Core requirements for successful data linkage: an example of a triangulation method.

OBJECTIVES: The aim was to explore the views of professional stakeholders and healthcare professionals (HCPs) on the linkage of UK National Health Service (NHS) data for paediatric pharmacovigilance purposes and to make recommendations for such a system. METHODS: A mixed methods approach including a literature review, interviews, focus groups and a three-round Delphi survey with HCPs in Scotland was followed by a triangulation process using a systematic protocol. The survey was structured using the Theoretical Domains Framework of behaviour change. Items retained after applying the matrix-based triangulation process were thematically coded. Ethical approval was granted by the North of Scotland Research Ethics Service. RESULTS: Results from 18 papers, 23 interviewees, 23 participants of focus groups and 61 completed questionnaires in the Delphi survey contributed to the triangulation process. A total of 25 key findings from all four studies were identified during triangulation. There was good convergence; 21 key findings were agreed and remained to inform recommendations. The items were coded as practical/technical (eg, decision about the unique patient identifier to use), mandatory (eg, governed by statute), essential (consistently mentioned in all studies and therefore needed to ensure professional support) or preferable. CONCLUSIONS: The development of a paediatric linked database has support from professional stakeholders and HCPs in Scotland. The triangulation identified three sets of core requirements for a new system of data linkage. An additional fourth set of 'preferable' requirements might increase engagement of HCPs and their support for the new system.

Linking NHS data for pediatric pharmacovigilance: Results of a Delphi survey.

BACKGROUND: Adverse drug events are a major cause of patient safety incidents. Current systems of pharmacovigilance under-report adverse drug reactions (ADRs), especially in children, leading to delays in their identification. This is of particular concern, as children especially have an increased vulnerability to ADRs. OBJECTIVES: The objective was to seek consensus among healthcare professionals (HCPs) about barriers and facilitators to the linkage of routinely collected health data for pediatric pharmacovigilance in Scotland. METHODS: A Delphi survey was conducted with a random sample of HCPs including nurses, pharmacists and doctors, working in primary or secondary care, in Scotland. Participants were identified from sampling frames of the target professionals such as an NHS workforce list for general practitioners and recruited by postal invitation. A total of 819 HCPs were invited to take part. Those agreeing to participate were given the option of completing the questionnaires online or as hard copy. Reminders were sent twice at a fortnightly interval. Questions content included description of professional role as well as testing for the willingness to support the proposed project and was informed by the Theoretical Domains Framework of Behavior Change (TDF) and earlier qualitative work. Three Delphi rounds were administered, including a first round for item generation. RESULTS: 121 of those invited agreed to take part (15%). The first round of the Delphi study included 21 open questions and generated over a 1000 individual statements from 61 participants that returned the questionnaires (50.4%). These were rationalized to 149 items for the second round in which participants rated their views on the importance (or not) of each item on a 9-point Likert scale (strongly disagree - strongly agree). After the third round, there was consensus on items that focused on professional standards, and practical requirements, overall there was support for data linkage and a multi-professional approach. CONCLUSIONS: It would be acceptable to stakeholders to introduce a data linkage system for pharmacovigilance as long as identified concerns are addressed. Concerns included adherence to current professional, legal and ethical standards, as well resolving practical issues.

Views of healthcare professionals to linkage of routinely collected healthcare data: a systematic literature review.

OBJECTIVE: To review the literature on the views of healthcare professionals to the linkage of healthcare data and to identify any potential barriers and/or facilitators to participation in a data linkage system. METHODS: Published papers describing the views of healthcare professionals (HCPs) to data sharing and linkage were identified by searches of Medline, EMBASE, SCOPUS, CINAHL, and PsychINFO. The searches were limited to papers published in the English language from 2001 to 2011. RESULTS: A total of 2917 titles were screened. From these, 18 papers describing the views of HCPs about data linkage or data sharing of routinely collected healthcare data at an individual patient level were included. Views were generally positive, and potential benefits were reported. Facilitators included having trust in the system including data governance, reliability, and feedback. Some negative views, identified as barriers were also expressed including costs, data governance, technical issues, and privacy concerns. Effects on the physician-patient relationship, and workload were also identified as deterrent. DISCUSSION: From the published literature included in this review, the views of HCPs were in general positive towards data sharing for public health purposes. The identification of barriers to contributing to a data linkage system allows these to be addressed in a planned data linkage project for pharmacovigilance. The main barriers identified were concerns about costs, governance and interference with the prescriber-patient relationship. These would have to be addressed if healthcare professionals are to support a data linkage system to improve patient safety.

