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1.  Cause‐specific long‐term mortality in survivors of childhood cancer in Switzerland: A population‐based study 
International Journal of Cancer  2016;139(2):322-333.
Survivors of childhood cancer have a higher mortality than the general population. We describe cause‐specific long‐term mortality in a population‐based cohort of childhood cancer survivors. We included all children diagnosed with cancer in Switzerland (1976–2007) at age 0–14 years, who survived ≥5 years after diagnosis and followed survivors until December 31, 2012. We obtained causes of death (COD) from the Swiss mortality statistics and used data from the Swiss general population to calculate age‐, calendar year‐, and sex‐standardized mortality ratios (SMR), and absolute excess risks (AER) for different COD, by Poisson regression. We included 3,965 survivors and 49,704 person years at risk. Of these, 246 (6.2%) died, which was 11 times higher than expected (SMR 11.0). Mortality was particularly high for diseases of the respiratory (SMR 14.8) and circulatory system (SMR 12.7), and for second cancers (SMR 11.6). The pattern of cause‐specific mortality differed by primary cancer diagnosis, and changed with time since diagnosis. In the first 10 years after 5‐year survival, 78.9% of excess deaths were caused by recurrence of the original cancer (AER 46.1). Twenty‐five years after diagnosis, only 36.5% (AER 9.1) were caused by recurrence, 21.3% by second cancers (AER 5.3) and 33.3% by circulatory diseases (AER 8.3). Our study confirms an elevated mortality in survivors of childhood cancer for at least 30 years after diagnosis with an increased proportion of deaths caused by late toxicities of the treatment. The results underline the importance of clinical follow‐up continuing years after the end of treatment for childhood cancer.
What's new?
As survivors of childhood cancer age, they are more likely to die prematurely than their peers. The causes of early death, however, are not fully understood, particularly for recently diagnosed children, who may benefit from newer treatment strategies. This study shows that for at least three decades after diagnosis, childhood cancer survivors suffer increased mortality. Disease recurrence initially accounts for the greatest proportion of deaths but is supplanted over time by late treatment‐related toxicities, including second cancers. The findings draw attention to the significance of lifelong follow‐up among survivors of childhood cancer, especially for high‐risk individuals.
PMCID: PMC5071665  PMID: 26950898
childhood cancer; cancer survivors; mortality; second primary cancers; cardiovascular; respiratory; causes of death; cancer registry
2.  Challenges in Collating Spirometry Reference Data for South-Asian Children: An Observational Study 
PLoS ONE  2016;11(4):e0154336.
Availability of sophisticated statistical modelling for developing robust reference equations has improved interpretation of lung function results. In 2012, the Global Lung function Initiative(GLI) published the first global all-age, multi-ethnic reference equations for spirometry but these lacked equations for those originating from the Indian subcontinent (South-Asians). The aims of this study were to assess the extent to which existing GLI-ethnic adjustments might fit South-Asian paediatric spirometry data, assess any similarities and discrepancies between South-Asian datasets and explore the feasibility of deriving a suitable South-Asian GLI-adjustment.
Spirometry datasets from South-Asian children were collated from four centres in India and five within the UK. Records with transcription errors, missing values for height or spirometry, and implausible values were excluded(n = 110).
Following exclusions, cross-sectional data were available from 8,124 children (56.3% male; 5–17 years). When compared with GLI-predicted values from White Europeans, forced expired volume in 1s (FEV1) and forced vital capacity (FVC) in South-Asian children were on average 15% lower, ranging from 4–19% between centres. By contrast, proportional reductions in FEV1 and FVC within all but two datasets meant that the FEV1/FVC ratio remained independent of ethnicity. The ‘GLI-Other’ equation fitted data from North India reasonably well while ‘GLI-Black’ equations provided a better approximation for South-Asian data than the ‘GLI-White’ equation. However, marked discrepancies in the mean lung function z-scores between centres especially when examined according to socio-economic conditions precluded derivation of a single South-Asian GLI-adjustment.
