Persistence of parental-reported asthma at early ages: A longitudinal twin study.

BACKGROUND: Currently, we cannot predict whether a pre-school child with asthma-like symptoms will have asthma at school age. Whether genetic information can help in this prediction depends on the role of genetic factors in persistence of pre-school to school-age asthma. We examined to what extent genetic and environmental factors contribute to persistence of asthma-like symptoms at ages 3 to asthma at age 7 using a bivariate genetic model for longitudinal twin data. METHODS: We performed a cohort study in monozygotic and dizygotic twins from the Netherlands Twin Register (NTR, n = 21,541 twin pairs). Bivariate genetic models were fitted to longitudinal data on asthma-like symptoms reported by parents at age 3 and 7 years to estimate the contribution of genetic and environmental factors. RESULTS: Bivariate genetic modeling showed a correlation on the liability scale between asthma-like symptoms at age 3 and asthma at age 7 of 0.746 and the contribution of genetics was estimated to be 0.917. The genetic analyses indicated a substantial influence of genetic factors on asthma-like symptoms at ages 3 and 7 (heritability 80% and 90%, respectively); hence, contribution of environmental factors was low. Persistence was explained by a high (rg = 0.807) genetic correlation. CONCLUSION: Parental-reported asthma-like symptoms at age 3 and asthma at age 7 are highly heritably. The phenotype of asthma-like symptoms at age 3 and 7 was highly correlated and mainly due to heritable factors, indicating high persistence of asthma development over ages 3 and 7.

Overuse of Oral Corticosteroids, Underuse of Inhaled Corticosteroids, and Implications for Biologic Therapy in Asthma.

BACKGROUND: Asthma patients using high cumulative doses of oral corticosteroids (OCSs) are at risk of serious adverse events and are increasingly being treated with steroid-sparing asthma biologics. However, it is unknown whether prescribing these expensive biologics is always justified. OBJECTIVES: This study aimed to (1) assess the prevalence of asthma patients using high cumulative doses of OCSs, (2) explore the role of suboptimal inhaler therapy, and (3) estimate the proportion of patients to whom asthma biologics might be prescribed unnecessarily. METHODS: All adults (n = 5,002) with at least 1 prescription of high-dose inhaled corticosteroids (≥500-1,000 mcg/day fluticasone-equivalent) and/or OCSs (GINA step 4-5) in 2010 were selected from a pharmacy database including 500,500 Dutch inhabitants, and sent questionnaires. Of 2,312 patients who returned questionnaires, 929 had asthma. We calculated the annual cumulative OCS dose and prescription fillings and checked inhaler technique in a sample of 60 patients. Patients estimated to have good adherence and inhaler proficiency who still required high doses of OCSs (≥420 mg/year) were considered candidates for initiating biologic treatment. RESULTS: 29.5% of asthma patients on GINA 4-5 therapy used high doses of OCSs, of which 78.1% were likely to have poor therapy adherence or inadequate inhaler technique. Only 21.9% were considered definitive candidates for biologic therapy. CONCLUSION: High OCS use in Dutch GINA 4-5 asthma patients was common. However, in 4 out of 5 patients adherence to inhaled corticosteroid therapy and/or inhalation technique was considered suboptimal. Since optimizing inhaler therapy may reduce the need for OCSs, this should be mandatory before prescribing expensive steroid-sparing drugs.

Association between asthma control trajectories in preschoolers and disease remission.

INTRODUCTION: Early disease morbidity has been associated with asthma persistence in wheezing preschoolers; however, whether asthma control trajectories shortly after diagnosis could influence remission is unknown. We examined the association between asthma control trajectories 2 years post-diagnosis in preschoolers and subsequent disease remission. METHODS: We conducted a multicentre population-based retrospective cohort study consisting of 48 687 children with asthma diagnosed before 5 years old and born between 1990 and 2013 in four Canadian provinces who had prolonged disease activity post-diagnosis. Prolonged disease activity was defined as one or more medical visits or medications for asthma every 6-month period for at least four of the six periods post-diagnosis. Follow-up began at 3 years post-diagnosis (at cohort entry). Remission was defined as 2 consecutive years without drug claims or medical visits for asthma or asthma-like conditions following cohort entry. Asthma control trajectories, ascertained over four 6-month periods following diagnosis using a validated index, were classified as: "controlled throughout", "improving control", "worsening control", "out of control throughout" and "fluctuating control". Adjusted Cox models estimated associations between asthma control trajectories and time to remission. A random effects meta-analysis summarised province-specific hazard ratios (HRs). RESULTS: The pooled remission rate was 8.91 (95% CI 8.80-9.02) per 100 person-years. Compared with children controlled throughout, poorer asthma control was associated with incrementally lower hazard ratios of remission in four other trajectories: improving control (HR 0.89, 95% CI 0.82-0.96), fluctuating control (HR 0.78, 95% CI 0.71-0.85), worsening control (HR 0.68, 95% CI 0.62-0.75) and out of control throughout (HR 0.52, 95% CI 0.45-0.59). CONCLUSIONS: Asthma control trajectories 2 years following a diagnosis in preschoolers were associated with remission, highlighting the clinical relevance of documenting control trajectories in early life.

