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Background and purpose Continuous improvement of health and healthcare system is hampered by inefficient processes of generating new evidence, particularly in the case of rare diseases and paediatrics. Currently, most evidence is generated through specific research projects, which typically require extra encounters with patients, are costly and entail long delays between the recognition of specific needs in healthcare and the generation of necessary evidence to address those needs. The Swiss Personalised Health Network (SPHN) aims to improve the use of data obtained during routine healthcare encounters by harmonizing data across Switzerland and facilitating accessibility for research. The project “Harmonising the collection of health-related data and biospecimens in paediatric hospitals throughout Switzerland (SwissPedData)” was an infrastructure development project funded by the SPHN, which aimed to identify and describe available data on child health in Switzerland and to agree on a standardised core dataset for electronic health records across all paediatric teaching hospitals. Here, we describe the results of a two-day symposium that aimed to summarise what had been achieved in the SwissPedData project, to put it in an international context, and to discuss the next steps for a sustainable future. The target audience included clinicians and researchers who produce and use health-related data on children in Switzerland. Key highlights The symposium consisted of state-of-the-art lectures from national and international keynote speakers, workshops and plenary discussions. This manuscript summarises the talks and discussions in four sections: (I) a description of the Swiss Personalized Health Network and the results of the SwissPedData project; (II) examples of similar initiatives from other countries; (III) an overview of existing health-related datasets and projects in Switzerland; and (IV) a summary of the lessons learned and future prospective from workshops and plenary discussions. Implications Streamlined processes linking initial collection of information during routine healthcare encounters, standardised recording of this information in electronic health records and fast accessibility for research are essential to accelerate research in child health and make it affordable. Ongoing projects prove that this is feasible in Switzerland and elsewhere. International collaboration is vital to success. The next steps include the implementation of the SwissPedData core dataset in the clinical information systems of Swiss hospitals, the use of this data to address priority research questions, and the acquisition of sustainable funding to support a slim central infrastructure and local support in each hospital. This will lay the foundation for a national paediatric learning health system in Switzerland.

Epidemiological studies of children's cancer risks associated with background gamma radiation exposure have used geographic exposure models to estimate exposure at their locations of residence. We measured personal exposure to background gamma radiation, and we investigated the extent to which it was associated with children's whereabouts. We collected data on whereabouts and exposure to background gamma radiation over a 5-day period among children aged 4-15 years in Switzerland. We used D-Shuttle dosimeters to measure children's exposure, and we asked parents to write their children's activities in diaries. We used Poisson mixed-effects and linear regression models to investigate the association of hourly and overall doses, respectively, with children's reported whereabouts. During the observed time, 149 participating children spent 66% indoors at home; 19% indoors away from home; and 15% outdoors. The mean personal exposure was 85.7 nSv/h (range 52.3 nSv/h-145 nSv/h). Exposure was 1.077 (95% CI 1.067, 1.087) times higher indoors than outdoors and varied by building material and (predicted) outdoor dose rates. Our study provides detailed information about children's patterns of exposure to background gamma radiation in Switzerland. Dwelling building materials and outdoor dose rates are important determinants of children's exposure. Future epidemiological studies may benefit from including information about building materials.

RationaleThe Predicting Asthma Risk in Children (PARC) tool uses questionnaire-based respiratory symptoms collected from preschool children to predict their risk of asthma 5 years later. The tool was originally developed and externally validated in population-based settings and has not yet been validated in a clinical setting.ObjectiveTo externally validate the PARC tool in children seen in paediatric pulmonology clinics.MethodsThe Swiss Paediatric Airway Cohort (SPAC) is a prospective study of children seen in respiratory outpatient clinics across Switzerland. This analysis included children seen at ages 1-6 years for cough or wheeze at baseline and who completed the follow-up questionnaire 2 years later. The outcome was defined as current wheeze plus use of asthma medication. In sensitivity analyses, we explored effects of varied inclusion criteria and outcomes. We assessed performance by describing sensitivity, specificity, negative and positive predictive value (NPV, PPV), area under the curve (AUC), scaled Brier’s score and Nagelkerke’s R2 scores and compared performance in SPAC to that achieved in the original population, the Leicester Respiratory Cohort (LRC).ResultsAmong the 346 children included, 125 (36%) reported the outcome after 2 years. At a PARC score cut-off of 4, sensitivity was higher (95% vs 79%) but specificity lower (14% vs 57%) in SPAC compared to LRC. NPV was comparable (0.84 vs. 0.87) as was PPV (0.37 vs.0.42). Discrimination was lower in SPAC (AUC of 0.71 vs 0.78), as were Nagelkerke’s R2 (0.18 vs 0.28) and scaled Brier’s scores (0.13 vs 0.22). When the outcome was changed to moderately severe asthma (>4 attacks plus use of asthma medication), there were improvements in AUC (0.74), sensitivity (0.97), specificity (0.22) and NPV (0.99), but some deterioration in PPV (0.13), R2 (0.15) and scaled Brier score (0.09).ConclusionWhile the PARC tool performs well in a population-based setting and has some clinical utility, in particular for ruling out the development of asthma, this study highlights the need for new prognostic prediction tools to be developed specifically for the clinical setting.FundingSNSF:320030_182628, SLA2019-03_641670