Until improved and more robust prediction equations can be derived, we recommend the use of ‘GLI-Black’ equations for interpreting most South-Asian data, although ‘GLI-Other’ may be more appropriate for North Indian data. Prospective data collection using standardised protocols to explore potential sources of variation due to socio-economic circumstances, secular changes in growth/predictors of lung function and ethnicities within the South-Asian classification are urgently required.
PMCID: PMC4847904  PMID: 27119342
3.  Collaborative Research in Childhood Cancer Survivorship: The Current Landscape 
Journal of Clinical Oncology  2015;33(27):3055-3064.
Survivors of childhood cancer carry a substantial burden of morbidity and are at increased risk for premature death. Furthermore, clear associations exist between specific therapeutic exposures and the risk for a variety of long-term complications. The entire landscape of health issues encountered for decades after successful completion of treatment is currently being explored in various collaborative research settings. These settings include large population-based or multi-institutional cohorts and single-institution studies. The ascertainment of outcomes has depended on self-reporting, linkage to registries, or clinical assessments. Survivorship research in the cooperative group setting, such as the Children's Oncology Group, has leveraged the clinical trials infrastructure to explore the molecular underpinnings of treatment-related adverse events, and to understand specific complications in the setting of randomized risk-reduction strategies. This review highlights the salient findings from these large collaborative initiatives, emphasizing the need for life-long follow-up of survivors of childhood cancer, and describing the development of several guidelines and efforts toward harmonization. Finally, the review reinforces the need to identify populations at highest risk, facilitating the development of risk prediction models that would allow for targeted interventions across the entire trajectory of survivorship.
PMCID: PMC4567704  PMID: 26304891
4.  Late Cardiac Events after Childhood Cancer: Methodological Aspects of the Pan-European Study PanCareSurFup 
PLoS ONE  2016;11(9):e0162778.
Background and Aim
Childhood cancer survivors are at high risk of long-term adverse effects of cancer and its treatment, including cardiac events. The pan-European PanCareSurFup study determined the incidence and risk factors for cardiac events among childhood cancer survivors. The aim of this article is to describe the methodology of the cardiac cohort and nested case-control study within PanCareSurFup.
Eight data providers in Europe participating in PanCareSurFup identified and validated symptomatic cardiac events in their cohorts of childhood cancer survivors. Data on symptomatic heart failure, ischemia, pericarditis, valvular disease and arrhythmia were collected and graded according to the Criteria for Adverse Events. Detailed treatment data, data on potential confounders, lifestyle related risk factors and general health problems were collected.
The PanCareSurFup cardiac cohort consisted of 59,915 5-year childhood cancer survivors with malignancies diagnosed between 1940 and 2009 and classified according to the International Classification of Childhood Cancer 3. Different strategies were used to identify cardiac events such as record linkage to population/ hospital or regional based databases, and patient- and general practitioner-based questionnaires.
The cardiac study of the European collaborative research project PanCareSurFup will provide the largest cohort of 5-year childhood cancer survivors with systematically ascertained and validated data on symptomatic cardiac events. The result of this study can provide information to minimize the burden of cardiac events in childhood cancer survivors by tailoring the follow-up of childhood cancer survivors at high risk of cardiac adverse events, transferring this knowledge into evidence-based clinical practice guidelines and providing a platform for future research studies in childhood cancer patients. 
PMCID: PMC5028033  PMID: 27643694
5.  Study protocol, rationale and recruitment in a European multi-centre randomized controlled trial to determine the efficacy and safety of azithromycin maintenance therapy for 6 months in primary ciliary dyskinesia 
BMC Pulmonary Medicine  2016;16:104.
