Next-gen sequencing workflow in full spate

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Adapted from J Mol Diagn. Vol.16, Pritchard CC, et al. “Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens,” 56–57. ©Elsevier (2014).

Of the clinical reporting of NGS results, Dr. Pritchard said it requires more than simply pushing a button. “Bioinformatics alone will not get us a correct diagnosis most of the time,” he said.

“Particularly among my basic research colleagues, although they know more about scripting, sometimes they miss the point of what is happening in the clinical lab. In reporting there needs to be a balance between how much is automated and how much the laboratory director reviews.

“Without bioinformatics there is no way we could do this,” he continued. “But I don’t think we could do this at all without expert people doing manual review. And I don’t think this is going to change anytime soon. We need to understand the patient and the subtleties of the data itself.”

Dr. Pritchard

Interpreting the pathogenicity of variants requires use of databases of known variants. “One of the best external databases is ClinVar, where you can review the evidence base for germline variants,” Dr. Pritchard said. Another good browser is ExAC, a database of variants from more than 60,000 cancer patients (exac.broadinstitute.org) established by the Exome Aggregation Consortium. “It is important to understand what ExAC is and is not,” Dr. Pritchard said. For instance, it does not include all types of variations, particularly not copy number alterations.

Sign-out in the UW genetics and solid tumors laboratory employs a multidirector, multidisciplinary model. To start, at least two reviewers select independently a short list of variants, which a review board then looks at. “We’re certainly not the only ones taking this approach,” Dr. Pritchard said. “Many centers doing large panels have a physician board review of one sort or another. It’s been a successful strategy for us. For every NGS panel we do, at least two people review the data, and often more”—typically four or five. One director writes the final report.

Of the cost of this approach, he said: “Local tumor boards enable true personalized medicine.” They’re good, too, for residents and fellows in pathology and laboratory medicine, who “almost universally love it.”

Dr. Shirts is a member of a large National Human Genome Research Institute-funded consortium called Clinical Sequencing Exploratory Research, consisting of 377 researchers from 21 institutions. It was established to guide the dissemination and implementation of best practices for integrating sequencing into clinical care. Dr. Shirts has been part of a working group that is looking at how exome and genome results are displayed in the electronic health record. In the exploratory survey of 17 institutions, they found that within the same hospital, genomic information can be displayed in many different formats: free text, structured data, physician notes. Moreover, the same molecular result can be in two formats depending on whether it was found in an exome or targeted gene test.

Molecular results can go in different places. Pathology reports usually go into a separate tab. Most institutions don’t have a structure for genetic results to go into a separate place where they can be queried quickly. Results were predominantly displayed as PDF documents without decision support (Tarczy-Hornoch P, et al. Genet Med. 2013;15:
824–832).

In an interview, Dr. Shirts addressed the question of decision support for genetic information.

“Imagine a test done several years ago, ordered by a different provider but pertinent to what the patient is experiencing now,” he said. “Electronic decision support could be aware of the past medical record and bring it to the attention of the physician. In order for the EHR to behave that way, someone needs to program that in, and in a way that is machine readable.

“One of the major priorities of our group is to move things in the direction that we can have electronic decision support remind physicians of what genetic information is telling them they should be doing for the patient.” Dr. Shirts noted one big difference between genetic information and other tests. “Once a person has a genetic test done, they wouldn’t have it done again. It could stay in the EMR for decades. But physicians look for the most recent results. So they might not see the outcome of a genetic test done a long time ago.”

Collaborating with another National Human Genome Research Institute working group, Electronic Medical Records and Genomics (eMERGE) Network, Dr. Shirts’ group came up with several recommendations, most centered around improved electronic decision support. Here are the three highest ranked recommendations, with the percent of respondents ranking each in their top four (Shirts B, et al. J Am Med Inform Assoc. 2015;22:
1231–1242):

• Provide clinical decision support for genetic results that are medically actionable (90 percent).
• Develop mechanisms to trigger an alert about drug interactions if a relevant drug is predicted (70 percent).
• Develop a mechanism for medically actionable genetic information to trigger an alert to the treating clinician (70 percent).

At this point the recommendations have only the force of persuasion, and that’s all right with Dr. Shirts. “There is currently no regulatory organization for this, and I don’t think we want one right now,” he said.

Dr. Shirts’ EHR working group is now lending its support to the action collaborative DIGITizE (Displaying and Integrating Genetic Information Through the EHR), formed under the auspices of the National Academies. DIGITizE is composed of people from industry, academia, and health care systems. Its goal is to create implementation guides for genomic computerized decision support. “We need to move the field forward a bit more before regulatory work would be beneficial,” Dr. Shirts said. To have FDA regulate NGS right now “could potentially be a disaster for the field,” in Dr. Shirts’ view.

“We do want to have more structures and more standards,” he said, “but we are still trying to figure out what standards make sense.”
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William Check is a writer in Ft. Lauderdale, Fla.