Population pharmacokinetics of single-dose intravenous paracetamol in children.

BACKGROUND: To determine the pharmacokinetics (PK) of a new i.v. formulation of paracetamol (Perfalgan) in children ≤15 yr of age. METHODS: After obtaining written informed consent, children under 16 yr of age were recruited to this study. Blood samples were obtained at 0, 15, 30 min, 1, 2, 4, 6, and 8 h after administration of a weight-dependent dose of i.v. paracetamol. Paracetamol concentration was measured using a validated high-performance liquid chromatographic assay with ultraviolet detection method, with a lower limit of quantification (LLOQ) of 900 pg on column and an intra-day coefficient of variation of 14.3% at the LLOQ. Population PK analysis was performed by non-linear mixed-effect modelling using NONMEM. RESULTS: One hundred and fifty-nine blood samples from 33 children aged 1.8-15 yr, weight 13.7-56 kg, were analysed. Data were best described by a two-compartment model. Only body weight as a covariate significantly improved the goodness of fit of the model. The final population models for paracetamol clearance (CL), V(1) (central volume of distribution), Q (inter-compartmental clearance), and V(2) (peripheral volume of distribution) were: 16.51×(WT/70)(0.75), 28.4×(WT/70), 11.32×(WT/70)(0.75), and 13.26×(WT/70), respectively (CL, Q in litres per hour, WT in kilograms, and V(1) and V(2) in litres). CONCLUSIONS: In children aged 1.8-15 yr, the PK parameters for i.v. paracetamol were not influenced directly by age but were by total body weight and, using allometric size scaling, significantly affected the clearances (CL, Q) and volumes of distribution (V(1), V(2)).

A retrospective observational study comparing rescue medication use in children on combined versus separate long-acting beta-agonists and corticosteroids.

BACKGROUND: Data on the efficacy and safety of long-acting ß2-agonists (LABA) in children are limited, and current guidelines recommend that LABA always be used with inhaled corticosteroids (ICS). OBJECTIVE: To compare asthma control, assessed by rescue medications use, in children prescribed LABA and ICS as a fixed-dose combination (LABA/ICS) or concurrently via separate inhalers (LABA+ICS). METHODS: Retrospective observational study of asthma medication prescribed to children aged 0-18 years registered with 40 primary care practices for the years 2002-6. Asthma control, reflected by requirement for oral corticosteroids (OCS) and/or six or more short-acting ß2-agonist (SABA) canisters per year, was assessed for children prescribed LABA/ICS or LABA+ICS. RESULTS: 10,454 (8%) of all registered children received at least one prescription for asthma medication over the study period. Prescribing of LABA/ICS increased significantly, with a concomitant decrease in prescribing of LABA+ICS. Use of OCS increased by 60%, with the lowest use in children prescribed only SABA and highest use in those prescribed LABA. Children prescribed LABA/ICS were significantly less likely than those prescribed LABA+ICS to require OCS rescue therapy and or >6 SABA inhalers a year (OR 1.6; 95% CI 1.1 to 2.2; p=0.04 and OR 1.7; 95% CI 1.1 to 2.5; p=0.005, respectively, for the years 2005-6). CONCLUSIONS: The results of this retrospective observational study suggest that children prescribed fixed-dose LABA-and-ICS combination devices achieve better asthma control, as reflected in reduced requirements for SABA and reduced courses of OCS than equivalent doses in separate devices.

Changes in the prevalence of asthma, eczema and hay fever in pre-pubertal children: a 40-year perspective.

Surveys of primary schools children in Aberdeen carried out in 1964, 1989, 1994 and 1999 suggested a slowing of the increase in parent-reported wheeze between 1994 and 1999. To assess whether this pattern had continued, questionnaires were distributed to 5712 children aged 7-12 years in the same schools in 2004. A total of 3271 (57.3%) completed questionnaires were returned. As in earlier surveys the results were divided into those for younger children (school years 3-4; age 7-9 years) and older children (school years 5-7; age 9-12 years). Compared with 1999, the 2004 results showed a decrease in the proportion of children with wheeze in the last 3 years from 30.1% to 23.3% (P < 0.001) in the younger group and from 27.6% to 25.1% (P = 0.052) in the older group. There was no significant change in the lifetime prevalence of asthma in either the younger or the older group, but the lifetime prevalence of eczema and hay fever increased by around 10% in both the younger and older groups (all P < 0.001). The differences in the time trends for the different conditions suggest that the causal factors for wheeze and asthma differ from those for other allergic diseases of childhood.

