Pharmacogenomic testing in paediatrics: Clinical implementation strategies.

Pharmacogenomics (PGx) relates to the study of genetic factors determining variability in drug response. Implementing PGx testing in paediatric patients can enhance drug safety, helping to improve drug efficacy or reduce the risk of toxicity. Despite its clinical relevance, the implementation of PGx testing in paediatric practice to date has been variable and limited. As with most paediatric pharmacological studies, there are well-recognised barriers to obtaining high-quality PGx evidence, particularly when patient numbers may be small, and off-label or unlicensed prescribing remains widespread. Furthermore, trials enrolling small numbers of children can rarely, in isolation, provide sufficient PGx evidence to change clinical practice, so extrapolation from larger PGx studies in adult patients, where scientifically sound, is essential. This review paper discusses the relevance of PGx to paediatrics and considers implementation strategies from a child health perspective. Examples are provided from Canada, the Netherlands and the UK, with consideration of the different healthcare systems and their distinct approaches to implementation, followed by future recommendations based on these cumulative experiences. Improving the evidence base demonstrating the clinical utility and cost-effectiveness of paediatric PGx testing will be critical to drive implementation forwards. International, interdisciplinary collaborations will enhance paediatric data collation, interpretation and evidence curation, while also supporting dedicated paediatric PGx educational initiatives. PGx consortia and paediatric clinical research networks will continue to play a central role in the streamlined development of effective PGx implementation strategies to help optimise paediatric pharmacotherapy.

Risk of Extrapyramidal Adverse Events With Aripiprazole.

Aripiprazole is a unique atypical antipsychotic with partial agonist activity on the dopamine-2 (D2) receptor. This unique pharmacological profile of aripiprazole was thought to lead to a lower incidence of extrapyramidal symptoms (EPSs). However, recent case reports have alluded to an increase in the risk of EPS in aripiprazole users compared with nonusers of the drug. No epidemiologic studies to date have quantified this risk. We conducted a pharmacoepidemiologic study composed of a nested case-control study using a large health claims database (IMS Health) in the United States. In the nested case-control analysis, there were 5242 cases of EPS with 50,532 corresponding controls in the entire cohort. The odds ratio (OR) for EPS among those with any prescription of aripiprazole was 5.38 (95% confidence interval [CI], 3.03-9.57). The OR was lower among those taking 2 to 3 prescriptions (OR, 2.9; 95% CI, 1.07-7.85) but increased in those receiving greater than 4 prescriptions (OR, 8.64; 95% CI, 2.63-28.38). All risk periods were compared with those of subjects who had not used aripiprazole or other antipsychotics. For the secondary outcome of dyskinesia, the risk for aripiprazole was 8.50 (95% CI, 8.53-2.27-31.97) compared with that of nonusers. In conclusion, we found an increase in the risk of EPS and dyskinesias among users of aripiprazole.

Pharmacogenomics in Pediatric Patients: Towards Personalized Medicine.

It is well known that drug responses differ among patients with regard to dose requirements, efficacy, and adverse drug reactions (ADRs). The differences in drug responses are partially explained by genetic variation. This paper highlights some examples of areas in which the different responses (dose, efficacy, and ADRs) are studied in children, including cancer (cisplatin), thrombosis (vitamin K antagonists), and asthma (long-acting ß2 agonists). For childhood cancer, the replication of data is challenging due to a high heterogeneity in study populations, which is mostly due to all the different treatment protocols. For example, the replication cohorts of the association of variants in TPMT and COMT with cisplatin-induced ototoxicity gave conflicting results, possibly as a result of this heterogeneity. For the vitamin K antagonists, the evidence of the association between variants in VKORC1 and CYP2C9 and the dose is clear. Genetic dosing models have been developed, but the implementation is held back by the impossibility of conducting a randomized controlled trial with such a small and diverse population. For the long-acting ß2 agonists, there is enough evidence for the association between variant ADRB2 Arg16 and treatment response to start clinical trials to assess clinical value and cost effectiveness of genotyping. However, further research is still needed to define the different asthma phenotypes to study associations in comparable cohorts. These examples show the challenges which are encountered in pediatric pharmacogenomic studies. They also display the importance of collaborations to obtain good quality evidence for the implementation of genetic testing in clinical practice to optimize and personalize treatment.

High use of health services in patients with suboptimal asthma drug regimens: a population-based assessment in British Columbia, Canada.

BACKGROUND: Despite numerous clinical guidelines on asthma management, patients often receive suboptimal drug therapy. This study identified patients who received suboptimal regimens according to the National Heart, Lung and Blood Institute (NHLBI) Guidelines for the Diagnosis and Management of Asthma in a complete population (residents of British Columbia, Canada) and determined the association between patients' regimens and utilization of healthcare services. METHODS: A total of 65,345 asthma patients were identified using provincial health service utilization data (including all respiratory-related prescription medication dispensings, physician and hospital visits) for the 2009 fiscal year. Patient-specific regimens of inhaled short-acting bronchodilators (SABA) with or without inhaled corticosteroids (ICS) were categorized as optimal or suboptimal. Logistic regression models were used to determine the association between regimen optimality and health service utilization, adjusted for socioeconomic status, prior year hospital and emergency department (ED) visits for asthma. RESULTS: Patients with suboptimal regimens had significantly greater risk of using health services than patients with optimal regimens of SABA and/or ICS. In particular, adolescents with suboptimal regimens were the most likely to have hospital admissions (odds ratio (OR) 3.8; 95% confidence interval (CI) 1.8-7.8), visit the ED (OR 2.2; 95% CI 1.6-3.1) and be high users of family physician services (OR 5.7; 95% CI 4.0-8.1) compared with patients in other age groups. CONCLUSIONS: Suboptimal regimens are associated with significantly high usage of health services. Identifying patients with suboptimal regimens and improving their medication management in accordance with asthma clinical guidelines are likely to result in lower health service utilization.