Clinical management of primary ciliary dyskinesia (PCD) respiratory disease is currently based on improving mucociliary clearance and controlling respiratory infections, through the administration of antibiotics. Treatment practices in PCD are largely extrapolated from more common chronic respiratory disorders, particularly cystic fibrosis, but no randomized controlled trials (RCT) have ever evaluated efficacy and safety of any pharmacotherapeutics used in the treatment of PCD. Maintenance therapy, with the macrolide antibiotic azithromycin, is currently widely used in chronic respiratory diseases including PCD. In addition to its antibacterial properties, azithromycin is considered to have beneficial anti-inflammatory and anti-quorum-sensing properties.
The aim of this study is to determine the efficacy of azithromycin maintenance therapy for 6 months on respiratory exacerbations in PCD. The secondary objectives are to evaluate the efficacy of azithromycin on lung function, ventilation inhomogeneity, hearing impairment, and symptoms (respiratory, sinus, ears and hearing) measured on a PCD-specific health-related quality of life instrument, and to assess the safety of azithromycin maintenance therapy in PCD.
The BESTCILIA trial is a European multi-centre, double-blind, randomized, placebo-controlled, parallel group study. The intervention is tablets of azithromycin 250/500 mg according to body weight or placebo administered three times a week for 6 months. Subjects with a confirmed diagnosis of PCD, age 7–50 years, are eligible for inclusion. Chronic pulmonary infections with Gram-negative bacteria or any recent occurrence of non-tuberculous mycobacteria are exclusion criteria. The planned number of subjects to be included is 125. The trial has been approved by the Research Ethics Committees of the participating institutions.
We present a study protocol of an ongoing RCT, evaluating for the first time, the efficacy and safety of a pharmacotherapeutic treatment for patients with PCD. The RCT evaluates azithromycin maintenance therapy, a drug already commonly prescribed in other chronic respiratory disorders. Furthermore, the trial will utilize the Lung clearance index and new, PCD-specific quality of life instruments as outcome measures for PCD. Recruitment is hampered by frequent occurrence of Pseudomonas aeruginosa infection, exacerbations at enrolment, and the patients’ perception of disease severity and necessity of additional management and treatment during trial participation.
Trial registration
EudraCT 2013-004664-58 (date of registration: 2014-04-08).
PMCID: PMC4957315  PMID: 27450411
Primary ciliary dyskinesia; Azithromycin; Lung clearance index; Multiple breath washout; Health-related quality of life; QOL-PCD; Exacerbation
6.  Breastfeeding, lung volumes and alveolar size at school-age 
BMJ Open Respiratory Research  2015;2(1):e000081.
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.
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 3Helium (3He) 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.
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.
Confirmation of effects of breastfeeding on lung volumes would have important implications for public health. Further investigations with larger sample sizes are warranted.
PMCID: PMC4499711  PMID: 26180638
Paediatric asthma
7.  Income in Adult Survivors of Childhood Cancer 
PLoS ONE  2016;11(5):e0155546.
Little is known about the impact of childhood cancer on the personal income of survivors. We compared income between survivors and siblings, and determined factors associated with income.
As part of the Swiss Childhood Cancer Survivor Study (SCCSS), a questionnaire was sent to survivors, aged ≥18 years, registered in the Swiss Childhood Cancer Registry (SCCR), diagnosed at age <21 years, who had survived ≥5 years after diagnosis of the primary tumor. Siblings were used as a comparison group. We asked questions about education, profession and income and retrieved clinical data from the SCCR. We used multivariable logistic regression to identify characteristics associated with income.
We analyzed data from 1’506 survivors and 598 siblings. Survivors were less likely than siblings to have a high monthly income (>4’500 CHF), even after we adjusted for socio-demographic and educational factors (OR = 0.46, p<0.001). Older age, male sex, personal and parental education, and number of working hours were associated with high income. Survivors of leukemia (OR = 0.40, p<0.001), lymphoma (OR = 0.63, p = 0.040), CNS tumors (OR = 0.22, p<0.001), bone tumors (OR = 0.24, p = 0.003) had a lower income than siblings. Survivors who had cranial irradiation, had a lower income than survivors who had no cranial irradiation (OR = 0.48, p = 0.006).