Background Pesticide exposure is a suspected risk factor for childhood cancer. We investigated the risk of developing childhood cancer in relation to parental occupational exposure to pesticides in Switzerland for the period 1990–2015. Methods From a nationwide census-based cohort study in Switzerland, we included children aged

RATIONALE The lung clearance index (LCI) is increasingly being used in the clinical surveillance of patients with cystic fibrosis (CF). However, there are limited data on long-term variability and clinically relevant changes in LCI during routine clinical surveillance. OBJECTIVES To evaluate long-term variability of LCI and propose a threshold for a physiologically relevant change. METHODS Children with CF aged 4-18 years performed LCI measurements every three months as part of routine clinical surveillance during 2011-2020 in two centers. The variability of LCI during periods of clinical stability was assessed using mixed-effects models and was used to identify thresholds for clinically relevant changes. RESULTS Repeated LCI measurements of acceptable quality (N= 858) were available in 100 patients with CF, for 74 patients 399 visits at clinical stability were available. Variability of repeated LCI measurements over time expressed as coefficient of variation (CV%) was 7.4%. The upper limit of normal (ULN) for relative changes in LCI between visits was 19%. CONCLUSION We report the variability of LCI in children and adolescents with CF during routine clinical surveillance. According to our data, a change in LCI beyond 19% may be considered physiologically relevant. These findings will help guide clinical decisions according to LCI changes. This article is protected by copyright. All rights reserved.

Motor vehicle exhaust is a major contributor to air pollution, and exposure to benzene or other carcinogenic components may increase cancer risks. We aimed to investigate the association between traffic-related air pollution and risk of childhood cancer in a nationwide cohort study in Switzerland. We identified incident cases from the Swiss Childhood Cancer Registry diagnosed < 16 years of age between 1990 and 2015 and linked them probabilistically with the census-based Swiss National Cohort study. We developed land use regression models to estimate annual mean ambient levels of nitrogen dioxide (NO2) and benzene outside 1.4 million children's homes. We used risk-set sampling to facilitate the analysis of time-varying exposure and fitted conditional logistic regression models adjusting for neighborhood socio-economic position, level of urbanization, and background ionizing radiation. We included 2,960 cancer cases in the analyses. The adjusted hazard ratios (HR) and 95% confidence intervals for exposure to NO2 per 10 mug/m(3) were 1.00 (95%-CI 0.88-1.13) for acute lymphoblastic leukemia (ALL) and 1.31 (95%-CI 1.00-1.71) for acute myeloid leukemia (AML). Using exposure lagged by 1 to 5 years instead of current exposure attenuated the effect for AML. The adjusted HR for exposure to benzene per 1 mug/m(3) was 1.03 (95%-CI 0.86-1.23) for ALL and 1.29 (95%-CI 0.86-1.95) for AML. We also observed increased HRs for other diagnostic groups, notably non-Hodgkin lymphoma. Our study adds to the existing evidence that exposure to traffic-related air pollution is associated with an increased risk of childhood leukemia, particularly AML.

BACKGROUND Improvement of paediatric healthcare is hampered by inefficient processes for generating new evidence. Clinical research often requires extra encounters with patients, is costly, takes place in an artificial situation with a biased selection of patients, and entails long delays until new evidence is implemented into health care. Electronic health records (EHR) contain detailed information on real patients and cover the entirety of patients. However, the use of EHR for research is limited because they are not standardised between hospitals. This leads to disproportionate amounts of work for extracting data of interest and frequently data are incomplete and of poor quality. AIMS SwissPedData aims to lay the foundation for a paediatric learning health system in Switzerland by facilitating EHR-based research. In this project, we aimed to assess the way routine clinical data are currently recorded in large paediatric clinics in Switzerland and to develop a national EHR-based set of common data elements (CDEs) that covers all processes of routine paediatric care in hospitals. METHODS A taskforce of paediatricians from large Swiss children's hospitals reviewed the current status of routine data documentation in paediatric clinical care and the extent of digitalisation. We then used a modified Delphi method to reach a broad consensus on a national EHR-based set of CDEs. RESULTS All Swiss children's hospitals use EHR to document some or all aspects of care. One hundred and nineteen paediatricians, representing eight hospitals and all paediatric subspecialties, participated in an extended Delphi process to create SwissPedData. The group agreed on a national set of CDEs that comprises a main module with general paediatric data and sub-modules relevant to paediatric subspecialties. The data dictionary includes 336 CDEs: 76 in the main module on general paediatrics and between 11 and 59 CDEs per subspecialty module. Among these, 266 were classified as mandatory, 52 as recommended and 18 as optional. CONCLUSION SwissPedData is a set of CDEs for information to be collected in EHR of Swiss children's hospitals. It covers all care processes including clinical and paraclinical assessment, diagnosis, treatment, disposition and care site. All participating hospitals agreed to implement SwissPedData in their clinical routine and clinic information systems. This will pave the way for a national paediatric learning health system in Switzerland that enables fast and efficient answers to urgent clinical questions by facilitating high-quality nationwide retrospective and prospective observational studies and recruitment of patients for nested prospective studies and clinical trials.

