Mandy Vogel

The LIFE Child study: a population-based perinatal and pediatric cohort in Germany

The LIFE Child study is a large population-based longitudinal childhood cohort study conducted in the city of Leipzig, Germany. As a part of LIFE, a research project conducted at the Leipzig Research Center for Civilization Diseases, it aims to monitor healthy child development from birth to adulthood and to understand the development of lifestyle diseases such as obesity. The study consists of three interrelated cohorts; the birth cohort, the health cohort, and the obesity cohort. Depending on age and cohort, the comprehensive study program comprises different medical, psychological, and sociodemographic assessments as well as the collection of biological samples. Optimal data acquisition, process management, and data analysis are guaranteed by a professional team of physicians, certified study assistants, quality managers, scientists and statisticians. Due to the high popularity of the study, more than 3000 children have already participated until the end of 2015, and two-thirds of them participate continuously. The large quantity of acquired data allows LIFE Child to gain profound knowledge on the development of children growing up in the twenty-first century. This article reports the number of available and analyzable data and demonstrates the high relevance and potential of the study.

Clinical evidence-based cutoff limits for GH stimulation tests in children with a backup of results with reference to mass spectrometry

CONTEXT Cutoff limits of GH stimulation tests to diagnose GH deficiency (GHD) in children and adolescents are not sufficiently validated by clinical studies due to discrepancies in the performance of GH immunoassays and lack of available study populations. OBJECTIVE We aimed to establish new cutoff limits for GH stimulation tests based on clinical evidence and compared these immunoassay-based values with an antibody-independent mass spectrometric method. DESIGN AND SETTING In a retrospective study, GH cutoff limits for eight different immunoassays and isotope dilution mass spectrometry (ID-MS) were calculated from hGH peak concentrations of short-statured children with and without GHD. PATIENTS We compared the serum GH peak concentrations at GH stimulation test of 52 short-statured children and adolescents, who have normal GH secretion at initial workup and normal growth in the follow-up, with the serum GH peak concentrations of 44 GHD patients in the same age range, in order to optimize the cutoff limit calculation. RESULTS Discriminant analysis of re-measured GH led to a new cutoff limit of 7.09 μg/l using the iSYS assay (IDS) and the limits for the other seven hGH assays varied between 4.32 and 7.77 μg/l. For ID-MS, cutoffs of 5.48 μg/l (22k GH) and 7.43 μg/l (total GH) were ascertained. CONCLUSION The establishment of method-specific clinical evidence-based GH cutoff limits is of importance to ensure adequate clinical diagnosis and treatment of children and adolescents with GHD. ID-MS may become an important tool for providing both reliable and sustainable SI traceability of GH measurements in the future.

Pediatric reference data of serum lipids and prevalence of dyslipidemia: Results from a population-based cohort in Germany.

BACKGROUND Serum lipid concentrations are thought to be risk factors for the development of cardiovascular disease. The present study aims to investigate the prevalence of dyslipidemia and provide sex- and age-related reference values for triglycerides, total cholesterol, LDL and HDL cholesterol as well as apolipoproteins A1 and B by using modern analytical approaches. MATERIALS AND METHODS Venous blood and anthropometric data were collected from 2571 subjects of the LIFE Child study, aged between 0.5 and 16years. Age- and gender-related reference intervals (3rd and 97th percentiles) were established by using Coles LMS method. RESULTS Serum concentrations of TC, LDL-C, TG and ApoB were higher in girls than in boys. In girls TC reached peak levels two years earlier than in boys. Triglyceride levels initially declined until the school age. Until early adolescence there was a steady increase. The LDL-C concentrations in girls and boys followed similar patterns to that of TC. Up to the age of 8years, a continuous increase in HDL levels for both sexes was found. Due to the strong correlation between HDL-C and ApoA1 (r=0.87) or rather between LDL-C and ApoB (r=0.93), the respective percentiles showed very similar patterns. Dyslipidemia prevalence were as follows: increased TC 7.8%, increased LDL 6.1%, increased TG 0-9years 22.1%, increased TG 10-16years 11.7%, and decreased HDL 8.0%. CONCLUSION Age- and sex-related trends for all parameters are similar to those of the German KIGGS study. With the exception of HDL cholesterol, the prevalence of dyslipidemias in the German LIFE Child cohort are similar to the US-American prevalence.

