3.3 Interpretive consults and clinical decision support alerts
An interpretive pharmacogenetics consult placed in the medical record
assigned G6PD phenotype based on genotype alone or based on genotype and
activity if an activity result was already available. Examples of
interpretive consults which assign G6PD phenotype from G6PDgenotype and activity are provided in Supplemental Figs. S2A and S2B.
Four CDS alerts were implemented in the EHR. For patients with G6PD
deficiency, when a high-risk medication is prescribed, a CDS alert is
presented to the prescriber, recommending avoiding the drug (Fig. 3) or
using caution with the drug (Supplemental Fig. S3A). Additionally, for
patients without a G6PD genotype or G6PD activity result, when a
high-risk medication is prescribed, an alert is presented to the
prescriber with a recommendation to order a G6PD activity test to assign
a G6PD status (Supplemental Fig. S3B). Similarly, when a high-risk
medication is prescribed to a patient with variable G6PD phenotype, an
alert is presented to the prescriber with a recommendation to order a
G6PD activity test to assess for G6PD deficiency (Supplemental Fig.
S3C).
Discussion
Our results highlight the need to assess for interferences when
interpreting G6PD activity results to prevent a potentially incorrect
G6PD phenotype assignment.
Patients incorrectly phenotyped by
G6PD activity alone in our study included those with severe anemia,
reticulocytosis, recent red blood cell transfusion, and new leukemia
diagnoses. These patients were correctly categorized by G6PDgenotyping. Additionally, for some patients (e.g., those with sickle
cell disease or those with anemia) G6PD activity results may be
uninterpretable due to abnormal hematologic parameters, makingG6PD genotype the only available method to confirm G6PD
deficiency and prevent adverse effects, such as hemolytic anemia, from
high-risk medications.
We describe the clinical implementation of G6PD genotype testing
performed preemptively in the context of a multi-gene panel. This
preemptive approach is relatively inexpensive on a per-gene basis, as
the cost to test many genes is not much greater than the cost to test
one gene. With this preemptive testing approach, the results are already
in hand at the time of prescribing a high-risk drug, removing the time
constraints of ordering and waiting for a test result. The majority of
patients have at least one high-risk pharmacogenetic result returned
from a multi-gene panel approach.23
In the current cohort, adding G6PD genotype to G6PD activity
resulted in a change in G6PD status in 1% of patients, relative to
status previously assigned based on G6PD activity alone. Incorrect
phenotype assignment from G6PD activity results had implications for
both false negatives (1 of 3 incorrectly identified as normal received a
high risk drug and developed drug-induced hemolytic anemia), and for
false positives (2 were incorrectly identified as deficient but were
normal), and these latter patients can have the diagnosis of G6PD
deficiency removed from their problem list and receive G6PD drugs
normally. This current report suggests that G6PD genotype is a
reliable method for assigning G6PD phenotype, as all patients with
deficient activity in our cohort were deficient by genotype, and
discordances between genotype and activity were explained by
interferences in the G6PD activity assay. The 83.3% sensitivity of the
activity test in females and 86.7% sensitivity in males highlights the
opportunity for a genotype result to improve identification of patients
with G6PD deficiency, especially in those with abnormal hematologic
parameters which may interfere with the activity test results and
interpretation. G6PD activity testing is affected by various hematologic parameters.
Despite these limitations and because of its relatively quick turnaround
(i.e., same day at our institution) compared to G6PD genotyping
(two weeks at our institution), G6PD activity has been the gold standard
test for G6PD phenotype assignment. As G6PD genotype results are
becoming increasingly available to clinicians through clinical
sequencing or genotyping tests, we provide clinicians with a method to
assign a G6PD phenotype using genotype alone and using genotype and
activity results when both are available.
Acknowledgments The authors would like to thank the St. Jude Children’s Research
Hospital PG4KDS team for their assistance in implementing G6PDgenotyping/testing as well as Amy Turner, Gunter Scharer, and Praful
Aggarwal of RPRD Diagnostics for their work in providing G6PDgenotyping. NIH Grants CA 21765, GM 115279 and ALSAC.
Conflicts of Interest The authors declare that there is no conflict of interest.