Jedes Jahr werden in der Schweiz mehr als 40000 neue Krebserkrankungen diagnostiziert und Krebs ist die zweithäufigste Todesursache. Dieser dritte schweizerische Krebsbericht zeigt die aktuelle Situation von Krebs in der Schweiz und die Entwicklung der letzten 30 Jahre sowie regionale und internationale Vergleiche auf. Der Bericht präsentiert gesamtschweizerische Schätzungen zu Neuerkrankungen, Todesfällen, Überlebensraten und zur Anzahl von an Krebs erkrankten Personen. Die Zahlen werden ergänzt durch die Erläuterung von Risikofaktoren, die in der wissenschaftlichen Literatur als gesichert gelten. Nach einem allgemeinen Überblick über Krebs folgen Kapitel mit detaillierten Informationen über die wichtigsten Krebsarten bei Erwachsenen sowie bei Kindern und Jugendlichen. Die zur Erarbeitung dieses Berichts verwendeten Methoden sind in einem separaten Methodenbericht detailliert dargestellt.

Continuous improvement of health and healthcare system is hampered by inefficient processes of generating new evidence, particularly in the case of rare diseases and paediatrics. Currently, most evidence is generated through specific research projects, which typically require extra encounters with patients, are costly and entail long delays between the recognition of specific needs in ealthcare and the generation of necessary evidence to address those needs. The Swiss Personalised Health Network (SPHN) aims to improve the use of data obtained during routine healthcare encounters by harmonizing data across Switzerland and facilitating accessibility for research. The project “Harmonising the collection of health-related data and biospecimens in paediatric hospitals throughout Switzerland (SwissPedData)” was an infrastructure development project funded by the SPHN, which aimed to identify and describe available data on child health in Switzerland and to agree on a standardised core dataset for electronic health records across all paediatric teaching hospitals. Here, we describe the results of a two-day symposium that aimed to summarise what had been achieved in the SwissPedData project, to put it in an international context, and to discuss the next steps for a sustainable future. The target audience included clinicians and researchers who produce and use health-related data on children in Switzerland.

Background The aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. This study is the first investigation of the spatial disease mapping of childhood cancers using exact geocodes of place of residence. Methods We included 5947 children diagnosed with cancer in Switzerland during 1985–2015 at 0–15 years of age from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardisation to adjust for age and year of diagnosis. We examined whether the spatial variation of risk can be explained by modelled ambient air concentration of NO2, modelled exposure to background ionising radiation, area-based socio-economic position (SEP), linguistic region, duration in years of general cancer registration in the canton or degree of urbanisation. Results For all childhood cancers combined, the posterior median relative risk (RR), compared to the national level, varied by location from 0.83 to 1.13 (min to max). Corresponding ranges were 0.96 to 1.09 for leukaemia, 0.90 to 1.13 for lymphoma, and 0.82 to 1.23 for central nervous system (CNS) tumours. The covariates considered explained 72% of the observed spatial variation for all cancers, 81% for leukaemia, 82% for lymphoma and 64% for CNS tumours. There was weak evidence of an association of CNS tumour incidence with modelled exposure to background ionising radiation (RR per SD difference 1.17; 0.98–1.40) and with SEP (1.6; 1.00–1.13). Conclusion Of the investigated diagnostic groups, childhood CNS tumours showed the largest spatial variation. The selected covariates only partially explained the observed variation of CNS tumours suggesting that other environmental factors also play a role.

Additional file 1 S1: Job categories assigned a high likelihood of exposure to pesticides by CLIC-JEM and their prevalence among parents of children included in the study. S2: Directed Acyclic Graphs (DAG) of known and suspected associations with childhood cancers (Potential confounders for which data were available and which were considered in the analyses are shown in bold). S3: Exposure prevalence among parents of children included in the analysis based on CLIC-JEM and reported job categories at censuses 1990 and 2000. S4: Frequency of paternal and maternal occupational exposure to pesticides among children included in both analyses (n = 1,407,503). S5: Association between potential confounders and likelihood of paternal exposure to pesticides. S6: Association between potential confounders and likelihood of maternal exposure to pesticides. S7: Cases of childhood cancers included in analyses and likelihood of parental occupational exposure to pesticides. S8: Association between parental occupational exposure to pesticides and risk of childhood cancer in the Swiss National Cohort. S9: Association between parental occupational exposure to pesticides and risk of childhood cancer in the Swiss National Cohort stratified by census year of entry (only outcomes with evidence of interaction shown). S10: Association between parental occupational exposure to pesticides and risk of childhood cancer in the Swiss National Cohort, classifying non-economically active parents as missing. S11: Sensitivity analysis classifying mothers reporting “housework” as having high likelihood of exposure if the father reported an occupation in agriculture. S12: Additional analysis comparing children for whom at least one parent had high likelihood of exposure to children whose parents both had no or minimal exposure. S13: Change of parental occupational pesticides exposure between 1990 and 2000.

BACKGROUND The nitrogen multiple breath washout (N2MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N2MBW outcomes in a cohort of healthy Caucasian school-aged children. METHODS N2MBW data from healthy Caucasian school-age children between 6 and 18 years were collected from four experienced centers. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analyzed with commercial software (Spiroware, 3.2.1, Eco Medics AG). Normative values and upper limits of normal were generated for lung clearance index at 2.5% (LCI2.5%) and at 5% (LCI5%), moment ratios (M1/M0 and M2/M0), and a prediction equation generated for functional residual capacity (FRC). RESULTS Four hundred and eighty five trials from 180 healthy Caucasian children aged from 6 to 18 years were used for analysis. While LCI increased with age, this increase was negligible (0.04 units/year for LCI2.5%) and therefore fixed upper limits of normal were defined for this age group. These limits were 7.91 for LCI2.5%, 5.73 for LCI5%, 1.75 for M1/M0, and 6.15 for M2/M0 respectively. Height and weight were found to be independent predictors of FRC. CONCLUSION We report reference values for N2MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease.