Even after adjusting for socio-demographic characteristics, education and working hours, survivors of various diagnostic groups have lower incomes than siblings. Further research needs to identify the underlying causes.
PMCID: PMC4877063  PMID: 27213682
8.  A parent‐completed respiratory questionnaire for 1‐year‐old children: repeatability 
Archives of Disease in Childhood  2007;92(10):861-865.
Background and aims
There are few standardised questionnaires for the assessment of respiratory symptoms in preschool children. We have developed and tested the short‐term repeatability of a postal questionnaire on respiratory symptoms for 1‐year‐old children.
A newly developed postal questionnaire for the assessment of wheeze and other respiratory symptoms was sent to parents of a population‐based random sample of 4300 children aged 12–24 months. After an interval of 3 months, a random sample of 800 respondents received the questionnaire a second time. The responses were compared using Cohen's kappa (κ) to assess agreement corrected for chance.
The first questionnaire was returned by 3194 (74%) families, the second one by 460/800 (58%). Repeatability was excellent (κ 0.80–0.96) for questions on household characteristics, environmental exposures and family history, good (κ 0.61–0.80) for questions on prevalence, severity and treatment of wheeze, and moderate (κ 0.39–0.66) for chronic cough and upper respiratory symptoms.
This short postal questionnaire designed for use in population‐based studies has excellent repeatability for family and household characteristics and good repeatability for questions on wheeze. Short‐term changes in symptom status might be responsible for variable answers on recent chronic cough and upper respiratory symptoms. Overall, the questionnaire is a valuable instrument for community‐based research on respiratory symptoms in 1 to 2‐year‐old children.
PMCID: PMC2083231  PMID: 17502330
preschool; asthma; kappa; repeatability; questionnaire
9.  Socioeconomic Status and Childhood Leukemia Incidence in Switzerland 
Frontiers in Oncology  2015;5:139.
Socioeconomic status (SES) discrepancies exist for child and adult cancer morbidity and are a major public health concern. In this Swiss population-based matched case–control study on the etiology of childhood leukemia, we selected the cases from the Swiss Childhood Cancer Registry diagnosed since 1991 and the controls randomly from census. We assigned eight controls per case from the 1990 and 2000 census and matched them by the year of birth and gender. SES information for both cases and controls was obtained from census records by probabilistic record linkage. We investigated the association of SES with childhood leukemia in Switzerland, and explored whether it varied with different definitions of socioeconomic status (parental education, living condition, area-based SES), time period, and age. In conditional logistic regression analyses of 565 leukemia cases and 4433 controls, we found no consistent evidence for an association between SES and childhood leukemia. The odds ratio comparing the highest with the lowest SES category ranged from 0.95 (95% CI: 0.71–1.26; Ptrend = 0.73) for paternal education to 1.37 (1.00–1.89; Ptrend = 0.064) for maternal education. No effect modification was found for time period and age at diagnosis. Based on this population-based study, which avoided participation and reporting bias, we assume the potential association of socioeconomic status and childhood leukemia if existing to be small. This study did not find evidence that socioeconomic status, of Switzerland or comparable countries, is a relevant risk factor or strong confounder in etiological investigations on childhood leukemia.
PMCID: PMC4485172  PMID: 26175964
childhood cancer; leukemia; socioeconomic status; risk factor; case–control study
10.  PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia 
The European Respiratory Journal  2016;47(4):1103-1112.
Symptoms of primary ciliary dyskinesia (PCD) are nonspecific and guidance on whom to refer for testing is limited. Diagnostic tests for PCD are highly specialised, requiring expensive equipment and experienced PCD scientists. This study aims to develop a practical clinical diagnostic tool to identify patients requiring testing.
