Börge Schmidt

Whole-Body MR Imaging in the German National Cohort: Rationale, Design, and Technical Background

PURPOSE To detail the rationale, design, and future perspective of implementing whole-body magnetic resonance (MR) imaging in the German National Cohort, a large multicentric population-based study. MATERIALS AND METHODS All institutional review boards approved the study, and informed consent is obtained before study enrollment. Participants are enrolled from a random sample of the general population at five dedicated imaging sites among 18 recruitment centers. MR imaging facilities are equipped with identical 3.0-T imager technology and use uniform MR protocols. Imager-specific hardware and software settings remained constant over the study period. On-site and centralized measures of image quality enable monitoring of completeness of the acquisitions and quality of each of the MR sequences. Certified radiologists read all MR imaging studies for presence of incidental findings according to predefined algorithms. RESULTS Over a 4-year period, six participants per day are examined at each center, totaling a final imaging cohort of approximately 30 000 participants. The MR imaging protocol is identical for each site and comprises a set of 12 native series to cover neurologic, cardiovascular, thoracoabdominal, and musculoskeletal imaging phenotypes totaling approximately 1 hour of imaging time. A dedicated analysis platform as part of a central imaging core incorporates a thin client-based integrative and modular data handling platform to enable multicentric off-site image reading for incidental findings. Scientific analysis will be pursued on a per-project hypothesis-driven basis. CONCLUSION Population-based whole-body MR imaging as part of the German National Cohort will serve to compile a comprehensive image repository, will provide insight into physiologic variants and subclinical disease burden, and has the potential to enable identification of novel imaging biomarkers of risk.

Predictive markers for the FSH sensitivity of women with polycystic ovarian syndrome

STUDY QUESTION Do parameters which are involved in pathogenesis of polycystic ovarian syndrome (PCOS) predict the dosage of recombinant FSH required to achieve monofollicular development for ovulation induction? SUMMARY ANSWER Anti-Mullerian hormone (AMH) appeared to be an independent predictor of the required dosage of FSH to achieve monofollicular development for ovulation induction in a study sample of clomiphene-resistant PCOS patients. WHAT IS KNOWN ALREADY AMH plays a key role in the pathogenesis of PCOS. This is the first study that has evaluated the association between AMH and the required FSH dosage to achieve the development of a large follicle of at least 18 mm, in the presence of additional predictors of ovarian responsiveness. In the few studies to date which have evaluated predictors of ovarian responsiveness in PCOS patients, fasting insulin has been shown to be a significant predictor. STUDY DESIGN, SIZE, DURATION A total of 48 infertile PCOS patients aged 18-43 years were enrolled in this prospective, observational study between 2009 and 2013. Study participants received between one and six cycles of ovarian stimulation with recombinant FSH using a step-up protocol. The mean total FSH dosage per cycle for reaching a monofollicular development for ovulation induction was evaluated to investigate its association with AMH, LH, FSH, LH/FSH-ratio, sex hormone-binding globulin (SHBG), androstendione, testosterone, free testosterone index, antral follicle count, ovarian volume, body mass index (BMI) and the age of patients. PARTICIPANTS/MATERIALS, SETTING, METHODS We used AMH-Gen-II ELISA (Beckman Coulter, Immunotech, Webster, TX, USA) for the assessment of AMH levels. Crude and multiple linear regression models were fitted to explore potential predictors of the required FSH dosage. MAIN RESULTS AND THE ROLE OF CHANCE An interquartile range (IQR) increase in AMH was associated with a 51.4% [95% confidence interval (CI): 24.7-79.0%; P = 0.0003] increase in the mean total FSH dosage per cycle (in IU) in a crude regression model, corresponding to a 7.2% increase in the mean total FSH dosage per cycle per ng/ml AMH. Adjustment for BMI augmented the effect of AMH, with a 58.3% (95% CI: 33.2-84.2%; P = 1.8 × 10(-5)) increase in FSH dosage per IQR AMH (corresponding to an 8.2% increase per ng/ml AMH) and a 46.2% (95% CI: 16.5-76.6%; P = 0.003) increase per IQR BMI (corresponding to a 3.7% increase per kg/m(2)). AMH was the only independent variable for which the effect on FSH dosage was statistically significant in the crude regression model as well as after adjustment for other promising predictors. The association of BMI with FSH dosage was statistically significant while adjusted for AMH, but not in the crude model. LIMITATIONS, REASONS FOR CAUTION The impact of metabolic parameters such as insulin resistance on the reported association between AMH and FSH dosage was not assessed. WIDER IMPLICATIONS OF THE FINDINGS Knowledge about the predictors of ovarian sensitivity to FSH can facilitate a physicians decision-making in providing the optimal infertility therapy for PCOS patients. STUDY FUNDING/COMPETING INTERESTS Funding was provided by the University Hospital of Essen.

