At Velsera we meet and talk with all sorts of laboratory professionals working across various applications of clinical genomics and we commonly work with labs who are new to next generation sequencing (NGS). New labs, or labs offering new testing, don’t often know who their ordering physicians will be and their expected volumes. Thus, they may decide to delay hiring support staff who they will eventually need to work through the time-intensive NGS workflows for analysis and interpretation. Even established labs may find it hard to hire an entry-level employee and train them to be proficient at variant analysis, made even more challenging as there are no industry standard guidelines for this position. After hearing the struggle that labs go through to identify and/or train Variant Analysts we asked ourselves, “What are the most important things that a Variant Analyst needs to know?”
1. Foundations of Human Biology and Genetics
One of the first things that comes to mind is a good foundational knowledge of human biology and genetics. A Variant Analyst’s work is highly specialized, and a solid understanding of cellular processes, molecular biology, and human genetics is essential for the ability to interpret how genetic variation impacts gene function and disease. Without this foundation, a Variant Analyst would be blindly following checklists without the ability to see the larger picture of the patient and their disease.
2. NGS and Bioinformatic Pipelines
In-depth knowledge of next generation sequencing methods and bioinformatics isn’t necessarily required for a Variant Analyst to perform their job, but it helps with their overall understanding of test results and the ability to use data to make decisions on what to include or not. It also improves their versatility in the clinical realm, where troubleshooting poor test performance may be necessary. Knowing the details of each step; nuclei acid extraction, NGS (multiplexing, library preparation, and sequencing), and the bioinformatic pipeline (conversion of file formats, alignment, variant calling, and filtering) will allow Variant Analysts to understand how the results were obtained and where to investigate if anything goes wrong.
3. Knowing Your Test
One of the most important aspects of clinical testing is to know the ins and outs of the assay being used. Knowing the target space, the reported variant types, validation results (input, samples per run, LLOD, etc.) and subsequent filtering strategies used, sample and QC acceptability requirements, and test limitations are all important aspects to consider. Does my test have the sensitivity necessary to report somatic variants or mosaicism? What are the various error rates associated with my sequencing method? The ability for a Variant Analyst to comprehend these details is essential, as ultimately they are making the critical decisions on if a variant meets the necessary quality requirements to be included in a report.
4. Knowing Your Patients
Furthermore, test results need to be evaluated in the context of the patient’s disease. Each test will have an intended use that specifies which patients, diseases, and specimens are appropriate. Being well versed in things like the NCCN guidelines for the diseases your lab will test for will ensure that you understand the clinical utility of the test, the important variants specific to the disease, and any available treatments. Various details a Variant Analyst will need to know include: the mechanism of disease, variant types considered pathogenic, mode of inheritance, and follow up recommendations (genetic counseling or further testing). If you are testing for AML and your test doesn’t detect FLT3-ITDs you should make sure to supplement the test for these or recommend follow up testing. A variant analyst will need to consider all these and more to interpret genetic results properly.
5. Standardization – Classification Guidelines and Nomenclature
Standardization is necessary with how complex NGS results and their usage have become. Luckily, there are several groups working to this end. One of the most impactful developments has been the formation of guidelines for NGS variant classification. About 10 years ago the first NGS guidelines were released and since then guidelines have shifted from generic to disease-specific, driven by expert working groups. These guidelines use research and clinical evidence from many sources to support a final classification. A Variant Analyst’s job is to know which guidelines to use, the basis of why each criterion is important for classification, and where to find supporting evidence.
Another necessary element of standardization is nomenclature. The Human Genome Variation Society (HGVS) provides standardized nomenclature for NGS results. There are many rules to follow, they change based on the sample and variant type, and a Variant Analysts needs to know this to report results the correct way and to identify supporting evidence in literature and variant databases.
6. Creating Written Variant Interpretations
Professional writing and critical thinking are also very important skills for a Variant Analyst. In the clinical setting, test results are often accompanied by a written interpretation to facilitate better comprehension from the ordering physician and others who will read the report. It’s the job of the Variant Analyst to describe a variant and its characteristics to the reader, as well as its relevance in the context of the patient’s disease. Variant Analysts need to combine the various supporting evidence in a clear manner and provide any recommendations or considerations for follow up testing. Disseminating complex science in an easy to understand manner is important to ensure that the ordering physicians as well as the patients themselves are able to understand the implications of their tests.
Putting it all together
As it turns out, Variant Analysts need to know a lot of things… and it makes sense that all types of labs struggle to hire and train Variant Analysts. Other specialized laboratory professionals and physicians often have a clear path towards working in a clinical sequencing lab. For instance, doctors who want to specialize go through years of training as fellows to learn. Afterwards they prove their proficiency by taking their boards and, upon passing, receiving board certification. Lab technicians and genetic counselors have similar paths, and often multiple options for them. There isn’t a similar, recognized certification for Variant Analysts, and at Velsera we aim to change that…
Our team of Clinical Genomic Scientists and Variant Analysts have used our 83+ years of collective experience in this space to identify the key topics needed and we’re working on launching a certification to help you train in this area. Look for more from us as we get closer to launching in the next few months – or reach out if you’d like to learn more and be considered as a beta participant.