Patients consecutively referred for testing were studied. Information readily obtained from patient history was correlated with diagnostic outcome. Using logistic regression, the predictive performance of the best model was tested by receiver operating characteristic curve analyses. The model was simplified into a practical tool (PICADAR) and externally validated in a second diagnostic centre.
Of 641 referrals with a definitive diagnostic outcome, 75 (12%) were positive. PICADAR applies to patients with persistent wet cough and has seven predictive parameters: full-term gestation, neonatal chest symptoms, neonatal intensive care admittance, chronic rhinitis, ear symptoms, situs inversus and congenital cardiac defect. Sensitivity and specificity of the tool were 0.90 and 0.75 for a cut-off score of 5 points. Area under the curve for the internally and externally validated tool was 0.91 and 0.87, respectively.
PICADAR represents a simple diagnostic clinical prediction rule with good accuracy and validity, ready for testing in respiratory centres referring to PCD centres.
PICADAR is a simple diagnostic prediction tool for PCD with good accuracy and validity that is now ready for testing
PMCID: PMC4819882  PMID: 26917608
11.  Employment Situation of Parents of Long-Term Childhood Cancer Survivors 
PLoS ONE  2016;11(3):e0151966.
Taking care of children diagnosed with cancer affects parents’ professional life. The impact in the long-term however, is not clear. We aimed to compare the employment situation of parents of long-term childhood cancer survivors with control parents of the general population, and to identify clinical and socio-demographic factors associated with parental employment.
As part of the Swiss Childhood Cancer Survivor Study, we sent a questionnaire to parents of survivors aged 5–15 years, who survived ≥5 years after diagnosis. Information on control parents of the general population came from the Swiss Health Survey (restricted to men and women with ≥1 child aged 5–15 years). Employment was categorized as not employed, part-time, and full-time employed. We used generalized ordered logistic regression to determine associations with clinical and socio-demographic factors. Clinical data was available from the Swiss Childhood Cancer Registry.
We included 394 parent-couples of survivors and 3’341 control parents (1’731 mothers; 1’610 fathers). Mothers of survivors were more often not employed (29% versus 22%; ptrend = 0.007). However, no differences between mothers were found in multivariable analysis. Fathers of survivors were more often employed full-time (93% versus 87%; ptrend = 0.002), which remained significant in multivariable analysis. Among parents of survivors, mothers with tertiary education (OR = 2.40, CI:1.14–5.07) were more likely to be employed. Having a migration background (OR = 3.63, CI: 1.71–7.71) increased the likelihood of being full-time employed in mothers of survivors. Less likely to be employed were mothers of survivors diagnosed with lymphoma (OR = 0.31, CI:0.13–0.73) and >2 children (OR = 0.48, CI:0.30–0.75); and fathers of survivors who had had a relapse (OR = 0.13, CI:0.04–0.36).
Employment situation of parents of long-term survivors reflected the more traditional parenting roles. Specific support for parents with low education, additional children, and whose child had a more severe cancer disease could improve their long-term employment situation.
PMCID: PMC4798766  PMID: 26990301
12.  Use of Complementary and Alternative Medicine in Children with Cancer: A Study at a Swiss University Hospital 
PLoS ONE  2015;10(12):e0145787.
Though complementary and alternative medicine (CAM) are frequently used by children and adolescents with cancer, there is little information on how and why they use it. This study examined prevalence and methods of CAM, the therapists who applied it, reasons for and against using CAM and its perceived effectiveness. Parent-perceived communication was also evaluated. Parents were asked if medical staff provided information on CAM to patients, if parents reported use of CAM to physicians, and what attitude they thought physicians had toward CAM.
Study Design
All childhood cancer patients treated at the University Children’s Hospital Bern between 2002–2011 were retrospectively surveyed about their use of CAM.