High birth weights but not excessive weight gain prior to manifestation are related to earlier onset of diabetes in childhood: ‘accelerator hypothesis’ revisited

Aim of this study was to test Wilkins ‘accelerator hypothesis’: whether excessive weight gain accelerates the onset of type 1 diabetes.

Evaluation of hair cortisol and cortisone change during pregnancy and the association with self-reported depression, somatization, and stress symptoms

Abstract Hair cortisol levels are used to measure long-term stress, while its inactive metabolite cortisone is often not assessed. We measured hair cortisol concentrations (HCC) and hair cortisone concentrations (HCNC) via liquid chromatography quadrupole linear ion trap mass spectrometry (LC-MS3) in 62 pregnant women who participated in the LIFE CHILD STUDY in their 2nd and 3rd trimester between 12/2011 and 11/2014. Sociodemographic factors, pregnancy-related factors, and hair characteristics were assessed. Degree of severity of depression, somatization, and stress were evaluated in both trimesters with a self-reported Patient Health Questionnaire (PHQ). Multivariate regression analyses were conducted between HCC and potential influencing factors, as well as with subscales of the PHQ, with HCNC and with the ratio of HCNC to HCC. Spearman correlation coefficients were calculated between steroid concentrations and subscale scores of the PHQ, as well as between the log2-fold change in HCC and HCNC and the change in PHQ subscale scores. HCC increased 1.3-fold and HCNC increased 1.5-fold by the 3rd trimester. HCNC was more than three times higher than HCC in both trimesters. We found significant associations of PHQ subscores with HCNC. The PHQ depression score was negatively correlated with HCNC in the 2nd trimester (p < .05). The PHQ stress score change was negatively correlated with the fold change of HCNC (p < .05) and with the change in the ratio of HCNC to HCC (p < .001). Our study suggests an association of cortisol/cortisone metabolism with self-reported stress in the 2nd and 3rd trimester of pregnancy. Since associations with PHQ subscores were only found with cortisone or the ratio of cortisone to cortisol, but not with cortisol alone, both cortisone and cortisol should be used as a marker for stress in pregnant woman.

Cystic-fibrosis related-diabetes (CFRD) is preceded by and associated with growth failure and deteriorating lung function

Abstract Background: Impaired glucose metabolism and cystic fibrosis (CF)-related diabetes (CFRD) are associated with insufficient weight gain and impaired lung function in children and adolescents with CF. We have asked whether imminent CFRD may be a cause of poor growth in children and adolescents. Methods: A retrospective case control study including 32 patients with CF with or without diabetes was conducted. Sixteen pairs, matched according to age, gender and exocrine pancreatic insufficiency, were analysed. Standard deviation scores (SDS) of height, growth, weight, body mass index (BMI), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and forced expiratory flow at 75% of expired FVC (FEF75) were recorded during a mean observation period of 13 years per patient. Results: SDS of height and weight were reduced in CF patients with diabetes compared to those without, not only at the point of diagnosis (both p<0.05) but years before the evidence of diabetes. Afterwards there was a significant decline in height (p<0.001) and weight (p<0.01) SDS in CFRD patients and an increasing difference between the height and weight of CF patients with or without diabetes. In contrast, no significant reduction of BMI-SDS was observed in CFRD patients. All analysed lung function parameters showed a marked decline in CFRD patients starting 1 year prior to the diagnosis of diabetes. Conclusions: Deteriorating growth, reduced weight and impaired lung function are related to the development of CFRD and are obvious several years before the actual diagnosis of diabetes.