Additional file 1. Supplementary text, tables and figures supporting the main manuscript.

BACKGROUND External validation of prediction models is important to assess generalisability to other populations than the one used for model development. The Predicting Asthma Risk in Children (PARC) tool, developed in the Leicestershire Respiratory Cohort (LRC), uses information on preschool respiratory symptoms to predict asthma at school age. OBJECTIVE We performed an external validation of PARC using the Avon Longitudinal Study of Parents and Children (ALSPAC). METHODS We defined inclusion criteria, prediction score items at baseline and asthma at follow-up in ALSPAC to match those used in LRC using information from parent-reported questionnaires. We assessed performance of PARC by calculating sensitivity, specificity, predictive values, likelihood ratios, area under the curve (AUC), Brier score and Nagelkerke's R-squared. Sensitivity analyses varied inclusion criteria, scoring items and outcomes. RESULTS The validation population included 2690 children with preschool respiratory symptoms of which 373 (14%) had asthma at school age. Discriminative performance of PARC was similar in ALSPAC (AUC=0.77, Brier score 0.13) as in LRC (0.78, 0.22). The score cut-off of 4 showed the highest sum of sensitivity (69%) and specificity (76%) and positive and negative likelihood ratios of 2.87 and 0.41, respectively. Changes to inclusion criteria, scoring items or outcome definitions barely altered the prediction performance. CONCLUSION Performing equally well in the validation cohort as in the development cohort, PARC is a valid tool for predicting asthma in population based cohorts. Its use in clinical practice is ready to be tested.

Background Exposure to medium or high doses of ionizing radiation is a known risk factor for cancer in children. The extent to which low-dose radiation from natural sources contributes to the risk of childhood cancer remains unclear. Objectives In a nationwide census-based cohort study, we investigated whether the incidence of childhood cancer was associated with background radiation from terrestrial gamma and cosmic rays. Methods Children < 16 years of age in the Swiss National Censuses in 1990 and 2000 were included. The follow-up period lasted until 2008, and incident cancer cases were identified from the Swiss Childhood Cancer Registry. A radiation model was used to predict dose rates from terrestrial and cosmic radiation at locations of residence. Cox regression models were used to assess associations between cancer risk and dose rates and cumulative dose since birth. Results Among 2,093,660 children included at census, 1,782 incident cases of cancer were identified including 530 with leukemia, 328 with lymphoma, and 423 with a tumor of the central nervous system (CNS). Hazard ratios for each millisievert increase in cumulative dose of external radiation were 1.03 (95% CI: 1.01, 1.05) for any cancer, 1.04 (95% CI: 1.00, 1.08) for leukemia, 1.01 (95% CI: 0.96, 1.05) for lymphoma, and 1.04 (95% CI: 1.00, 1.08) for CNS tumors. Adjustment for a range of potential confounders had little effect on the results. Conclusions Our study suggests that background radiation may contribute to the risk of cancer in children, including leukemia and CNS tumors. Citation Spycher BD, Lupatsch JE, Zwahlen M, Röösli M, Niggli F, Grotzer MA, Rischewski J, Egger M, Kuehni CE, for the Swiss Pediatric Oncology Group and the Swiss National Cohort. 2015. Background ionizing radiation and the risk of childhood cancer: a census-based nationwide cohort study. Environ Health Perspect 123:622–628; http://dx.doi.org/10.1289/ehp.1408548

The aetiology of childhood leukaemia remains largely unknown. Several hypotheses involve environmental exposures that could implicate spatial clustering of cases. The evidence from previous clustering studies is inconclusive. Most of them used areal data and thus had limited spatial resolution. We investigated whether childhood leukaemia tends to cluster in space using exact geocodes of place of residence both at the time of birth or diagnosis. We included 1,871 leukaemia cases diagnosed between 1985 and 2015 at age 0-15 years from the Swiss Childhood Cancer Registry. For each case, we randomly sampled 10 age and sex matched controls from national censuses closest in time. We used the difference of k-functions, Cuzick-Edwards' test and Tango's index for point data to assess spatial clustering and Kulldorff's circular scan to detect clusters. We separately investigated acute lymphoid leukaemia (ALL), acute myeloid leukaemia (AML), different age groups at diagnosis (0-4, 5-15 years) and adjusted for multiple testing. After adjusting for multiple testing, we found no evidence of spatial clustering of childhood leukaemia neither around time of birth (p = 0.52) nor diagnosis (p = 0.51). Individual tests indicated spatial clustering for leukaemia diagnosed at age 5-15 years, p k-functions = 0.05 and p Cuzick-Edwards' = 0.04 and a cluster of ALL cases diagnosed at age 0-4 years in a small rural area (p = 0.05). This study provides little evidence of spatial clustering of childhood leukaemia in Switzerland and highlights the importance of accounting for multiple testing in clustering studies.

