Analysis of Phenotypic Variation in Childhood Wheezing Disorders

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.

Health-Related Quality of Life of Young Adults Treated with Recombinant Human Growth Hormone during Childhood.

BACKGROUND 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. CONCLUSIONS/SIGNIFICANCE 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.

Socioeconomic Status and Childhood Leukemia Incidence in Switzerland.

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; P trend = 0.73) for paternal education to 1.37 (1.00-1.89; P trend = 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.

Collaborative Research in Childhood Cancer Survivorship: The Current Landscape.

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.

Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone.

BACKGROUND 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. CONCLUSION 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.

Meta-analysis identifies seven susceptibility loci involved in the atopic march.

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.

Follow-up care of young childhood cancer survivors: attendance and parental involvement.

PURPOSE Despite recommendations, only a proportion of long-term childhood cancer survivors attend follow-up care. We aimed to (1) describe the follow-up attendance of young survivors aged 11-17 years; (2) describe the parental involvement in follow-up, and (3) investigate predictors of follow-up attendance and parental involvement. METHODS As part of the Swiss Childhood Cancer Survivor Study, a follow-up questionnaire was sent to parents of childhood cancer survivors aged 11-17 years. We assessed follow-up attendance of the child, parents' involvement in follow-up, illness perception (Brief IPQ), and sociodemographic data. Clinical data was available from the Swiss Childhood Cancer Registry. RESULTS Of 309 eligible parents, 189 responded (67 %; mean time since diagnosis 11.3 years, range 6.8-17.2) and 75 % (n = 141) reported that their child still attended follow-up. Of these, 83 % (n = 117) reported ≥1 visit per year and 17 % (n = 23) reported <1 visit every year. Most survivors saw pediatric oncologists (n = 111; 79 % of 141), followed by endocrinologists (n = 24, 17 %) and general practitioners (n = 22, 16 %). Most parents (92 %) reported being involved in follow-up (n = 130). In multivariable and Cox regression analyses, longer time since diagnosis (p = 0.025) and lower perceived treatment control (assessed by IPQ4: how much parents thought follow-up can help with late effects; p = 0.009) were associated with non-attendance. Parents' overall information needs was significantly associated with parental involvement in the multivariable model (p = 0.041). CONCLUSION Educating survivors and their parents on the importance and effectiveness of follow-up care might increase attendance in the longer term.

Socioeconomic disparities in childhood cancer survival in Switzerland.

In this study, we investigated whether childhood cancer survival in Switzerland is influenced by socioeconomic status (SES), and if disparities vary by type of cancer and definition of SES (parental education, living condition, area-based SES). Using Cox proportional hazards models, we analyzed 5-year cumulative mortality in all patients registered in the Swiss Childhood Cancer Registry diagnosed 1991-2006 below 16 years. Information on SES was extracted from the Swiss census by probabilistic record linkage. The study included 1602 children (33% with leukemia, 20% with lymphoma, 22% with central nervous system (CNS) tumors); with an overall 5-year survival of 77% (95%CI 75-79%). Higher SES, particularly parents' education, was associated with a lower 5-year cumulative mortality. Results varied by type of cancer with no association for leukemia and particularly strong effects for CNS tumor patients, where mortality hazard ratios for the different SES indicators, comparing the highest with the lowest group, ranged from 0.48 (95%CI: 0.28-0.81) to 0.71 (95%CI: 0.44-1.15). We conclude that even in Switzerland with a high quality health care system and mandatory health insurance, socioeconomic differences in childhood cancer survival persist. Factors causing these survival differences have to be further explored, to facilitate universal access to optimal treatment and finally eliminate social inequalities in childhood cancer survival. This article is protected by copyright. All rights reserved.

Employment Situation of Parents of Long-Term Childhood Cancer Survivors.

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSION 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.

Cause-Specific Long-Term Mortality in Survivors of Childhood Cancer in Switzerland: A Population Based Study.

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. This article is protected by copyright. All rights reserved.

Space-time clustering of childhood cancers in Switzerland: A nationwide study.

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 <16 years between 1985 and 2010 from the Swiss Childhood Cancer Registry. Knox tests were performed on geocoded residence at birth and diagnosis separately for leukaemia, acute lymphoid leukaemia (ALL), lymphomas, tumours of the central nervous system, neuroblastomas and soft tissue sarcomas. We used Baker's Max statistic to correct for multiple testing and randomly sampled time-, sex- and age-matched controls from the resident population to correct for uneven regional population shifts. We observed space-time clustering of childhood leukaemia at birth (Baker's Max p = 0.045) but not at diagnosis (p = 0.98). Clustering was strongest for a spatial lag of <1 km and a temporal lag of <2 years (Observed/expected close pairs: 124/98; p Knox test = 0.003). A similar clustering pattern was observed for ALL though overall evidence was weaker (Baker's Max p = 0.13). Little evidence of clustering was found for other diagnostic groups (p > 0.2). Our study suggests that childhood leukaemia tends to cluster in space-time due to an etiologic factor present in early life.