Impact of maternal serum levels of Visfatin, AFP, PAPP-A, sFlt-1 and PlGF at 11–13 weeks gestation on small for gestational age births

Abstract Objective: Investigating potential value of maternal serum Visfatin, sFlt-1, PlGF, AFP, PAPP-A levels at first trimester for prediction of small for gestational age (SGA) at birth. Methods: Measurements were performed in 20 SGA and 65 control cases. Logistic regression analysis adjusted for age and weeks of pregnancy at data collection was performed to estimate odds ratios (OR), 95% confidence intervals (95% CI) and p values separately for each potential predictor. A multiple regression model was used to assess the impact of all the promising predictors adjusted for each other. Receiver operating characteristic (ROC) analysis was used to indicate the ability to discriminate between SGA cases and controls. Results: There was an association of serum PlGF levels (OR 0.53 per interquartile range [IQR] increase in PlGF; 95% CI 0.24–1.16), sFlt-1/PlGF ratio (OR 1.42 per IQR increase in sFlt-1/PlGF; 95% CI 1.03–1.96), serum Visfatin levels (OR 0.31 per IQR increase in Visfatin; 95% CI 0.10–0.95) and smoking (OR 4.24; 95% CI 1.10–16.37) with SGA at birth. Conclusions: Associations between SGA and lower PlGF, Visfatin levels as well as increased sFlt-1/PlGF ratio and smoking status were detected which may contribute to predict SGA.

Harmonizing Biomarker Measurementsin Longitudinal Studies of Children’s Healthand the Environment

Abstract Large scale studies of environmental influences on children’s health and development are being planned or conducted in many places, including Japan, France, Shanghai (China), the United States, and Germany. The objective of these “next generation” studies is to better understand a broad range of environmental and social factors that influence the health and well-being of children. Some of these studies are designed to enroll tens of thousands of children and follow them for many years to investigate the influence of the environment on child growth, development and health. Environment is broadly defined in these studies and includes investigation of chemical, biological, physical and socioeconomic factors. An international group composed of study teams from Japan, France, Shanghai (China), the United States, and Germany has been meeting since 2011 to exchange information and work towards harmonization of processes that would provide the opportunity to compare methods and develop procedures to conduct combined analyses of results and data pooling procedures. Harmonization of infant health outcomes, biomarkers, environmental measurements, socioeconomic and migration status has been initiated. This manuscript provides an overview of the Environment and Child Health International Birth Cohort Group and its history, describes the progress of work, and discusses the advantages of this international collaborative effort.

Low 25(OH)-vitamin D concentrations are associated with emotional and behavioral problems in German children and adolescents

Background Evidence has accumulated for the association between low vitamin D serum concentrations and mental health disorders in both children and adults. We performed a cross-sectional analysis in a population-based sample of children and adolescents to detect associations between 25(OH)-vitamin D serum [25(OH)D] concentrations and scores of the five Strengths and Difficulties Questionnaire (SDQ) subscales and the total difficulties score in different age groups (age ≥3-<12 years and ≥12-<18 years). Methods 9068 participants of the population-based, nation-wide German Health Interview and Examination Survey for Children and Adolescents (KIGGS) with information on mental health status assessed by the SDQ and 25(OH)D levels were included in the analysis. For statistical analysis we used linear regression models stratified by gender based on different adjustment sets. For the younger subsample the analysis was additionally adjusted for the frequency of playing outside. We compared the associations based on parent- and self-ratings of the SDQ for children and adolescents aged ≥12-<18 years. Results We found inverse associations between 25(OH)D concentrations and the subscales emotional problems, peer relationship problems and the total difficulties score in both genders after adjustment for potential confounders. The strongest associations were observed in the older subsample for parent-ratings in boys and self-ratings in girls. In the younger subsample the associations were less strong and no longer evident after adjustment for potential confounders such as migration background, socioeconomic status and frequency of playing outside. Conclusion Based on the large-scale cross-sectional study in a German population-based sample of children and adolescents we detected inverse associations between 25(OH)D concentrations and both parent- and self-rated SDQ scores of the total difficulties scale and different subscales with the strongest association in the subsample aged ≥12-<18 years for both genders. Migration background and socioeconomic status were detected as relevant confounders. Further studies–particularly in countries with comparatively low mean 25(OH)D concentrations–in childhood and adolescence are warranted. Longitudinal studies are also necessary to infer direction of effects. Finally, RCTs in children and adolescents are required to determine whether Vitamin D is beneficial for mental health.