Data was collected from 133 patients (response rate: 52%). Of those, 53% had used CAM (mostly classical homeopathy) and 25% of patients received information about CAM from medical staff. Those diagnosed more recently were more likely to be informed about CAM options. The most frequent reason for choosing CAM was that parents thought it would improve the patient’s general condition. The most frequent reason for not using CAM was lack of information. Of those who used CAM, 87% perceived positive effects.
Since many pediatric oncology patients use CAM, patients’ needs should be addressed by open communication between families, treating oncologists and CAM therapists, which will allow parents to make informed and safe choices about using CAM.
PMCID: PMC4687920  PMID: 26694320
13.  Development and Validation of a Symptom-Based Activity Index for Adults with Eosinophilic Esophagitis 
Gastroenterology  2014;147(6):1255-66.e21.
Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE), to provide endpoints for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patients’ assessments of disease severity. We also evaluated relationships between patients’ assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings.
We collected information from 186 patients with EoE in Switzerland and the US (69.4% male; median age, 43 years) via surveys (n = 135), focus groups (n = 27), and semi-structured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patients’ assessment of EoE severity. The PRO instrument was prospectively used in 153 adult patients with EoE (72.5% male; median age, 38 years), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 years).
Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patients’ assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity and PRO score was 0.13 (on a scale from 0 to 10).
We developed and validated an EoE scoring system based on 7 PRO items that assesses symptoms over a 7-day recall period. number: NCT00939263.
PMCID: PMC4425255  PMID: 25160980
disease activity measurement; esophagus; patient reported outcome; marker
14.  Health-Related Quality of Life of Young Adults Treated with Recombinant Human Growth Hormone during Childhood 
PLoS ONE  2015;10(10):e0140944.
Since recombinant human growth hormone (rhGH) became available in 1985, the spectrum of indications has broadened and the number of treated patients increased. However, long-term health-related quality of life (HRQoL) after childhood rhGH treatment has rarely been documented. We assessed HRQoL and its determinants in young adults treated with rhGH during childhood.
Methodology/Principal Findings
For this study, we retrospectively identified former rhGH patients in 11 centers of paediatric endocrinology, including university hospitals and private practices. We sent a questionnaire to all patients treated with rhGH for any diagnosis, who were older than 18 years, and who resided in Switzerland at time of the survey. Three hundred participants (58% of 514 eligible) returned the questionnaire. Mean age was 23 years; 56% were women; 43% had isolated growth hormone deficiency, or idiopathic short stature; 43% had associated diseases or syndromes, and 14% had growth hormone deficiency after childhood cancer. Swiss siblings of childhood cancer survivors and the German norm population served as comparison groups. HRQoL was assessed using the Short Form-36. We found that the Physical Component Summary of healthy patients with isolated growth hormone deficiency or idiopathic short stature resembled that of the control group (53.8 vs. 54.9). Patients with associated diseases or syndromes scored slightly lower (52.5), and former cancer patients scored lowest (42.6). The Mental Component Summary was similar for all groups. Lower Physical Component Summary was associated with lower educational level (coeff. -1.9). Final height was not associated with HRQoL.
In conclusion, HRQoL after treatment with rhGH in childhood depended mainly on the underlying indication for rhGH treatment. Patients with isolated growth hormone deficiency/idiopathic short stature or patients with associated diseases or syndromes had HRQoL comparable to peers. Patients with growth hormone deficiency after childhood cancer were at high risk for lower HRQoL. This reflects the general impaired health of this vulnerable group, which needs long-term follow-up.
PMCID: PMC4608786  PMID: 26474398
17.  Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone 
Hormone Research in Pædiatrics  2015;84(3):172-183.
The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies. Patients and Methods: The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this.
The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country.
PMCID: PMC4611066  PMID: 26227295
Growth hormone; Cohort; Europe; Cancer; Mortality
18.  Estimating the risk for late effects of therapy in children newly diagnosed with standard risk acute lymphoblastic leukemia using an historical cohort: A report from the Childhood Cancer Survivor Study 
The Lancet. Oncology  2014;15(8):841-851.