Climate change and respiratory disease: European Respiratory Society position statement.

Climate change will affect individuals with pre-existing respiratory disease, but the extent of the effect remains unclear. The present position statement was developed on behalf of the European Respiratory Society in order to identify areas of concern arising from climate change for individuals with respiratory disease, healthcare workers in the respiratory sector and policy makers. The statement was developed following a 2-day workshop held in Leuven (Belgium) in March 2008. Key areas of concern for the respiratory community arising from climate change are discussed and recommendations made to address gaps in knowledge. The most important recommendation was the development of more accurate predictive models for predicting the impact of climate change on respiratory health. Respiratory healthcare workers also have an advocatory role in persuading governments and the European Union to maintain awareness and appropriate actions with respect to climate change, and these areas are also discussed in the position statement.

Early rattles, purrs and whistles as predictors of later wheeze.

BACKGROUND: Asthma is a common condition characterised by wheeze. Many different respiratory sounds are interpreted by parents as "wheeze" in young children. AIM: To relate different respiratory sounds reported as wheeze in 2-year-olds to asthma outcomes at age 5 years. METHODS: As part of a longitudinal cohort study, parents completed respiratory questionnaires for their children at 2 and 5 years of age. Parents who reported wheeze were given options to describe the sound as rattling, purring or whistling. RESULTS: Of the 1371 2-year-olds surveyed, 210 had current wheeze, of whom 124 had rattle, 49 purr and 24 whistle. Children with whistle at 2 years were more likely to have mothers with asthma, and children with rattle and purr were more likely to be exposed to tobacco smoke. Wheeze status was ascertained at age 5 years in 162 (77%) children with wheeze at 2 years of age. Whistle persisted in 47% of affected children, rattle in 20%, and purr in 13% (p = 0.023). At 5 years of age, asthma medication was prescribed in 40% with whistle, 11% with rattle, and 18% with purr at 2 years of age (p = 0.017). CONCLUSIONS: This study shows different risk factors and outcomes for different respiratory sounds in 2-year-olds: compared with other respiratory sounds, whistle is likely to persist and require asthma treatment in future.

Factor analysis in the Genetics of Asthma International Network family study identifies five major quantitative asthma phenotypes.

BACKGROUND: Asthma is a clinically heterogeneous disease caused by a complex interaction between genetic susceptibility and diverse environmental factors. In common with other complex diseases the lack of a standardized scheme to evaluate the phenotypic variability poses challenges in identifying the contribution of genes and environments to disease expression. OBJECTIVE: To determine the minimum number of sets of features required to characterize subjects with asthma which will be useful in identifying important genetic and environmental contributors. Methods Probands aged 7-35 years with physician diagnosed asthma and symptomatic siblings were identified in 1022 nuclear families from 11 centres in six countries forming the Genetics of Asthma International Network. Factor analysis was used to identify distinct phenotypes from questionnaire, clinical, and laboratory data, including baseline pulmonary function, allergen skin prick test (SPT). RESULTS: Five distinct factors were identified:(1) baseline pulmonary function measures [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)], (2) specific allergen sensitization by SPT, (3) self-reported allergies, (4) symptoms characteristic of rhinitis and (5) symptoms characteristic of asthma. Replication in symptomatic siblings was consistent with shared genetic and/or environmental effects, and was robust across age groups, gender, and centres. Cronbach's alpha ranged from 0.719 to 0.983 suggesting acceptable internal scale consistencies. Derived scales were correlated with serum IgE, methacholine PC(20), age and asthma severity (interrupted sleep). IgE correlated with all three atopy-related factors, the strongest with the SPT factor whereas severity only correlated with baseline lung function, and with symptoms characteristic of rhinitis and of asthma. CONCLUSION: In children and adolescents with established asthma, five distinct sets of correlated patient characteristics appear to represent important aspects of the disease. Factor scores as quantitative traits may be better phenotypes in epidemiological and genetic analyses than those categories derived from the presence or absence of combinations of +ve SPTs and/or elevated IgE.

Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report.

Asthma is the leading chronic disease among children in most industrialized countries. However, the evidence base on specific aspects of pediatric asthma, including therapeutic strategies, is limited and no recent international guidelines have focused exclusively on pediatric asthma. As a result, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams to find a consensus to serve as a guideline for clinical practice in Europe as well as in North America. This consensus report recommends strategies that include pharmacological treatment, allergen and trigger avoidance and asthma education. The report is part of the PRACTALL initiative, which is endorsed by both academies.

Effects of treating postnatal depression on mother-infant interaction and child development: systematic review.

BACKGROUND: Postnatal depression has detrimental effects on the child's cognitive and emotional development. AIMS: To assess the benefits of treating postnatal depression for mother-infant interaction and child development. METHOD: A systematic search was made of 12 electronic bibliographic databases for randomised controlled trials and controlled clinical trials on treatment of mothers with postnatal depression, where outcomes were assessed in children; findings were assessed. RESULTS: Only eight trials met the inclusion criteria. Of those included, interventions varied widely but all involved therapies directed at the mother-infant relationship. One study with intensive and prolonged therapy showed cognitive improvement, whereas two others with briefer interventions improved maternal-infant relationships but did not affect the child's cognitive or behavioural development. All five studies assessing only mother-infant relationships showed improvements. CONCLUSIONS: Cognitive development in children of depressed mothers, along with better mother-infant relationships, might be improved with sustained interventions. Trials assessing treatments for postnatal depression would benefit from looking more closely at benefits for children as well as mothers, using validated objective measures.

A critical review of the use of Clara cell secretory protein (CC16) as a biomarker of acute or chronic pulmonary effects.

Biomarkers associated with asthma aetiology and exacerbation have been sought to shed light on this multifactorial disease. One candidate is the serum concentration of the Clara cell secretory protein (CC16, sometimes referred to as CC10 or uteroglobin). In this review, we examine serum CC16's relation to asthma aetiology and exacerbation. There is evidence that acute exposures to certain pulmonary irritants can cause a transient increase in serum CC16 levels, and limited evidence also suggests that a transient increase in serum CC16 levels can be caused by a localized pulmonary inflammation. Research also indicates that a transient increase in serum CC16 is not associated with measurable pulmonary damage or impairment of pulmonary function. The biological interpretation of chronic changes in serum CC16 is less clear. Changes in serum CC16 concentrations (either transient or chronic) are not specific to any one agent, disease state, or aetiology. This lack of specificity limits the use of serum CC16 as a biomarker of specific exposures. To date, many of the critical issues that must be understood before serum CC16 levels can have an application as a biomarker of effect or exposure have not been adequately addressed.

Maternal food consumption during pregnancy and asthma, respiratory and atopic symptoms in 5-year-old children.

BACKGROUND: Associations between maternal vitamin E, vitamin D and zinc intakes during pregnancy and asthma, wheeze and eczema in 5-year-old children have previously been reported. A study was undertaken to investigate whether maternal intake of specific foods during pregnancy is associated with asthma and allergic outcomes in the same children. METHODS: A longitudinal birth cohort study was conducted in 1,924 children born to women recruited during pregnancy. Maternal diet during pregnancy was assessed by food frequency questionnaire (FFQ). Cohort children were followed up at 5 years by symptom questionnaire and FFQ. Food groups of interest were fruit, vegetables, fruit juice, whole grain products, fish, dairy products and fat spreads. Trends across outcome groups defined by level of food intake are presented. RESULTS: 1,253 children participated at 5 years and maternal FFQ data were available for 1,212. No consistent associations were found between childhood outcomes and maternal intake of the analysed foods except for apples and fish. Maternal apple intake was beneficially associated with ever wheeze (OR highest vs lowest tertile 0.63, 95% CI 0.42 to 0.95), ever asthma (OR 0.54, 95% CI 0.32 to 0.92) and doctor-confirmed asthma (OR 0.47, 95% CI 0.27 to 0.82) in the children. Maternal fish consumption was beneficially associated with doctor-confirmed eczema (OR >or=1/week vs never 0.57, 95% CI 0.35 to 0.92). CONCLUSION: There was no evidence for associations between maternal intake of most foods during pregnancy and asthma, respiratory and allergic outcomes in 5-year-old children, except for apples and fish. Consumption of apples and fish during pregnancy may have a protective effect against the development of childhood asthma and allergic disease.