Follistatin during pregnancy and its potential role as an ovarian suppressing agent

OBJECTIVE Ovarian quiescence is a common condition during pregnancy. In vitro, follistatin, an antagonist of follicle-stimulating hormone, blocks follicular development at early stages, and its serum levels increase during pregnancy. A possible surrogate biomarker of ovarian arrest during pregnancy is a decrease in anti-mullerian hormone (AMH) levels followed by an increase in these levels on the second day after labor. The purpose of this study was to determine whether follistatin could act as an ovarian-suppressing agent during pregnancy. Follistatin levels and AMH levels were determined at various stages of pregnancy and postpartum. STUDY DESIGN The follistatin and AMH levels of 69 patients were retrospectively determined with the AMH Gen II ELISA and with the Human Follistatin Quantikine ELISA Kit. For 49 patients, samples were available from various trimesters for cross-sectional analysis; for the other 20, samples were available longitudinally from day one before labor and then daily on days 1 through 4 after labor. Statistical significance was determined with linear regression, the Friedman rank sum test and the Wilcoxon-Nemenyi-McDonald-Thompson post hoc test. RESULTS The behavior of follistatin levels was exactly opposite that of AMH levels: Follistatin levels increased significantly during pregnancy and on the first day after parturition but declined afterwards, whereas AMH levels decreased significantly during pregnancy and increased after labor. CONCLUSION Follistatin can induce ovarian arrest during pregnancy.

Serum concentrations of soluble B7-H4 in early pregnancy are elevated in women with preterm premature rupture of fetal membranes

To determine the association between maternal soluble B7‐H4 (sB7‐H4) and the preterm premature rupture of the amniotic membranes (pPROM), the blood serum concentration levels of sB7‐H4 were studied.

Change of anti-Mullerian-hormone levels during follicular phase in PCOS patients.

Abstract Anti-Mullerian-hormone (AMH) does not seem to fluctuate significantly during the menstrual cycle in healthy women. However, little is known about cycle fluctuations of AMH levels in patients with polycystic ovarian syndrome (PCOS). The purpose of this study was to examine AMH fluctuations during the follicular phase in PCOS patients receiving antiestrogens or recombinant follicle-stimulating hormone (FSH). About 40 PCOS patients diagnosed according to Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group 2003 and 19 controls were prospectively enrolled. PCOS patients received either antiestrogens or recombinant FSH for monoovulation induction and controls received antiestrogens. AMH levels were determined (1) between the 2nd and the 5th day of follicular phase and (2) when a single large dominant follicle ≥18 mm had appeared. Our study shows that AMH levels do not change during follicular development in controls as well as in PCOS patients with AMH levels < 5 ng/ml, irrespective of antiestrogen or FSH therapy. However, in PCOS patients with AMH levels ≥5 ng/ml, AMH declines significantly during follicular development (p < 0.01). We conclude that AMH levels should be determined in the early follicular phase in PCOS patients without the influence of antiestrogens or exogenous FSH, because these interventions may lower AMH values in patients with high levels. Chinese abstract 抗苗勒管激素（AMH）在健康妇女月经周期中似乎并没有明显波动。然而多囊卵巢综合征（PCOS）患者月经期AMH水平的变化却鲜为人知。本研究的目的是检测PCOS患者卵泡期接受抗雌激素或重组卵泡刺激素（FSH）治疗后AMH水平的波动。其中40名患者诊断为PCOS（根据2003年欧洲人类生殖与胚胎学会和美国生殖医学会发起的PCOS共识研讨会），19人纳入对照组。PCOS患者采用抗雌激素或重组FSH诱发单卵泡发育，对照组接受抗雌激素治疗。(1)月经第2天至第5天和（2）出现单个优势卵泡（卵泡直径≥18mm）时分别监测AMH水平。我们的研究表明无论是否接受抗雌激素或FSH治疗，对照组和AMH＜5ng/ml的PCOS组AMH水平在卵泡发育过程中并没有波动。而AMH＞5ng/ml的PCOS组，AMH在卵泡发育过程中则显著下降（P＜0.01）。我们得出结论PCOS患者AMH水平应在没有接受抗雌激素或外源FSH治疗的早卵泡期测定，因为对于高AMH水平的PCOS患者这些干预治疗可能会降低AMH水平。

