Integrating Large-Scale Genomic Information into Clinical Practice: Workshop Summary by Steve Olson

Author:Steve Olson
Language: eng
Format: epub
Tags: ebook, book
ISBN: 0309220378
Publisher: The National Academies Press
Published: 2012-12-21T00:00:00+00:00

Challenges in Implementation

Implementing this system has revealed several challenges that future genomic medicine initiatives will likely face, Relling said. First, she said, there is a lack of consensus or guidelines on which drug–gene diplotypes are most important, although she acknowledged that “it is better to have experts review the evidence and come up with some recommendations” even if they are not in agreement than to make each individual clinician have to synthesize his or her entire knowledge and medical practice experience. The PG4KDS program is addressing this issue through the PGRN. Specifically, a subgroup called the Clinical Pharmacogenetics Implementation Consortium has been formed to evaluate drug–gene pairs using standard grading systems, the peer-reviewed literature, and other information. Severity of disease, therapeutic alternatives, consequences of giving the wrong drug, and consequence of giving the right dose all have to be taken into account when making these decisions.

Another complication is that once a gene test is in the EMR, clinicians are obligated to use those results for all drugs affected by the test. Even rarely prescribed drugs need decision support. “It is going to take a lot of work to go through and make rules that we are all comfortable with,” Relling said.

Diplotypes are sometimes ambiguous because of the nature of the testing. For example, the DMET array often produces ambiguous calls, Relling said. “We have to look very carefully at the reasons for those ambiguous diplotype assignments. Is it the fact that you can’t phase haplotypes, so we can’t always distinguish between a heterozygous- and a homozygous-deficient patient? Or is it because of a simple no call of a probe for a rarely involved SNP? Someone has to decide whether those [ambiguous assignments are actually important] or not, and again that takes a high level of knowledge of the genes and the drugs.”

Using a software program called PHASE, a much higher percentage of diplotype assignments can be made non-ambiguous, but it is a judgment call as to whether to deliver that information to the clinician. Interpretation is complex and time consuming, and it changes over time, Relling observed. For example, even with the relatively simple TPMT diplotypes, about 8 percent of patients have an ambiguous diplotype. Some patients are homozygous deficient, and if they get a normal dose of thiopurine, there is a high probability they will die of toxicity, whereas other patients can tolerate doses for a much longer time period. “Basically, we have to write very specific [reports] to say what the caveat is in interpreting these kinds of results.”

Multiple testing of the same gene over the lifetime of the patient requires that someone check to see whether the results contain discrepancies. One must also check other details such as whether the race of a patient in the EMR agrees with the patient’s self-declared race or whether the sex in the EMR agrees with the self-declared sex. “Flagging some of those genotypes and eventually manually approving them to move from the research laboratory into the EMR takes a lot of steps,” Relling said.

Download

Copyright Disclaimer:
This site does not store any files on its server. We only index and link to content provided by other sites. Please contact the content providers to delete copyright contents if any and email us, we'll remove relevant links or contents immediately.