Pediatric acute lymphoblastic leukemia (ALL) therapy has evolved such that the risk for late effects in ALL survivors treated on contemporary protocols is likely different from that observed in survivors treated in prior eras. We estimated the risk for late effects in children with standard-risk ALL treated in the current era using data from similarly treated members of the Childhood Cancer Survivor Study (CCSS) cohort.
The CCSS is a multi-centre North American study of five-year survivors of childhood cancer diagnosed between 1970 and1986. Cohort members were eligible for this analysis if they were aged 1·0–9·9 years at the time of ALL diagnosis and received therapy consistent with contemporary standard-risk ALL protocols. Outcomes were compared to a sibling cohort (n=2788) and the general United States population.
556/5980 cohort members treated for ALL met the inclusion criteria. After a median follow up of 18·4 years (range 0·0–33·0) from cohort entry, 28/556 (5%) had died (standardized mortality ratio, 3·5; 95% CI, 2·3–5·0). Sixteen deaths were due to causes other than ALL recurrence. Among 556 survivors, six (1%) developed a subsequent malignant neoplasm (standardized incidence ratio, 2·6; 95% CI, 1·0–5·7). 107 subjects in each group would need to be followed for one year in order to observe one extra chronic health condition in the ALL group compared to the sibling group (95% CI, 81–193). 415 subjects in each group would need to be followed for one year to observe one extra severe, life-threatening or fatal condition in the ALL group (95% CI, 376–939) Survivors did not differ from siblings in their educational attainment, rate of marriage or independent living.
Overall, the expected prevalence of adverse long-term outcomes among children treated for standard risk ALL on contemporary protocols is low, but regular care from a knowledgeable primary care practitioner is warranted.
National Cancer Institute, Cancer Center Support, American Lebanese-Syrian Associated Charities, Cancer Research Switzerland.
PMCID: PMC4142216  PMID: 24954778
19.  “Attacks” or “Whistling”: Impact of Questionnaire Wording on Wheeze Prevalence Estimates 
PLoS ONE  2015;10(6):e0131618.
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.
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.
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<0.001). Prevalence of other respiratory symptoms did not differ between groups. Wheeze tended to be more severe in the attack group. The strength of association with risk factors was comparable in the two groups.
The wording of questions on wheeze can affect estimates of prevalence, but has less impact on measured associations with risk factors. Question wording is a potential source of between-study-heterogeneity in meta-analyses.
PMCID: PMC4482591  PMID: 26114296
20.  Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study 
Environmental Health Perspectives  2015;123(6):622-628.
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.
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.
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.
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.
Our study suggests that background radiation may contribute to the risk of cancer in children, including leukemia and CNS tumors.
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;
PMCID: PMC4455589  PMID: 25707026
21.  Intra-Rater and Inter-Rater Reliability of a Medical Record Abstraction Study on Transition of Care after Childhood Cancer 
PLoS ONE  2015;10(5):e0124290.
The abstraction of data from medical records is a widespread practice in epidemiological research. However, studies using this means of data collection rarely report reliability. Within the Transition after Childhood Cancer Study (TaCC) which is based on a medical record abstraction, we conducted a second independent abstraction of data with the aim to assess a) intra-rater reliability of one rater at two time points; b) the possible learning effects between these two time points compared to a gold-standard; and c) inter-rater reliability.
Within the TaCC study we conducted a systematic medical record abstraction in the 9 Swiss clinics with pediatric oncology wards. In a second phase we selected a subsample of medical records in 3 clinics to conduct a second independent abstraction. We then assessed intra-rater reliability at two time points, the learning effect over time (comparing each rater at two time-points with a gold-standard) and the inter-rater reliability of a selected number of variables. We calculated percentage agreement and Cohen’s kappa.