Chronic respiratory symptoms, such as cough, wheeze and dyspnoea, are common in children; however, most research has, with the exception of a few large-scale clinical cohort studies, been performed in the general population or in small, highly-selected samples. The Swiss Paediatric Airway Cohort (SPAC) is a national, prospective clinical cohort of children and adolescents who visit physicians for recurrent conditions, such as wheeze and cough, and exercise-related respiratory problems. The SPAC is an observational study and baseline assessment includes standardised questionnaires for families and data extracted from hospital records, including results of clinically indicated investigations, diagnoses and treatments. Outcomes are assessed through annual questionnaires, monthly symptom reporting mobile phone and follow-up visits. The SPAC will address important questions about clinical phenotypes, diagnosis, treatment, and the short- and long-term prognosis of common respiratory problems in children. The cohort currently consists of 347 patients from four major hospitals (Bern, Zurich, Basel and Lucerne), with 70-80 additional patients joining each month. More centres will join and the target sample size is a minimum of 3000 patients. The SPAC will provide real-life data on children visiting the Swiss healthcare system for common respiratory problems and will provide a research platform for health services research and nested clinical and translational studies.

BackgroundThe multiple breath nitrogen washout (N2MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N2MBW outcomes in a cohort of healthy Caucasian school-aged children.MethodsN2MBW data from healthy Caucasian school-age children between 6 and 18 years old were collected from four experienced centres. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analysed with commercial software (Spiroware version 3.2.1, Eco Medics AG). Normative values and upper limits of normal (ULN) were generated for lung clearance index (LCI) at 2.5% (LCI2.5%) and at 5% (LCI5%) of the initial nitrogen concentration and for moment ratios (M1/M0 and M2/M0). A prediction equation was generated for functional residual capacity (FRC).ResultsAnalysis used 485 trials from 180 healthy Caucasian children aged from 6 to 18 years old. While LCI increased with age, this increase was negligible (0.04 units·year–1 for LCI2.5%) and therefore fixed ULN were defined for this age group. These limits were 7.91 for LCI2.5%, 5.73 for LCI5%, 1.75 for M1/M0 and 6.15 for M2/M0, respectively. Height and weight were found to be independent predictors of FRC.ConclusionWe report reference values for N2MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease.

Primary ciliary dyskinesia (PCD) has been considered to be relatively mild disease, especially compared to cystic fibrosis (CF), but studies on lung function in PCD patients have been few and small. This study compared lung function from spirometry of PCD patients to normal reference values and to published data from CF. We calculated z-scores and percentage of predicted values for FEV1 and FVC using the Global Lung Function Initiative 2012 for 991 patients from the international PCD (iPCD) Cohort. We then assessed associations with age, sex, country, diagnostic certainty, organ laterality, body mass index and age at diagnosis in linear regression models. Lung function in PCD patients was reduced compared to reference values in both sexes and all age groups. Children aged 6-9 years had the smallest impairment (FEV1 z-score -0.84 [-1.03 to -0.65], FVC z-score -0.31 [-0.51 to -0.11]). Compared to CF patients, FEV1 was similarly reduced in children (age 6-9 years PCD, 91% [88–93%]; CF, 90% [88–91%]), but less impaired in young adults (age 18-21 years PCD, 79% [76–82%]; CF, 66% [65–68%]). The results suggest that PCD affects lung function from early in life, which emphasizes the importance of early, standardised care for all patients.

© 2018, Cancer Research UK. Background: Although studies have consistently found an association between childhood leukaemia risk and magnetic fields, the associations between childhood leukaemia and distance to overhead power lines have been inconsistent. We pooled data from multiple studies to assess the association with distance and evaluate whether it is due to magnetic fields or other factors associated with distance from lines. Methods: We present a pooled analysis combining individual-level data (29,049 cases and 68,231 controls) from 11 record-based studies. Results: There was no material association between childhood leukaemia and distance to nearest overhead power line of any voltage. Among children living < 50 m from 200 + kV power lines, the adjusted odds ratio for childhood leukaemia was 1.33 (95% CI: 0.92–1.93). The odds ratio was higher among children diagnosed before age 5 years. There was no association with calculated magnetic fields. Odds ratios remained unchanged with adjustment for potential confounders. Conclusions: In this first comprehensive pooled analysis of childhood leukaemia and distance to power lines, we found a small and imprecise risk for residences < 50 m of 200 + kV lines that was not explained by high magnetic fields. Reasons for the increased risk, found in this and many other studies, remains to be elucidated.

Chronic respiratory symptoms, such as cough, wheeze and dyspnoea, are common in children; however, most research has, with the exception of a few large-scale clinical cohort studies, been performed in the general population or in small, highly-selected samples. The Swiss Paediatric Airway Cohort (SPAC) is a national, prospective clinical cohort of children and adolescents who visit physicians for recurrent conditions, such as wheeze and cough, and exercise-related respiratory problems. The SPAC is an observational study and baseline assessment includes standardised questionnaires for families and data extracted from hospital records, including results of clinically indicated investigations, diagnoses and treatments. Outcomes are assessed through annual questionnaires, monthly symptom reporting mobile phone and follow-up visits. The SPAC will address important questions about clinical phenotypes, diagnosis, treatment, and the short- and long-term prognosis of common respiratory problems in children. The cohort currently consists of 347 patients from four major hospitals (Bern, Zurich, Basel and Lucerne), with 70-80 additional patients joining each month. More centres will join and the target sample size is a minimum of 3000 patients. The SPAC will provide real-life data on children visiting the Swiss healthcare system for common respiratory problems and will provide a research platform for health services research and nested clinical and translational studies.

