The association between a genetic risk score for allergy and the risk of developing allergies in childhood-Results of the WHISTLER cohort.

BACKGROUND: Several genetic variants have been associated with the susceptibility to allergic disease in adults, but it remains unclear whether these genetic variants are also associated with the onset of allergic disease early in life. The aim of this study was to develop a genetic risk score (GRS) for allergy based on findings in adults and study its predictive capacity for allergy in children. METHODS: A GRS was constructed based on 10 SNPs previously associated with allergies in adults. The GRS was tested in children who participated in a population-based newborn cohort (WHISTLER) and were followed from birth to school age. Logistic regression analysis was used to study the association between the GRS and the parental-reported allergies at age 5 (based on a reported allergy to ≥1 of the following allergens: pollen, house dust mites, or pets). A Cox regression model was used to study the association between GRS and a physician-diagnosed allergy during follow-up (allergic conjunctivitis, allergic rhinitis, and eczema/dermatitis). Cohen's kappa coefficient was calculated to study the agreement between physician-diagnosed allergy and parental-reported allergy at age 5. RESULTS: The GRS was significantly associated with parental-reported allergy (odds ratio: 15.9, 95% confidence interval (CI): 1.07-233.73) at age 5, as well as with a physician-diagnosed allergy during follow-up (hazard ratio: 1.89, 95% CI: 1.05-3.41). The overall agreement between physician-diagnosed and parental-reported allergies was 70.5% (kappa: 0.10, 95% CI: 0.03-0.18). CONCLUSIONS: An adult-derived GRS for allergy predicts the risk of developing allergies in childhood.

High incidence of oral corticosteroids prescriptions in children with asthma in early childhood.

OBJECTIVE: Severe asthma exacerbations are often treated with short courses of oral corticosteroids (OCS). This study assessed the incidence of OCS being prescribed in asthmatic children of various age groups and calculated their chances of receiving subsequent OCS prescriptions. METHODS: Longitudinal Dutch community pharmacy data of 2272 children who were regular users of asthma medication was analyzed retrospectively. Incidence rates for first, second and third prescriptions of OCS were calculated, stratified by age and sex. Probabilities of receiving first, second or third OCS prescriptions were assessed with Kaplan-Meier analysis. RESULTS: Incidence rates for first OCS prescriptions were 4.5 for the 1(st) year of life per 100 person-years (100PY); 3.9 for the 2(nd); 4.6 for the 3(rd); 4.2 for the 4(th), and 4.7 for the 5(th) year of life per 100PY. This was relatively high compared to incidence rates for children between the ages of 6 and 11 (ranging between 2.2 per 100PY (age 9) and 3.7(age 11)). Incidence rates for second and third OCS prescriptions were very high: 78.2(95%CI: 45.0-123.7) and 241.2(95%CI: 81.2-583.4) per 100PY for infants, respectively. The chances of receiving a first OCS prescription was higher in males (P value < 0.01). CONCLUSIONS: In the Netherlands, the incidence of OCS being prescribed to children being treated with asthma medication in early childhood is relatively high for first OCS prescriptions and extremely high for second and third OCS prescriptions compared to other ages. Furthermore, there is a high probability of receiving a further OCS prescription shortly after an OCS prescription.

Characteristics and severity of asthma in children with and without atopic conditions: a cross-sectional study.

