Assessment of the Implementation of Pharmacogenomic Testing in a Pediatric Tertiary Care Setting.

Importance: Pharmacogenomic (PGx) testing provides preemptive pharmacotherapeutic guidance regarding the lack of therapeutic benefit or adverse drug reactions of PGx targeted drugs. Pharmacogenomic information is of particular value among children with complex medical conditions who receive multiple medications and are at higher risk of developing adverse drug reactions. Objectives: To assess the implementation outcomes of a PGx testing program comprising both a point-of-care model that examined targeted drugs and a preemptive model informed by whole-genome sequencing that evaluated a broad range of drugs for potential therapy among children in a pediatric tertiary care setting. Design, Setting, and Participants: This cohort study was conducted at The Hospital for Sick Children in Toronto, Ontario, from January 2017 to September 2020. Pharmacogenomic analyses were performed among 172 children who were categorized into 2 groups: a point-of-care cohort and a preemptive cohort. The point-of-care cohort comprised 57 patients referred to the consultation clinic for planned therapy with PGx targeted drugs and/or for adverse drug reactions, including lack of therapeutic benefit, after the receipt of current or past medications. The preemptive cohort comprised 115 patients who received exploratory whole-genome sequencing-guided PGx testing for their heart conditions from the cardiac genome clinic at the Ted Rogers Centre for Heart Research. Exposures: Patients received PGx analysis of whole-genome sequencing data and/or multiplex genotyping of 6 pharmacogenes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, VKORC1, and TPMT) that have established PGx clinical guidelines. Main Outcomes and Measures: The number of patients for whom PGx test results warranted deviation from standard dosing regimens. Results: A total of 172 children (mean [SD] age, 8.5 [5.6] years; 108 boys [62.8%]) were enrolled in the study. In the point-of-care cohort, a median of 2 target genes (range, 1-5 genes) were investigated per individual, with CYP2C19 being the most frequently examined; genotypes in 21 of 57 children (36.8%) were incompatible with standard treatment regimens. As expected from population allelic frequencies, among the 115 children in the whole-genome sequencing-guided preemptive cohort, 92 children (80.0%) were recommended to receive nonstandard treatment regimens for potential drug therapies based on their 6-gene pharmacogenetic profile. Conclusions and Relevance: In this cohort study, among both the point-of-care and preemptive cohorts, the multiplex PGx testing program provided dosing recommendations that deviated from standard regimens at an overall rate that was similar to the population frequencies of relevant variants.

Return of genetic and genomic research findings: experience of a pediatric biorepository.

BACKGROUND: Assess process, uptake, validity and resource needs for return of actionable research findings to biobank participants. METHODS: Participants were prospectively enrolled in a multicenter biorepository of childhood onset heart disease. Clinically actionable research findings were reviewed by a Return of Research Results Committee (RRR) and returned to the physician or disclosed directly to the participant through a research genetic counselor. Action taken following receipt of this information was reviewed. RESULTS: Genetic data was generated in 1963 of 7408 participants. Fifty-nine new findings were presented to the RRR committee; 20 (34%) were deemed reportable. Twelve were returned to the physician, of which 7 were disclosed to participants (median time to disclosure, 192 days). Seven findings were returned to the research genetic counselor; all have been disclosed (median time to disclosure, 19 days). Twelve families (86%) opted for referral to clinical genetics after disclosure of findings; 7 results have been validated, 5 results are pending. Average cost of return and disclosure per reportable finding incurred by the research program was $750 when utilizing a research genetic counselor; clinical costs associated with return were not included. CONCLUSIONS: Return of actionable research findings was faster if disclosed directly to the participant by a research genetic counselor. There was a high acceptability amongst participants for receiving the findings, for referral to clinical genetics, and for clinical validation of research findings, with all referred cases being clinically confirmed.

Validation of the Brief Confusion Assessment Method for Screening Delirium in Elderly Medical Patients in a German Emergency Department.

BACKGROUND: Delirium is frequent in elderly patients presenting in the emergency department (ED). Despite the severe prognosis, the majority of delirium cases remain undetected by emergency physicians (EPs). At the time of our study there was no valid delirium screening tool available for EDs in German-speaking regions. We aimed to evaluate the brief Confusion Assessment Method (bCAM) for a German ED during the daily work routine. METHODS: We implemented the bCAM into practice in a German interdisciplinary high-volume ED and evaluated the bCAM's validity in a convenience sample of medical patients aged ≥ 70 years. The bCAM, which assesses four core features of delirium, was performed by EPs during their daily work routine and compared to a criterion standard based on the criteria for delirium as described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. RESULTS: Compared to the criterion standard, delirium was found to be present in 46 (16.0%) of the 288 nonsurgical patients enrolled. The bCAM showed 93.8% specificity (95% confidence interval [CI] = 90.0%-96.5%) and 65.2% sensitivity (95% CI = 49.8%-78.7%). Positive and negative likelihood ratios were 10.5 and 0.37, respectively, while the odds ratio was 28.4. Delirium was missed in 10 of 16 cases, since the bCAM did not indicate altered levels of consciousness and disorganized thinking. The level of agreement with the criterion standard increased for patients with low cognitive performance. CONCLUSION: This was the first study evaluating the bCAM for a German ED and when performed by EPs during routine work. The bCAM showed good specificity, but only moderate sensitivity. Nevertheless, application of the bCAM most likely improves the delirium detection rate in German EDs. However, it should only be applied by trained physicians to maximize diagnostic accuracy and hence improve the bCAM's sensitivity. Future studies should refine the bCAM.