A prospective questionnaire assessment of attitudes and experiences of off label prescribing among hospital based paediatricians.

OBJECTIVE: To assess current attitudes of hospital based paediatricians to off label prescribing, and the performance of clinical trials in children. DESIGN: A prospective, questionnaire based study. SETTING: 257 hospital based consultants and specialist registrars in paediatric practice in Scotland during 2003-2004. RESULTS: A 25 item questionnaire was sent to 257 hospital based paediatricians and 151 (59%) were returned completed. Over 90% of responders were familiar with the concept of, and knowingly prescribed, off label drugs; 55% of responders stated that such prescribing disadvantaged children, and 47% expressed concerns about the efficacy of off label medicines. Although 70% of responders expressed concerns about safety, only 17% had observed an adverse event, and 47% a treatment failure, while 69% did not obtain informed consent or tell parents they were prescribing off label, and 67% did not inform the family's general practitioner. Many respondents did not believe it was necessary to carry out clinical trials in children for new (46%) or generic (64%) medicines. However, 52% of respondents stated that they would be willing to undertake clinical studies and recruit their own patients (61%) or children (73%) to take part in such studies. CONCLUSIONS: Among Scottish paediatricians there is concern about off label prescribing, although the majority do not consider it necessary to inform parents or GP colleagues. The need for clinical trials in children was recognised but there was a less than wholehearted acceptance of the need for such studies, at variance with the current drive to promote clinical trials in this age group.

Adolescent use of the combined oral contraceptive pill: a retrospective observational study.

AIMS: To determine the extent of combined oral contraceptive use by girls aged 10-16 years in Scotland. METHODS: Assessment of combined oral contraceptive prescribing in 35 414 girls for the year 1 November 1999-31 October 2000 from data retrieved from 161 primary care practices taking part in the Scottish Programme for Improving Clinical Effectiveness in Primary Care, and from national aggregated data from family planning clinics. RESULTS: During the study period the oral contraceptive pill (OCP) was prescribed by a primary care physician to 1531 girls (4.3%) aged 10-16 years. The age specific prevalence rates per 1000 girls registered with their family doctor rose from 0.9/1000 girls aged 12 years or younger, to 6.9, 30, 86.3, and 174.8/1000 for girls aged 13, 14, 15, and 16 years respectively. The overall prevalence of combined oral contraceptive prescribing by primary care physicians was 43.2/1000 girls aged 10-16 years. A further 1765 girls aged 13-16 years obtained a prescription for the OCP from a Scottish family planning clinic, giving an overall prevalence rate for family planning clinic prescribing of 8.0/1000 girls aged 10-16 years. Despite reportedly high levels of sexual activity and teenage pregnancy in this age group, these results confirm that OCP use is relatively low. CONCLUSIONS: The UK has the highest rate of teenage pregnancy in Western Europe, but despite the medical and social concerns about the sexual health of teenagers, the level of oral contraceptive use in this young age group remains low.

Preferential transmission and association of the -403 G --> A promoter RANTES polymorphism with atopic asthma.

Asthma is a complex inherited disease. The study was undertaken to identify the association of RANTES promoter polymorphisms with atopy and asthma using family-based association tests (FBATs) and generation-specific case-control analyses. We identified 154 nuclear families (453 individuals) in whom we established RANTES promoter status using the RFLP-PCR method. Of the two known promoter polymorphisms -403G/A and -28C/G, only the former appeared with a clinically relevant frequency. A total of 61 families were eligible for assessment of transmission of the allele with asthma and atopy by the pedigree disequilibrium test (PDT). Overall, allele frequency for -403A was 38.3% and 84 of 89 (94.3%) alleles were transmitted with physician diagnosed asthma (PDA) (P=0.001). All 89 children with atopy received the mutant allele, which was more than expected following Mendelian Laws of transmission (P=0.0001). In 303 unrelated parents, significant associations of the mutant allele were for atopy with or without asthma (P=0.001). In 150 unrelated children, significant associations were for atopy alone (P=0.001) and asthma (P=0.001). No associations were found for bronchial hyper-responsiveness (BHR). The -403 G --> A is transmitted with atopy and atopic asthma, although its contribution appears to relate more to atopy than asthma and BHR.