For the assessment of the intra-rater reliability we included 154 records (80 for rater 1; 74 for rater 2). For the inter-rater reliability we could include 70 records. Intra-rater reliability was substantial to excellent (Cohen’s kappa 0-6-0.8) with an observed percentage agreement of 75%-95%. In all variables learning effects were observed. Inter-rater reliability was substantial to excellent (Cohen’s kappa 0.70-0.83) with high agreement ranging from 86% to 100%.
Our study showed that data abstracted from medical records are reliable. Investigating intra-rater and inter-rater reliability can give confidence to draw conclusions from the abstracted data and increase data quality by minimizing systematic errors.
PMCID: PMC4441480  PMID: 26001046
23.  Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children 
Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.
We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).
First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes.
Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27).
Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.
PMCID: PMC4024198  PMID: 24529685
Gestational age; low birth weight; infant growth; wheezing; asthma; children; cohort studies; epidemiology; BMI, Body mass index; ISAAC, International Study on Asthma and Allergy in Childhood; OR, Odds ratio; pOR, Pooled odds ratio; SDS, Standard deviation scores
24.  Copy Number Variation of the Beta-Defensin Genes in Europeans: No Supporting Evidence for Association with Lung Function, Chronic Obstructive Pulmonary Disease or Asthma 
PLoS ONE  2014;9(1):e84192.
Lung function measures are heritable, predict mortality and are relevant in diagnosis of chronic obstructive pulmonary disease (COPD). COPD and asthma are diseases of the airways with major public health impacts and each have a heritable component. Genome-wide association studies of SNPs have revealed novel genetic associations with both diseases but only account for a small proportion of the heritability. Complex copy number variation may account for some of the missing heritability. A well-characterised genomic region of complex copy number variation contains beta-defensin genes (DEFB103, DEFB104 and DEFB4), which have a role in the innate immune response. Previous studies have implicated these and related genes as being associated with asthma or COPD. We hypothesised that copy number variation of these genes may play a role in lung function in the general population and in COPD and asthma risk. We undertook copy number typing of this locus in 1149 adult and 689 children using a paralogue ratio test and investigated association with COPD, asthma and lung function. Replication of findings was assessed in a larger independent sample of COPD cases and smoking controls. We found evidence for an association of beta-defensin copy number with COPD in the adult cohort (OR = 1.4, 95%CI:1.02–1.92, P = 0.039) but this finding, and findings from a previous study, were not replicated in a larger follow-up sample(OR = 0.89, 95%CI:0.72–1.07, P = 0.217). No robust evidence of association with asthma in children was observed. We found no evidence for association between beta-defensin copy number and lung function in the general populations. Our findings suggest that previous reports of association of beta-defensin copy number with COPD should be viewed with caution. Suboptimal measurement of copy number can lead to spurious associations. Further beta-defensin copy number measurement in larger sample sizes of COPD cases and children with asthma are needed.
PMCID: PMC3880289  PMID: 24404154
25.  Catch-up Alveolarization in Ex-Preterm Children. Evidence from 3He Magnetic Resonance 
Rationale: Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair.
Objectives: To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance.
Methods: We recruited schoolchildren aged 10–14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37–42 wk; n = 61); (2) mild preterm (32–36 wk; n = 21); (3) extreme preterm (<32 wk, not oxygen dependent at 4 wk; n = 19); and (4) extreme preterm with chronic lung disease (<32 wk and oxygen dependent beyond 4 wk; n = 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance.
Measurements and Main Results: The two extreme preterm groups had a lower FEV1 (P = 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm2/second (95% confidence interval, 0.089–0.095) in the term group. Corresponding values were 0.096 (0.091–0.101), 0.090 (0085–0.095), and 0.089 (0.083–0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders.
Conclusions: Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.
PMCID: PMC3734619  PMID: 23491406
alveolar structure; lung acinus; bronchopulmonary dysplasia; neonatal chronic lung disease

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