Diagnostic testing for vaccinomics: is the regulatory approval framework adequate? A comparison of Canada, the United States, and Europe.

Vaccinomics aims to integrate variability information from multiple levels of the biological hierarchy from genome to proteome to metabolome, and ways in which these biological parts interact with each other and the environment. Vaccinomics holds significant promise as a new public health tool in designing safer and more effective vaccines for both developed and developing countries. Vaccinomics tests that are envisioned to be used in tandem with vaccine-based health interventions could permit an informed forecast of individual and subpopulation variations in immune responses to vaccines, reduce adverse effects, and contribute to a foundation for rational and directed use of vaccines. A proactive, multidisciplinary engagement with vaccinomics is now timely and much needed in order to develop regulations that best ensure the protection of the public and promote the transition of vaccinomics innovations from discovery to real-life public health applications. This article examines and compares the regulatory oversight of vaccinomics tests in Canada, the United States, and Europe. Recent trends in these jurisdictions suggest that regulatory agencies view personalized genomics/omics medicine, such as vaccinomics, as a desirable goal. At the same time, proposals to increase oversight could impact progress in the field and affect the availability of vaccinomics tests in public health practice and the diagnostic test market. The comparative analysis of vaccinomics in three jurisdictions presented in this article highlights both the convergence and divergence of regulatory oversight. In a rapidly emerging field such as vaccinomics that is pivotal for global public health, achieving better harmonization of policies may be an advantageous target, while ensuring that symmetry exists between the goals of public safety and promoting public health innovation. We suggest it is now timely to proactively initiate a constructive dialogue among all stakeholders (publics, policymakers, researchers, private sector, governments) to foster the development of appropriately targeted regulatory policies in this field.

The added burden of comorbidity in patients with asthma.

OBJECTIVE: Compare the prevalence of comorbidities in adults with and without asthma in Canada and investigate the association between comorbidities in patients with asthma and the occurrence of asthma symptoms or attacks. METHODS: Survey data from the 2005 Canadian Community Health Survey (CCHS) were analyzed. A total of 132,221 Canadians participated in the national survey; 10,089 adult respondents from 10 Canadian provinces and 3 territories reported having asthma. Analyses focused on 11 major chronic comorbidities. RESULTS: Respondents with asthma were more likely to have comorbidities except cancer; 31% of respondents with asthma and comorbidities reported their health status to be fair or poor. For respondents with asthma, non-asthma chronic respiratory disease, mental illness, and allergy were significantly associated with having asthma symptoms or attacks. CONCLUSIONS: Many Canadians with asthma report a high comorbidity burden. These patients will likely require more health services and more complex health management strategies. Comorbid conditions should be clearly identified with particular emphasis on management of mood disorders and anxiety because these conditions are likely to increase asthma symptomatology and may be unrecognized by clinicians.

Identifying persons with treated asthma using administrative data via latent class modelling.

OBJECTIVE: To develop a parsimonious model of the respiratory patient population in British Columbia (BC), Canada through latent class modelling (LCM), using administrative data records and to assess conventional case definitions for asthma in relation to model-based case selection. DATA SOURCES: 1996-2001 data from linked provincial databases containing fee-for-service physician billing records, hospital inpatient separation abstracts, and prescription drug purchase records for 1.9 million BC respiratory patients. STUDY DESIGN: This is a retrospective methodological/descriptive study that assesses case definitions for asthma in terms of sensitivity and specificity using a model fitted to seven physician, hospital and medication utilization markers in place of a conventional gold standard. DATA COLLECTION: We computed values of the treatment markers for each of the 5 years for each patient aged 5-55 years who had had at least one occurrence of a respiratory diagnosis code. PRINCIPAL FINDINGS: The marker for prescription of short-acting beta agonists (SABAs) consistently had the highest sensitivity. Markers' specificities ranged from 0.97 to 1.0. The conventional case definitions' sensitivities were 0.41-0.87; specificities ranged from 0.98 to 0.997. Model-based estimates of asthma prevalence increased from 827/10,000 in 1996 to 992/10,000 in 2001. Conventional case definitions' estimates were consistently lower. CONCLUSIONS: The linkage between utilization and case status is more complex than conventional case definitions allow for. LCM-based case classification was consistent over time and tends to lead to larger prevalence estimates than conventional definitions. The estimated increases in asthma prevalence are reliable. LCM provides health services planners with a useful probability-based approach for developing and assessing case definitions and estimating case prevalence.