OBJECTIVE To assess the epidemiology of blood culture-proven early- (EOS) and late-onset neonatal sepsis (LOS). STUDY DESIGN All newborn infants admitted to tertiary care neonatal intensive care units in Switzerland and presenting with blood culture-proven sepsis between September 2011 and December 2015 were included in the study. We defined EOS as infection occurring 48 hours after admission. Incidence was estimated based on the number of livebirths in Switzerland and adjusted for the proportion of admissions at centers participating in the study. RESULTS We identified 444 episodes of blood culture-proven sepsis in 429 infants; 20% of cases were EOS, 62% hospital-acquired LOS, and 18% community-acquired LOS. The estimated national incidence of EOS, hospital-acquired LOS, and community-acquired LOS was 0.28 (95% CI 0.23-0.35), 0.86 (0.76-0.97), and 0.28 (0.23-0.34) per 1000 livebirths. Compared with EOS, hospital-acquired LOS occurred in infants of lower gestational age and was more frequently associated with comorbidities. Community-acquired LOS was more common in term infants and in male infants. Mortality was 18%, 12%, and 0% in EOS, hospital-acquired LOS, and community-acquired LOS, and was higher in preterm infants, in infants with septic shock, and in those requiring mechanical ventilation. CONCLUSIONS We report a high burden of sepsis in neonates with considerable mortality and morbidity. EOS, hospital-acquired LOS, and community-acquired LOS affect specific patient subgroups and have distinct clinical presentation, pathogens and outcomes.

BACKGROUND: Previous studies on occupational exposures in parents and cancer risks in their children support a link between solvents and paints with childhood leukaemia. Few studies have focused specifically on benzene. OBJECTIVES: To examine whether parental occupational exposure to benzene is associated with an increased cancer risk in a census-based cohort of children. METHODS: From a census-based cohort study in Switzerland, we included children aged

BACKGROUND Many studies have observed space-time clustering of childhood leukemia (CL) yet few have attempted to elicit etiological clues from such clustering. We recently reported space-time clustering of CL around birth, and now aim to generate etiological hypotheses by comparing clustered and nonclustered cases. We also investigated whether the clustering resulted from many small aggregations of cases or from a few larger clusters. METHODS We identified cases of persons born and diagnosed between 1985 and 2014 at age 0-15 years from the Swiss Childhood Cancer Registry. We determined spatial and temporal lags that maximized evidence of clustering based on the Knox test and classified cases born within these lags from another case as clustered. Using logistic regression adjusted for child population density, we determined whether clustering status was associated with age at diagnosis, immunophenotype, cytogenetic subtype, perinatal and socioeconomic characteristics, and pollution sources. RESULTS Analyses included 1,282 cases of which 242 were clustered (born within 1 km and 2 years from another case). Of all investigated characteristics only the t(12;21)(p13;q22) translocation (resulting in ETV6-RUNX1 fusion) differed significantly in prevalence between clustered and nonclustered cases (40% and 25%, respectively; adjusted OR 2.54 [1.52-4.23]; p = 0.003). Spatio-temporal clustering was driven by an excess of aggregations of two or three children rather than by a few large clusters. CONCLUSION Our findings suggest ETV6-RUNX1 is associated with space-time clustering of CL and are consistent with an infection interacting with that oncogene in early life leading to clinical leukemia.

BACKGROUND Wheezing illnesses are characterized by phenotypic variability, which changes with age, but few studies report on a wide age range of children. We studied how prevalence, severity, and triggers of wheeze vary throughout childhood. METHODS We analyzed data from a large population-based cohort of children from Leicestershire, UK, who were followed from infancy through late adolescence using postal questionnaires. We used generalized estimating equations to describe age-related changes in prevalence of any wheeze: episodic viral and multiple trigger wheeze; wheeze triggered by exercise, aeroallergens, food/drinks, laughing/crying; and of severe wheeze (frequent attacks, shortness of breath, sleep disturbance, disturbance of daily activities) from age 1-18 years. We analyzed this in the entire cohort (absolute prevalence) and separately among children with wheeze (relative prevalence). RESULTS This study included 7670 children. Current wheeze was most common in 1-year-olds (36%) and then decreased in prevalence to reach 17% in children aged 14-17 years. Absolute prevalence of episodic viral wheeze (EVW) decreased with age (from 24% to 7%), while multiple trigger wheeze (MTW) remained relatively constant throughout childhood (8-12%). Among children with wheeze, the proportion with EVW decreased, and the proportion with MTW increased with age. In older children, wheeze triggered by exercise or aeroallergens, and wheeze accompanied by shortness of breath became more frequent, while wheeze triggered by food or laughter, and sleep disturbance decreased in prevalence. CONCLUSION Knowledge of these age-related changes in wheezing illness is informative for health care planning and the design of future research projects and questionnaires.