Genome-wide association studies of exacerbations in children using long-acting beta2-agonists.

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. RESULTS: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10-6 ) associated with exacerbations despite LABA use. CONCLUSION: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

Pharmacoepidemiology: A time for a new multidisciplinary approach to precision medicine.

The advent of the genomic age has created a rapid increase in complexity for the development and selection of drug treatments. A key component of precision medicine is the use of genetic information to improve therapeutic effectiveness of drugs and prevent potential adverse drug reactions. Pharmacoepidemiology, as a field, uses observational methods to evaluate the safety and effectiveness of drug treatments in populations. Pharmacoepidemiology by virtue of its focus, tradition, and research orientation can provide appropriate study designs and analysis methods for precision medicine. The objective of this manuscript is to demonstrate how pharmacoepidemiology can impact and shape precision medicine and serve as a reference for pharmacoepidemiologists interested in contributing to the science of precision medicine. This paper depicts the state of the science with respect to the need for pharmacoepidemiology and pharmacoepidemiological methods, tools and approaches for precision medicine; the need for and how pharmacoepidemiologists use their skills to engage with the precision medicine community; and recommendations for moving the science of precision medicine pharmacoepidemiology forward. We propose a new integrated multidisciplinary approach dedicated to the emerging science of precision medicine pharmacoepidemiology.

Postpartum Analgesia in New Mothers (PAIN) Study: A Survey of Canadian Obstetricians' Post-Delivery Opioid-Prescribing Practices.

OBJECTIVE: We aimed to describe opioid prescribing practices after obstetric delivery and to evaluate how these practices compare with national opioid prescribing guidelines. METHODS: A closed survey was developed, evaluated for validity and reliability, and distributed by email to obstetrician members of the Society of Obstetricians and Gynaecologists of Canada (SOGC) in December 2018. Descriptive statistics were used to summarize respondent demographics, pharmaceutical pain management strategies, and opioid prescribing practices. Logistic regression was used to measure associations between respondent characteristics and high-risk opioid prescribing practices (e.g., prescribing >50 mg morphine equivalent dose per day, prescribing >5 days, not screening for substance/opioid use disorder before prescribing). RESULTS: Our survey had high content validity (content validity index 0.89; 95% CI 0.78-1.00) and adequate reliability (Kappa 0.70; 95% CI 0.63-0.84 and intraclass correlation coefficient 0.70; 95% CI 0.67-0.81). Of the 1019 SOGC members reached, 243 initiated the survey (response rate, 24%). Among respondents, 235 (92%) completed the survey. Among opioid prescribers, 47% reported at least 1 high-risk opioid prescribing practice, the most frequent being a lack of substance/opioid use disorder screening. In the adjusted logistic regression model, being in practice more than 20 years (adjusted odds ratio [aOR] 0.53; 95% CI 0.29-0.93) and practising in a non-central area of Canada (aOR 0.49; 95% CI 0.28-0.84) reduced the odds of high-risk prescribing. CONCLUSION: Further research on barriers to screening are needed to support and enhance safer opioid prescribing practices among Canadian obstetricians.

Communication of Pharmacogenomic test results and treatment plans in pediatric oncology: deliberative stakeholder consultations with parents.

BACKGROUND: Effective communication in support of clinical decision-making is central to the pediatric cancer care experience for families. A new laboratory derived pharmacogenetic test (LDT) that can diagnose difficult-to-treat brain cancers has been developed to stratify children based on their ability to respond to available treatment; however, the potential implementation of the LDT may make effective communication challenging since it can potentially remove the option for curative treatment in those children identified as non-responders, i.e. those with a catastrophic diagnosis. OBJECTIVE: We solicited the perspectives of parents of children with difficult-to-treat brain cancer on communication preferences surrounding the potential implementation of the LDT in standard care using deliberative stakeholder consultations. METHODS: Eight bereaved parents of children who succumbed to difficult-to-treat brain cancer, and four parents of children currently undergoing treatment for similar cancers attended separate small-group deliberative consultations - a stakeholder engagement method that enables the co-creation of recommendations following the consideration of competing arguments and diverse opinions of parents with different experiences. In the small-group consultations (Phase I), parents discussed four questions about potential communication issues that may arise with the LDT in practice. In Phase II, a total of five parents from both stakeholder groups (4 bereaved and 1 in current treatment) attended a consultation, known as the 'mixed' consultation, with the purpose of co-developing concrete recommendations for implementation of the LDT. RESULTS: Explaining the risks, benefits, and accuracy of the LDT were considered essential to parents. Once an LDT-based diagnosis/prognosis can be made, parents valued honesty, empathy, and clarity in communication. Parents also requested that all results and treatment options be presented to them in measured doses, and in an unbiased manner over the course of several meetings. This communication strategy allowed sufficient time to understand and accept the diagnosis/prognosis, particularly if it was catastrophic. Continuous access to the appropriate psychological and social support or counselling at and post-diagnosis was also strongly recommended. CONCLUSIONS: Deliberants co-created family-centered recommendations surrounding communication issues of the LDT, providing guidance to pediatric oncologists that could implement the test in practice.