Thyroid Hormone Status in Overweight Children with Attention Deficit/Hyperactivity Disorder

Background: There is an ongoing discussion whether thyroid hormones are involved in the development and course of attention deficit/hyperactivity disorder (ADHD). Since obesity is associated with both higher thyroid-stimulating hormone (TSH) and free triiodothyronine (fT3) concentrations and increased rates of ADHD, we hypothesized that overweight children with ADHD show higher TSH and fT3 concentrations compared to overweight children without ADHD. Methods: TSH, fT3, fT4, and leptin levels were analyzed in 230 children (60.9% boys, 9.3 ± 1.7 years old, 35.7% migration background). The children were divided into four groups (I = 26 overweight children with ADHD, II = 56 normal-weight children with ADHD, III = 66 overweight children without ADHD, and IV = 82 normal-weight children without ADHD). Severity of ADHD was determined by the parent version of the Connors 3® rating scales. Results: Overweight children with ADHD did not differ significantly from overweight children without ADHD with respect to TSH, fT3, or fT4 concentrations. Comparing the thyroid hormones between the four groups also demonstrated no significant differences for TSH and fT4 concentrations. fT3 concentrations were significantly higher in normal-weight children with ADHD compared to normal-weight children without ADHD. Inattention and hyperactivity/impulsivity scores were not significantly related to TSH or fT3 in multiple regression analyses adjusted for age, gender, and migration background. In these analyses, TSH was associated with BMI SDS (β coefficient 0.19 ± 0.12, p = 0.002) and leptin (exp[β coefficient] 1.87 ± 1.36, p < 0.001). fT3 (β coefficient 0.06 ± 0.05, p = 0.009) and leptin (exp[β coefficient] 1.17 ± 1.13, p = 0.009) were also associated with BMI SDS. Conclusions: Our findings confirm the relation between overweight and thyroid hormones but point against the hypothesis that thyroid hormones might link overweight and ADHD in children.

Intraindividual right-left comparison of sonographic features in polycystic ovary syndrome (PCOS) diagnosis

OBJECTIVE Sonographic features of polycystic ovaries consist of elevated antral follicle count or ovarian volume of at least one ovary. The aim of this prospective cross-sectional study was to estimate intraindividual differences in sonographic measurements between the both ovaries of PCOS patients and controls and clinical consequences. STUDY DESIGN Both ovaries of 85 PCOS patients and 48 controls were scanned transvaginally and agreement of sonographic measurements was analyzed using the Bland-Altman method. Concordance correlation coefficients (CCC) were computed. RESULTS Mean differences between right and left ovaries were 0.24 (95% confidence interval [95% CI]: -0.32-0.80) follicles for AFC and 1.14 (95% CI: 0.34-1.92)ml for OV in the whole study population, 0.14 (95% CI: -0.68-0.96) follicles for AFC and 1.48 (95% CI: 0.39-2.58)ml for OV in PCOS patients, 0.42 (95% CI: -0.19-1.02) follicles for AFC and 0.53 (95% CI: -0.50-1.56)ml for OV in controls. Rather wide limits of agreement and low CCCs (<0.7 for all estimates) indicated poor agreement between the ovaries for both sonographic measurements. Width between lower and upper limits of agreement was higher for PCOS patients than for controls. 23.5% of the PCOS patients showed polycystic ovarian morphology (PCOM) only in one ovary, resulting in 9.4% potentially missed PCOS diagnosis according to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. CONCLUSION Substantial differences in antral follicle count and ovarian volume between the right and left ovary were observed. In approximately 10% of the PCOS patients in our study only the examination of both ovaries has led to a reliable diagnosis of PCOS. In clinical practice it is recommended to scan both ovaries for a reliable diagnosis of abnormal sonographic findings in PCOM and PCOS diagnosis.