No abstract available., + ID der Publikation: unilu_11267 + Sprache: Deutsch + Letzte Aktualisierung: 2019-02-19 17:21:16

The aetiology of childhood cancers remains largely unknown. It has been hypothesized that infections may be involved and that mini-epidemics thereof could result in space-time clustering of incident cases. Most previous studies support spatio-temporal clustering for leukaemia, while results for other diagnostic groups remain mixed. Few studies have corrected for uneven regional population shifts which can lead to spurious detection of clustering. We examined whether there is space-time clustering of childhood cancers in Switzerland identifying cases diagnosed at age 0.2). Our study suggests that childhood leukaemia tends to cluster in space-time due to an etiologic factor present in early life.

Eczema often precedes the development of asthma in a disease course called the ‘atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema., The development of asthma following eczema is known as the atopic march. Here the authors conduct a GWAS on affected children and identify two novel loci associated with the disease phenotype.

Objective: To examine the associations between pet keeping in early childhood and asthma and allergies in children aged 6-10 years. Design: Pooled analysis of individual participant data of 11 prospective European birth cohorts that recruited a total of over 22,000 children in the 1990s. Exposure definition: Ownership of only cats, dogs, birds, rodents, or cats/dogs combined during the first 2 years of life. Outcome definition: Current asthma (primary outcome), allergic asthma, allergic rhinitis and allergic sensitization during 610 years of age. Data synthesis: Three-step approach: (i) Common definition of outcome and exposure variables across cohorts; (ii) calculation of adjusted effect estimates for each cohort; (iii) pooling of effect estimates by using random effects meta-analysis models. Results: We found no association between furry and feathered pet keeping early in life and asthma in school age. For example, the odds ratio for asthma comparing cat ownership with no pets (10 studies, 11489 participants) was 1.00 (95% confidence interval 0.78 to 1.28) (I 2 = 9%; p = 0.36). The odds ratio for asthma comparing dog ownership with no pets (9 studies, 11433 participants) was 0.77 (0.58 to 1.03) (I-2 = 0%, p = 0.89). Owning both cat(s) and dog(s) compared to no pets resulted in an odds ratio of 1.04 (0.59 to 1.84) (I-2 = 33%, p = 0.18). Similarly, for allergic asthma and for allergic rhinitis we did not find associations regarding any type of pet ownership early in life. However, we found some evidence for an association between ownership of furry pets during the first 2 years of life and reduced likelihood of becoming sensitized to aero-allergens. Conclusions: Pet ownership in early life did not appear to either increase or reduce the risk of asthma or allergic rhinitis symptoms in children aged 6-10. Advice from health care practitioners to avoid or to specifically acquire pets for primary prevention of asthma or allergic rhinitis in children should not be given., This collaborative project was initiated, supported and funded by the Global Allergy and Asthma European Network (GA2LEN; www.ga2len.net) under the 6th framework programme of the European Commission (project no. FOOD-CT-2004-506378). Sources of funding of the individual birth cohort studies are described in their publications. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background: Previous studies on occupational exposures in parents and cancer risks in their children support a link between solvents and paints with childhood leukaemia. Few studies have focused specifically on benzene. Objectives: To examine whether parental occupational exposure to benzene is associated with an increased cancer risk in a census-based cohort of children. Methods: From a census-based cohort study in Switzerland, we included children aged

Background Benzene is a recognised carcinogen and an important component of traffic-related air pollution. Previous research on the association between air pollution and childhood cancer was mostly...

Rationale: The evidence for an effect of breastfeeding on lung function is conflicting in particular whether the effect is modified by maternal asthma. Objectives: To explore the association between breastfeeding and school age lung function. Methods: In the Leicestershire Cohort Studies we assessed duration of breastfeeding (not breastfed =3 months 4 6 months and >6 months) other exposures and respiratory symptoms by repeated questionnaires. Post bronchodilator FVC FEV 1 peak expiratory flow (PEF) forced midexpiratory flow (FEF 50) and skin prick tests were measured at age 12 years. We performed multivariable linear regression and tested potential causal pathways (N = 1458). Measurements and Main Results: In the entire sample FEF 50 was higher by 130 and 164 ml in children breastfed for 4 to 6 months and longer than 6 months respectively compared with those not breastfed (P = 0.048 and 0.041) with larger effects if the mother had asthma. FVC and FEV 1 were associated with breastfeeding only in children of mothers with asthma (P for interaction 0.018 and 0.008): FVC was increased by 123 and 164 ml for those breastfed 4 to 6 months or longer than 6 months respectively (P = 0.177 and 0.040) and FEV 1 was increased by 148 and 167 ml respectively (P =0.050 and 0.016). Results were unchanged after adjustment for respiratory infections in infancy and asthma and atopy in the child. Conclusions: In this cohort breastfeeding for more than 4 months was associated with increased FEF 50 and in children of mothers with asthma with increased FEV 1 and FVC. It seems that the effect is not mediated via avoidance of early infections or atopy but rather through a direct effect on lung growth. Copyright © 2012 by the American Thoracic Society.