BACKGROUND: Childhood allergic diseases have a major impact on a child's quality of life, as well as that of their parents. We studied the coexistence of reported allergies in children who use asthma medication. Additionally, we tested the hypothesis that asthma severity is greater among children with certain combinations of co-morbid allergic conditions. METHODS: For this cross-sectional study, 703 children (ages 4 to 12 years) from the PACMAN cohort study were selected. All of the children were regular users of asthma medication. The study population was divided into nine subgroups according to parental-reported allergies of the child (hay fever, eczema, food allergy or combinations of these). In order to assess whether these subgroups differed clinically, the groups were compared for child characteristics (age, gender, family history of asthma), asthma exacerbations in the past year (oral corticosteroids (OCS) use; asthma-related emergency department (ED) visits), asthma control, fractional exhaled nitric oxide level (FeNO), and antihistaminic usage. RESULTS: In our study, 79.0% of the parents reported that their child suffered from at least one atopic condition (hay fever, food allergy and eczema), and one quarter of the parents (25.6%) reported that their child suffered from all three atopic conditions. Having more than one atopic condition was associated with an increased risk of OCS use (OR = 3.3, 95% CI = 1.6 - 6.6), ED visits (OR = 2.3, 95% CI = 1.2 - 4.6) in the past year and inadequate short term asthma control (OR = 1.9, 95% CI = 1.3 - 2.8). CONCLUSIONS: Children who use asthma medication often also have other allergic conditions. Parental reported allergies were associated with a higher risk of more severe asthma (more asthma complaints and more asthma exacerbations).

[Threshold value for reimbursement of costs of new drugs: cost-effectiveness research and modelling are essential links]. / Drempelwaarde bij vergoeding van nieuwe medicatie: doelmatigheidsonderzoek en modellering als onmisbare schakels.

There is increasing discussion in the Netherlands about the introduction of a threshold value for the costs per extra year of life when reimbursing costs of new drugs. The Medicines Committee ('Commissie Geneesmiddelen'), a division of the Netherlands National Healthcare Institute ('Zorginstituut Nederland'), advises on reimbursement of costs of new drugs. This advice is based upon the determination of therapeutic value of the drug and the results of economic evaluations. Mathematical models that predict future costs and effectiveness are often used in economic evaluations; these models can vary greatly in transparency and quality due to author assumptions. Standardisation of cost-effectiveness models is one solution to overcome the unwanted variation in quality. Discussions about the introduction of a threshold value can only be meaningful if all involved are adequately informed, and by high quality in cost-effectiveness research and, particularly, economic evaluations. Collaboration and discussion between medical specialists, patients or patient organisations, health economists and policy makers, both in development of methods and in standardisation, are essential to improve the quality of decision making.

Pharmacogenetic analysis of GLCCI1 in three north European pediatric asthma populations with a reported use of inhaled corticosteroids.

BACKGROUND: GLCCI1 rs37972 has previously been associated with decreased lung function improvement upon treatment with inhaled corticosteroids (ICS) in asthmatics. AIM: To assess whether variation in rs37972 is associated with altered ICS efficacy in north European asthmatic children and young adults with a reported use of ICS. PATIENTS & METHODS: rs37972 was genotyped in three cohort studies of asthmatic children with a reported use of ICS. As an indicator for asthma exacerbations, asthma-related hospital visits and oral corticosteroid use were studied. Asthma control was assessed using a questionnaire. RESULTS: rs37972 T allele was not significantly associated with an increased risk of oral corticosteroid use (summary odds ratio: 1.20; 95% CI: 0.99-1.45), an increased risk of asthma-related hospital visits (summary odds ratio: 1.07; 95% CI: 0.89-1.29), uncontrolled symptoms (summary odds ratio: 1.01; 95% CI: 0.75-1.36) or higher ICS dosages (summary ß: 0.01, 95% CI: -0.06-0.08). CONCLUSION: Variation in GLCCI1 rs37972 genotype does not seem to affect ICS efficacy in north European asthmatic children. Original submitted 26 November 2013; Revision submitted 13 February 2014.

The fiduciary obligation of the physician-researcher in phase IV trials.

BACKGROUND: In this manuscript, we argue that within the context of phase IV, physician-researchers retain their fiduciary obligation to treat the patient-participants. DISCUSSION: We first clarify why the perspective that research ethics ought to be differentiated from clinical ethics is not applicable in phase IV, and therefore, why therapeutic orientation is most convivial in this phase. Next, assuming that ethics guidelines may be representative of common morality, we show that ethics guidelines see physician-researchers primarily as physicians and only secondarily as researchers. We then elaborate on what a fiduciary obligation is and how some of the obligations are default duties. Lastly, we look at the fiduciary obligation of the physician-researcher in phase IV interventional trials. CONCLUSION: The fiduciary obligation to treat is not as easily waived as in earlier trials. Assuming the entwinement of research and practice in phase IV, physician-researchers, in collaboration with other researchers, investigators, and research ethics committees, should ensure that in terms of study design, methodology, and research practice, the therapeutic value of the research to the patient-participants is not diminished.

