaround and may be a good choice for laboratories that want to service their internal practice for this clinical need. It is important to keep in mind that a timely orthogonal method for confirming reportable somatic testing results may need to be factored in, and could involve NGS sample processing in parallel. For many oncology and inherited disorder gene panel tests, there is a race between laboratories to provide the most comprehensive test. Laboratories and clinicians, however, need to realize that more is not always better. Labs need to be shrewd about their gene panel design, evaluating the clinical utility of each gene and including only those genes with a strong evidence base. Why is this important? Because the more genes that are included, the more variants are detected (including variants of uncertain significance [VUSs]), and, consequently, more variant interpretation and categorization will need to be carried out. All of this translates to resources spent by the laboratory, time spent by the clinician trying to understand and explain the results, a higher potential for incorrect interpretation of the report by clinician/patient, and potentially unnecessary follow-up testing on VUSs. So, careful upfront gene panel design with multiple iterations between genetic counselors, clinicians, and laboratory directors is time well spent. Notwithstanding all of the care that has gone into designing the gene panel, many laboratories will need to update their panel to add new genes every six to 12 months. There are two main reasons for this: first, clinician demand for a very specific panel (often a subpanel of a larger panel, especially in the cases of somatic testing); and, second, the discovery of new genes that may have clinical utility. Laboratories will find, however, that upgrading NGS tests is difficult; each panel needs to be redeveloped and revalidated as genes are added. Therefore, laboratories may want to think about upfront development and validation of a very large gene panel reagent (containing as many genes as could possibly be needed; perhaps even the exome or an enhanced medical exome reagent) and implementing sub-panels from it. This approach could prevent some of the later redevelopment and revalidation of tests, and would help to streamline validation efforts and workflows by having one large reagent with many sub-panel tests. Personnel can be another resource constraint. With the introduction of NGS comes the hiring of bioinformaticians. Because bioinformaticians are generally new to the clinical laboratory workspace, effort is required to thoroughly validate the bioinformatics pipeline and provide full training to ensure competency of bioinformaticians with respect to the clinical testing environment. This is unchartered territory for many labs, and there may be a steep learning curve initially. In addition, implementing NGS tests also dictates the need to increase genetic counselor capacity. Because of the increased demands on genetic counselors, and the general shortage of them, laboratories will need to implement creative solutions to offload some of their work without compromising the integrity of the test. While NGS testing can prove costly, there is a definite clinical need and benefit that is pushing many laboratories towards implementing it. My tips for minimizing resource constraints include thoughtful gene panel design; streamlining development, validation, and workflows through a maximized test reagent; preparedness in terms of assessing employee competence; and consideration of employee workload demands. Careful upfront thought and planning, though, will really help to prevent downstream unnecessary expenses as laboratories embark on their journey of NGS clinical testing.
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