Novel Insights in the Metabolic Syndrome in Childhood and Adolescence

Metabolic syndrome (MetS) is recognized as an escalating major health risk in adults as well as in children and adolescents. Its prevalence ranges from 6 to 39% depending on the applied definition criteria. To date, there is no consensus on a MetS definition for children and adolescents. However, most authors agree on essential components such as glucose intolerance, central obesity, hypertension, and dyslipidemia; each representing a risk for cardiovascular disease. Recently, associations between MetS and non-alcoholic fatty liver disease, hyperuricemia, and sleep disturbances have emerged. Biomarkers like adipocytokines are a subject of current research as they are implicated in the pathogenesis of the MetS. Epigenetics and gestational programming, especially the role of microRNA, comprise a novel, rapidly developing and promising research focus on the topic of MetS. MicroRNAs are increasingly valued for potential roles in the diagnosis, stratification, and therapeutics of MetS. Early detection of risk factors, screening for metabolic disturbances, and the identification of new therapies are major aims to reduce morbidity and mortality related to MetS. Dietary modification and physical activity are currently the only adopted treatment approaches. Pharmacological therapies and bariatric surgery are still contradictory and, therefore, are only recommended in selected high-risk cases.

Association between IgE-mediated allergies and diabetes mellitus type 1 in children and adolescents.

Type 1 diabetes mellitus (T1DM) is characterized by an immunological reaction that is dominated by type‐1 T helper (Th1) cells, whereas immunoglobulin E (IgE)‐mediated allergies are associated with Th2 cell. According to the Th1/Th2‐hypothesis, the immune system is said to either develop into the direction of Th1 or Th2 cells. This would mean that a child developing T1DM is unlikely to develop an IgE‐mediated allergy and vice versa.

Further stabilization and even decrease in the prevalence rates of overweight and obesity in German children and adolescents from 2005 to 2015: a cross-sectional and trend analysis

OBJECTIVE Recently several industrialized countries reported a stabilization or even a decrease in childhood overweight and obesity prevalence rates. In Germany, this trend started in 2004. The present study therefore aimed to evaluate whether this trend has continued or even leads in a clear direction. Design/Setting/Subjects BMI (>90th percentile (overweight), >97th percentile (obesity)) from the CrescNet database was analysed in 326 834 children and adolescents according to three age groups (4-7·99, 8-11·99 and 12-16 years), gender and between time points (2005-2015). RESULTS Trend analysis from 2005 to 2010 demonstrated that the prevalence of overweight and obesity decreased significantly in boys and girls in the entire group (4-16 years) and in 4-7·99-year-olds. From 2010 to 2015 there was a significant decrease in boys for overweight and obesity in the entire group and for overweight among 8-11·99-year-olds. Within the cross-sectional analysis, prevalence rates for overweight decreased significantly for both genders in the age groups of 4-7·99 and 8-11·99 years (2005 v. 2015). For obesity, prevalence rates showed a significant decrease for boys (2005 v. 2015) and girls (2005 v. 2010) in 4-7·99-year-olds. CONCLUSIONS We observed a further stabilization of overweight and obesity prevalence rates for all age groups and even a decrease in the rates for the younger ages (4-7·99 years, 8-11·99 years). As other industrialized countries have also reported similar trends, it seems that the epidemic of childhood overweight and obesity is reaching a turning point in the industrial part of the world.

A combined approach to generate laboratory reference intervals using unbalanced longitudinal data.

Abstract Background: The interpretation of individual laboratory test results requires the availability of population-based reference intervals. In children, reference interval estimation has to consider frequently the strong age-dependency. Generally, for the construction of reference intervals, a sufficiently large number of independent measurement values is required. Data selections from hospitals or cohort studies often comprise dependencies violating the independence assumption. Methods: In this article, we propose a combination of LMS-like (mean, M; coefficient of variation, S; skewness, λ or L) and resampling methods to overcome this drawback. The former is recommended by the World Health Organization (WHO) for the construction of continuous reference intervals of anthropometric measurements in children. The approach allows the inclusion of dependent measurements, for example, repeated measurements per subject. It also provides pointwise confidence envelopes as a measure of reliability. Results and conclusions: The combination of LMS-type methods and resampling provides a feasible approach to estimate age-dependent percentiles and reference intervals using unbalanced longitudinal data.