The impact of structural uncertainty on cost-effectiveness models for adjuvant endocrine breast cancer treatments: the need for disease-specific model standardization and improved guidance.

INTRODUCTION: Structural uncertainty relates to differences in model structure and parameterization. For many published health economic analyses in oncology, substantial differences in model structure exist, leading to differences in analysis outcomes and potentially impacting decision-making processes. The objectives of this analysis were (1) to identify differences in model structure and parameterization for cost-effectiveness analyses (CEAs) comparing tamoxifen and anastrazole for adjuvant breast cancer (ABC) treatment; and (2) to quantify the impact of these differences on analysis outcome metrics. METHODS: The analysis consisted of four steps: (1) review of the literature for identification of eligible CEAs; (2) definition and implementation of a base model structure, which included the core structural components for all identified CEAs; (3) definition and implementation of changes or additions in the base model structure or parameterization; and (4) quantification of the impact of changes in model structure or parameterizations on the analysis outcome metrics life-years gained (LYG), incremental costs (IC) and the incremental cost-effectiveness ratio (ICER). RESULTS: Eleven CEA analyses comparing anastrazole and tamoxifen as ABC treatment were identified. The base model consisted of the following health states: (1) on treatment; (2) off treatment; (3) local recurrence; (4) metastatic disease; (5) death due to breast cancer; and (6) death due to other causes. The base model estimates of anastrazole versus tamoxifen for the LYG, IC and ICER were 0.263 years, €3,647 and €13,868/LYG, respectively. In the published models that were evaluated, differences in model structure included the addition of different recurrence health states, and associated transition rates were identified. Differences in parameterization were related to the incidences of recurrence, local recurrence to metastatic disease, and metastatic disease to death. The separate impact of these model components on the LYG ranged from 0.207 to 0.356 years, while incremental costs ranged from €3,490 to €3,714 and ICERs ranged from €9,804/LYG to €17,966/LYG. When we re-analyzed the published CEAs in our framework by including their respective model properties, the LYG ranged from 0.207 to 0.383 years, IC ranged from €3,556 to €3,731 and ICERs ranged from €9,683/LYG to €17,570/LYG. CONCLUSION: Differences in model structure and parameterization lead to substantial differences in analysis outcome metrics. This analysis supports the need for more guidance regarding structural uncertainty and the use of standardized disease-specific models for health economic analyses of adjuvant endocrine breast cancer therapies. The developed approach in the current analysis could potentially serve as a template for further evaluations of structural uncertainty and development of disease-specific models.

Restoring trust in the pharmaceutical sector on the basis of the SSRI case.

The lack of public trust in the pharmaceutical sector (i.e. industry, authorities and doctors) could compromise the future of drug development and the regulatory system. Public trust integrates two important components, namely the vulnerability of the truster and the competence of the trustee. Because trust appears to have eroded as a result of drug safety controversies, this paper analyzes the role of public trust during the selective serotonin reuptake inhibitor (SSRI) and suicidality controversy focusing on the aforementioned trust components. Because the competence component of trust is argued to be paramount in determining and maintaining public trust, the SSRI case shows that this component is a part of public trust where these institutions can build on, and might therefore be better used to substantiate and reinforce, public trust. Efforts to build trust should rely on the ethical, professional (competence) and societal commitment of institutions and individuals to protect the vulnerability of the public during controversies. Because shared values can create trust or increase its levels within a specific environment, industry, authorities and physicians ought to develop novel and cooperative strategies to highlight their shared values and motivations. Rules, regulations and settlements are indispensable tools but undue regulation is costly and can backfire on the rather sensitive trust relationships in the pharmaceutical sector.

Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting ß2-agonists: results of the PACMAN cohort.

BACKGROUND: Current evidence suggests that asthma patients with the ADRB2 Arg16 genotype have a poorer response to long-acting ß2-agonists (LABA), but the results remain inconsistent. AIM: This study assessed the association between Arg16 variants and treatment outcome in children treated with inhaled corticosteroids (ICS) and LABA. MATERIALS & METHODS: ADRB2 Arg16 was genotyped in 597 children (4-12 years of age) participating in the PACMAN cohort study. A questionnaire was used to assess asthma control, frequency of asthma-related emergency department visits and use of oral corticosteroids in the past year. RESULTS: Arg/Arg carriers with a reported use of ICS and LABA had an increased risk of oral corticosteroid use (odds ratio: 14.9; 95% CI: 1.59-140.1) and emergency department visits in the past year (odds ratio: 11.9; 95% CI: 1.22-115.8) compared to Gly/Gly carriers. This effect was not observed in Arg/Arg genotype carriers reporting ICS use only. CONCLUSION: Children who are homozygous for ADRB2 Arg16 have an increased risk of exacerbations when treated with combined LABA and ICS.

The cloudy crystal ball of cost-effectiveness studies.

Despite the use of identical clinical trial data (Anastrazole, Tamoxifen, Alone or in Combination for the adjuvant treatment of postmenopausal women with localised hormone receptor-positive breast cancer data), not dependent on differences between countries, the outcome of 11 published cost-effectiveness analyses varied more than 20-fold. The observed wide variation in predicted life-years gained (a parameter derived from clinical trial data) demonstrates that authors used substantially different methods for handling the same data. We therefore consider it to be of utmost importance to strive for standardization of and better guidance for disease-specific modeling in economic evaluations.

Phase IV non-inferiority trials and additional claims of benefit.

BACKGROUND: Non-inferiority (NI) trials in drug research are used to demonstrate that a new treatment is not less effective than an active comparator. Since phase IV trials typically aim at informing a clinical decision, the value of a phase IV non-inferiority trial hinges also on its clinical relevance. In such trials, clinical relevance would refer to the added benefit claims of a specific drug, apart from efficacy, relative to its comparator drug in the trial. METHODS: In this study, we reviewed 41 phase IV trials and extracted information on whether the authors mentioned any additional benefit beyond the NI (efficacy) claim of the drug and whether the additional benefit was proven in the trial. We checked whether the additional claim was based on descriptions only or on formal statistical analyses. RESULTS: Our results showed that 22 out of the 41 NI trials mentioned additional benefit of the test drug and most of these claims were related to the safety profile. Of all the post-authorization NI trials that claimed additional benefit, 10 out of 22 NI trials used formal statistical analyses to show additional benefit, and only one included a sample size calculation for the additional benefit prior to the trial. CONCLUSION: We conclude that there is room for improvement in terms of designing phase IV NI trials with added benefit claims and in proving these additional claims.

Inflammatory phenotypes underlying uncontrolled childhood asthma despite inhaled corticosteroid treatment: rationale and design of the PACMAN2 study.

BACKGROUND: The diagnosis of childhood asthma covers a broad spectrum of pathological mechanisms that can lead to similarly presenting clinical symptoms, but may nonetheless require different treatment approaches. Distinct underlying inflammatory patterns are thought to influence responsiveness to standard asthma medication. METHODS/DESIGN: The purpose of the PACMAN2 study is to identify inflammatory phenotypes that can discriminate uncontrolled childhood asthma from controlled childhood asthma by measures in peripheral blood and exhaled air. PACMAN2 is a nested, case-control follow-up study to the ongoing pharmacy-based "Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects" (PACMAN) study. The original PACMAN cohort consists of children aged 4-12 years with reported use of asthma medication. The PACMAN2 study will be conducted within the larger PACMAN cohort, and will focus on detailed phenotyping of a subset of the PACMAN children. The selected participants will be invited to a follow-up visit in a clinical setting at least six months after their baseline visit based on their adherence to usage of inhaled corticosteroids, their asthma symptoms in the past year, and their age (≥ 8 years). During the follow-up visit, current and long-term asthma symptoms, medication use, environmental factors, medication adherence and levels of exhaled nitric oxide will be reassessed. The following measures will also be examined: pulmonary function, exhaled volatile organic compounds, as well as inflammatory markers in peripheral blood and blood plasma. Comparative analysis and cluster-analyses will be used to identify markers that differentiate children with uncontrolled asthma despite their use of inhaled corticosteroids (ICS) (cases) from children whose asthma is controlled by the use of ICS (controls). DISCUSSION: Asthmatic children with distinct inflammatory phenotypes may respond differently to anti-inflammatory therapy. Therefore, by identifying inflammatory phenotypes in children with the PACMAN2 study, we may greatly impact future personalised treatment strategies, uncover new leads for therapeutic targets and improve the design of future clinical studies in the assessment of the efficacy of novel therapeutics.