Assessing the quality of deliberative stakeholder consultations involving allied health professionals in pediatric palliative care and hematology/oncology in Canada.

BACKGROUND: In this paper we assess the quality of six deliberative stakeholder consultations regarding the implementation of a precision diagnostic for life-threatening pediatric brain tumors. Decision makers who base policy recommendations on the outputs of consultative exercises can presuppose that all deliberants are well informed of the policy issue, that participation in the deliberative process was fair, and that overcoming implementation barriers will necessarily result in practice change. Additional evidence is therefore needed to substantiate the informational quality of the deliberation, measure the equality of participation and study the effects on stakeholder reasoning to appropriately guide uptake of proposed recommendation(s). METHODS: Using the DeVries framework for assessing the deliberative quality, we analyzed data from 44 post-consultation evaluation surveys completed by pediatric oncology and palliative care teams at two tertiary pediatric healthcare centers in Canada. We also conducted turn-taking and word-contribution analyses from the text transcriptions of each deliberation to assess equality of participation using descriptive statistics. RESULTS: Deliberants agreed the quality of the deliberative process was fair (median ratings ranging from 9-10 out of 10) and the opportunities to receive expert information and discuss with others about the implementation of a new LDT were helpful (9.5 out of 10). While the session improved understanding of the implementation barriers and opportunities, it had marginal effects on deliberants' reasoning about whether LDTs would change their own clinical practice (3-10 out of 10). Participation was proportionate in at least four of the six deliberations, where no deliberant took more than 20% of total turns and contributed equal to, or less than 20% of total words. CONCLUSION: The quality assessment we performed demonstrates high informational value and perceived fairness of two deliberative stakeholder consultations involving pediatric palliative care and oncology teams in Canada. Quality assessments can reveal how the process of deliberation unfolds, whether deliberative outputs are the result of equitable participation among deliberants and what, if any, stakeholder voices may be missing. Such assessments should be routinely reported as a condition of methodological rigor and trustworthiness of deliberative stakeholder engagement research.

The Impact of Short-Term Exposure to Air Pollution on the Exhaled Breath of Healthy Adults.

Environmental factors, such as air pollution, can affect the composition of exhaled breath, and should be well understood before biomarkers in exhaled breath can be used in clinical practice. Our objective was to investigate whether short-term exposures to air pollution can be detected in the exhaled breath profile of healthy adults. In this study, 20 healthy young adults were exposed 2-4 times to the ambient air near a major airport and two highways. Before and after each 5 h exposure, exhaled breath was analyzed using an electronic nose (eNose) consisting of seven different cross-reactive metal-oxide sensors. The discrimination between pre and post-exposure was investigated with multilevel partial least square discriminant analysis (PLSDA), followed by linear discriminant and receiver operating characteristic (ROC) analysis, for all data (71 visits), and for a training (51 visits) and validation set (20 visits). Using all eNose measurements and the training set, discrimination between pre and post-exposure resulted in an area under the ROC curve of 0.83 (95% CI = 0.76-0.89) and 0.84 (95% CI = 0.75-0.92), whereas it decreased to 0.66 (95% CI = 0.48-0.84) in the validation set. Short-term exposure to high levels of air pollution potentially influences the exhaled breath profiles of healthy adults, however, the effects may be minimal for regular daily exposures.

The Influence of Smoking Status on Exhaled Breath Profiles in Asthma and COPD Patients.

Breath analysis using eNose technology can be used to discriminate between asthma and COPD patients, but it remains unclear whether results are influenced by smoking status. We aim to study whether eNose can discriminate between ever- vs. never-smokers and smoking <24 vs. >24 h before the exhaled breath, and if smoking can be considered a confounder that influences eNose results. We performed a cross-sectional analysis in adults with asthma or chronic obstructive pulmonary disease (COPD), and healthy controls. Ever-smokers were defined as patients with current or past smoking habits. eNose measurements were performed by using the SpiroNose. The principal component (PC) described the eNose signals, and linear discriminant analysis determined if PCs classified ever-smokers vs. never-smokers and smoking <24 vs. >24 h. The area under the receiver-operator characteristic curve (AUC) assessed the accuracy of the models. We selected 593 ever-smokers (167 smoked <24 h before measurement) and 303 never-smokers and measured the exhaled breath profiles of discriminated ever- and never-smokers (AUC: 0.74; 95% CI: 0.66-0.81), and no cigarette consumption <24h (AUC 0.54, 95% CI: 0.43-0.65). In healthy controls, the eNose did not discriminate between ever or never-smokers (AUC 0.54; 95% CI: 0.49-0.60) and recent cigarette consumption (AUC 0.60; 95% CI: 0.50-0.69). The eNose could distinguish between ever and never-smokers in asthma and COPD patients, but not recent smokers. Recent smoking is not a confounding factor of eNose breath profiles.