Recurrent wheezing or asthma is a common problem in children that has increased considerably in prevalence in the past few decades. The causes and underlying mechanisms are poorly understood and it is thought that a numb er of distinct diseases causing similar symptoms are involved. Due to the lack of a biologically founded classification system, children are classified according to their observed disease related features (symptoms, signs, measurements) into phenotypes. The objectives of this PhD project were a) to develop tools for analysing phenotypic variation of a disease, and b) to examine phenotypic variability of wheezing among children by applying these tools to existing epidemiological data. A combination of graphical methods (multivariate co rrespondence analysis) and statistical models (latent variables models) was used. In a first phase, a model for discrete variability (latent class model) was applied to data on symptoms and measurements from an epidemiological study to identify distinct phenotypes of wheezing. In a second phase, the modelling framework was expanded to include continuous variability (e.g. along a severity gradient) and combinations of discrete and continuo us variability (factor models and factor mixture models). The third phase focused on validating the methods using simulation studies. The main body of this thesis consists of 5 articles (3 published, 1 submitted and 1 to be submitted) including applications, methodological contributions and a review. The main findings and contributions were: 1) The application of a latent class model to epidemiological data (symptoms and physiological measurements) yielded plausible pheno types of wheezing with distinguishing characteristics that have previously been used as phenotype defining characteristics. 2) A method was proposed for including responses to conditional questions (e.g. questions on severity or triggers of wheezing are asked only to children with wheeze) in multivariate modelling.ii 3) A panel of clinicians was set up to agree on a plausible model for wheezing diseases. The model can be used to generate datasets for testing the modelling approach. 4) A critical review of methods for defining and validating phenotypes of wheeze in children was conducted. 5) The simulation studies showed that a parsimonious parameterisation of the models is required to identify the true underlying structure of the data. The developed approach can deal with some challenges of real-life cohort data such as variables of mixed mode (continuous and categorical), missing data and conditional questions. If carefully applied, the approach can be used to identify whether the underlying phenotypic variation is discrete (classes), continuous (factors) or a combination of these. These methods could help improve precision of research into causes and mechanisms and contribute to the development of a new classification of wheezing disorders in children and other diseases which are difficult to classify.

It has been suggested that there are several distinct phenotypes of childhood asthma or childhood wheezing. Here, we review the research relating to these phenotypes, with a focus on the methods used to define and validate them. Childhood wheezing disorders manifest themselves in a range of observable (phenotypic) features such as lung function, bronchial responsiveness, atopy and a highly variable time course (prognosis). The underlying causes are not sufficiently understood to define disease entities based on aetiology. Nevertheless, there is a need for a classification that would (i) facilitate research into aetiology and pathophysiology, (ii) allow targeted treatment and preventive measures and (iii) improve the prediction of long-term outcome. Classical attempts to define phenotypes have been one-dimensional, relying on few or single features such as triggers (exclusive viral wheeze vs. multiple trigger wheeze) or time course (early transient wheeze, persistent and late onset wheeze). These definitions are simple but essentially subjective. Recently, a multi-dimensional approach has been adopted. This approach is based on a wide range of features and relies on multivariate methods such as cluster or latent class analysis. Phenotypes identified in this manner are more complex but arguably more objective. Although phenotypes have an undisputed standing in current research on childhood asthma and wheezing, there is confusion about the meaning of the term 'phenotype' causing much circular debate. If phenotypes are meant to represent 'real' underlying disease entities rather than superficial features, there is a need for validation and harmonization of definitions. The multi-dimensional approach allows validation by replication across different populations and may contribute to a more reliable classification of childhood wheezing disorders and to improved precision of research relying on phenotype recognition, particularly in genetics. Ultimately, the underlying pathophysiology and aetiology will need to be understood to properly characterize the diseases causing recurrent wheeze in children.

BACKGROUND Estimates of prevalence of wheeze depend on questionnaires. However, wording of questions may vary between studies. We investigated effects of alternative wording on estimates of prevalence and severity of wheeze, and associations with risk factors. METHODS White and South Asian children from a population-based cohort (UK) were randomly assigned to two groups and followed up at one, four and six years (1998, 2001, 2003). Parents were asked either if their child ever had "attacks of wheeze" (attack group, N=535), or "wheezing or whistling in the chest" (whistling group, N=2859). All other study aspects were identical, including questions about other respiratory symptoms. RESULTS Prevalence of wheeze ever was lower in the attack group than in the whistling group for all surveys (32 vs. 40% in white children aged one year, p

BACKGROUND Previous studies found larger lung volumes at school-age in formerly breastfed children, with some studies suggesting an effect modification by maternal asthma. We wanted to explore this further in children who had undergone extensive lung function testing. The current study aimed to assess whether breastfeeding was associated with larger lung volumes and, if so, whether all compartments were affected. We also assessed association of breastfeeding with apparent diffusion coefficient (ADC), which measures freedom of gas diffusion in alveolar-acinar compartments and is a surrogate of alveolar dimensions. Additionally, we assessed whether these effects were modified by maternal asthma. METHODS We analysed data from 111 children and young adults aged 11-21 years, who had participated in detailed lung function testing, including spirometry, plethysmography and measurement of ADC of (3)Helium ((3)He) by MR. Information on breastfeeding came from questionnaires applied in early childhood (age 1-4 years). We determined the association between breastfeeding and these measurements using linear regression, controlling for potential confounders. RESULTS We did not find significant evidence for an association between duration of breastfeeding and lung volumes or alveolar dimensions in the entire sample. In breastfed children of mothers with asthma, we observed larger lung volumes and larger average alveolar size than in non-breastfed children, but the differences did not reach significance levels. CONCLUSIONS Confirmation of effects of breastfeeding on lung volumes would have important implications for public health. Further investigations with larger sample sizes are warranted.