Development of a framework for cohort simulation in cost-effectiveness analyses using a multistep ordinary differential equation solver algorithm in R.

INTRODUCTION: Dynamic processes in cost-effectiveness analysis (CEA) are typically described using cohort simulations, which can be implemented as Markov models, or alternatively using systems of ordinary differential equations (ODEs). In the field of CEA, simple and potentially inaccurate single-step algorithms are commonly used for solving ODEs, which can potentially induce bias, especially if an incorrect step size is used. The aims of this project were 1) to implement and demonstrate the use of a modern and well-established hybrid linear multistep ODE solver algorithm (LSODA) in the context of CEA using the statistical scripting language R and 2) to quantify bias in outcome for a case example CEA as generated by a commonly used single-step ODE solver algorithm. METHODS: A previously published CEA comparing the adjuvant breast cancer therapies anastrozole and tamoxifen was used as a case example to implement the computational framework. A commonly used single-step algorithm was compared with the proposed multistep algorithm to quantify bias in the single-step method. RESULTS: A framework implementing the multistep ODE solver LSODA was successfully developed. When a single-step ODE solver with step size of 1 year was used, incremental life-years gained was underestimated by 0.016 years (5.6% relative error, RE) and £158 (6.8% RE) compared with the multistep method. CONCLUSION: The framework was found suitable for the conduct of CEAs. We demonstrated how the use of single-step algorithms with insufficiently small step sizes causes unnecessary bias in outcomes measures of CEAs. Scripting languages such as R can further improve transparency, reproducibility, and overall integrity in the field of health economics.

A 10-year analysis of the effects of media coverage of regulatory warnings on antidepressant use in The Netherlands and UK.

BACKGROUND: In 2003-2004 and 2007-2008, the regulatory banning of SSRI use in pediatrics and young adults due to concerns regarding suicidality risk coincided with negative media coverage. SSRI use trends were analyzed from 2000-2010 in the Netherlands (NL) and the UK, and whether trend changes might be associated with media coverage of regulatory warnings. METHODS: Monthly SSRIs sales were presented as DDDs/1000 inhabitants/day. SSRI-use trends were studied using time-series segmented regression analyses. Timing of trend changes was compared with two periods of media coverage of warnings. Annual Dutch SSRI prescription data were analyzed by age group. RESULTS: Trend changes in SSRI use largely corroborated with the periods of media coverage of warnings. British SSRI use declined from 3.9 to 0.7 DDDs/month (95%CI 3.3;4.5 & 0.5;0.9, respectively) before the first warning period (2003-2004). A small decrease of -0.6 DDDs/month (-1.2; -0.05) was observed in Dutch SSRI use shortly after 2003-2004. From 2007-2008, British SSRI use stabilized, whilst Dutch SSRI use diminished to -0.04 DDDs/month (-0.4;0.3). Stratified analyses showed a rapid decrease of -1.2 DDDs/month (-2.1; -1.7) in UK paroxetine use before 2003-2004, but only a minimal change in Dutch paroxetine use (-0.3 DDDs/month -0.8;0.2). Other SSRI use, especially (es)citalopram, increased during 2003-2004 in both countries. Significant reductions in Dutch paroxetine use were observed in pediatrics, adolescents, and young adults after 2003-2004. CONCLUSION: Changes in SSRI use (NL & UK) were associated with the timing of the combined effect of media coverage and regulatory warnings. Our long-term assessment illustrates that changes in SSRI use were temporal, drug-specific and more pronounced in pediatrics and young adults. The twofold increase in SSRI use over one decade indicates that regulatory warnings and media coverage may come and go, but they do not have a significant impact on the overall upward trend of SSRI use as a class in both countries.

Decision theory and the evaluation of risks and benefits of clinical trials.

Research ethics committees (RECs) are tasked to assess the risks and the benefits of a clinical trial. In previous studies, it was shown that RECs find this task difficult, if not impossible, to do. The current approaches to benefit-risk assessment (i.e. Component Analysis and the Net Risk Test) confound the various risk-benefit tasks, and as such, make balancing impossible. In this article, we show that decision theory, specifically through the expected utility theory and multiattribute utility theory, enable for an explicit and ethically weighted risk-benefit evaluation. This makes a balanced ethical justification possible, and thus a more rationally defensible decision making.

Exhaled NO is a poor marker of asthma control in children with a reported use of asthma medication: a pharmacy-based study.

BACKGROUND: A high fraction of nitric oxide in exhaled breath (FeNO) has been suggested to be a marker of ongoing airway inflammation and poorly controlled disease in asthma. The usefulness of FeNO to monitor asthma control is still debated today. AIM: To assess the validity of FeNO as a marker of asthma control in children with reported use of asthma medication. METHODS: Fraction of nitric oxide in exhaled breath was measured in 601 children (aged 4-12 yr) with reported use of asthma medication in the past 6 months and in 63 healthy non-asthmatic children (aged 5-12). Asthma control was assessed by the Asthma Control Questionnaire (ACQ). A receiver-operator characteristics (ROC) curve was generated to assess the accuracy of FeNO as a marker for asthma control. Logistic regression analysis was used to study whether clinical, healthcare, medication, and environmental factors are associated with high FeNO levels (>25 ppb). RESULTS: Fraction of nitric oxide in exhaled breath had a poor accuracy to discriminate well-controlled from not well-controlled asthma [area under the ROC curve: 0.56 (95% CI: 0.52-0.61, p = 0.008)]. In addition, high FeNO (>25 ppb) was associated with lower medication adherence rates (OR: 0.4; 95% CI 0.3-0.6), fewer antibiotic courses in the past year (OR: 0.6; 95% CI: 0.4-0.9), fewer leukotriene antagonists use in the past year (OR: 0.4; 95% CI: 0.2-0.9), and fewer visits to a (pulmonary) pediatrician (OR: 0.6; 95% CI: 0.4-0.9). Children living in a non-urban environment had more often high FeNO levels (OR: 1.7; 95% CI: 1.1-2.6). CONCLUSION: High FeNO is a poor marker of asthma control in children with reported use of asthma medication. Various other factors, including medication adherence and medication use, are associated with increased FeNO levels.

The risk-benefit task of research ethics committees: an evaluation of current approaches and the need to incorporate decision studies methods.

BACKGROUND: Research ethics committees (RECs) are tasked to assess the risks and the benefits of a trial. Currently, two procedure-level approaches are predominant, the Net Risk Test and the Component Analysis. DISCUSSION: By looking at decision studies, we see that both procedure-level approaches conflate the various risk-benefit tasks, i.e., risk-benefit assessment, risk-benefit evaluation, risk treatment, and decision making. This conflation makes the RECs' risk-benefit task confusing, if not impossible. We further realize that RECs are not meant to do all the risk-benefit tasks; instead, RECs are meant to evaluate risks and benefits, appraise risk treatment suggestions, and make the final decision. CONCLUSION: As such, research ethics would benefit from looking beyond the procedure-level approaches and allowing disciplines like decision studies to be involved in the discourse on RECs' risk-benefit task.