Molecular genetic analyses in developmental dyslexia & related endophenotypes

Developmental dyslexia is one of the most common neurodevelopmental disorders, with a prevalence of 5% to 12% among school-aged children. It is a severe and specific impairment in the acquisition of reading and spelling skills, which is unexpected in relation to other cognitive abilities. It is widely accepted that genetic factors play an essential role in dyslexia susceptibility. In this thesis, genetic analyses have been conducted (i) to investigate known susceptibility variants and (ii) to identify new genetic variants that would explain the heritability observed for both, dyslexia as qualitative trait and dyslexia-related quantitative endophenotypes. Causal susceptibility variants have been reported for two genes on chromosome 6p22, namely DCDC2 and KIAA0319. In our German dyslexia (DYS-) sample, we were not able to replicate prior findings on an intronic deletion or a compound STR marker in intron 2 of DCDC2 to be causative for dyslexia. Also, the analysis of further common variants in KIAA0319 did not provide evidence for a genetic effect in the German DYS-sample. However, we were able to confirm previous findings on epistatic gene-gene interactions between an intronic DCDC2 two-marker risk haplotype and SNPs within KIAA0319. This suggests that genetic variation within KIAA0319 might confer small modifying effects on dyslexia susceptibility in the presence of the DCDC2 risk haplotype. We next analyzed quantitative measures using candidate-gene approaches. Dyslexic children often perform poorly in verbal short-term memory tasks, and GRIN2B has been reported to play an important role in human memory and cognition. Our genetic results provide evidence that variation within intron 3 of GRIN2B contributes to the weakness of dyslexic children in short-term memory. A non-synonymous variant within a second gene, LRRTM1, was found to be associated with the measure of relative hand skill, which represents a correlate for asymmetrical brain function, and has been suggested to partly underlie the neural signature of dyslexia. We also attempted to identify new variants contributing to the development of dyslexia using a genome-wide association approach. To increase power, we combined individual genotyping with large pooling efforts. Our study revealed four new susceptibility loci on chr. 5p13, 9q21, 21q21 and 22q13. Promising candidate genes within these regions include GRIK1, TMC1 and FBLN1. As each of the identified variants only confers a small effect size, replication in large, independent samples will be required to confirm our findings. The application of the genome-wide approach on quantitative dimensions of dyslexia led to the identification of new susceptibility variants for two dyslexia-related endophenotypes. First, an intergenic marker on chromosome 4q32.1 was found to be highly associated with mismatch negativity, a neural correlate of speech perception. Our data indicate that the locus mediates its function via trans-regulational effects on the expression level of SLC2A3, a facilitative glucose transporter expressed in brain. It can be suggested that the effect is functionally relevant during childhood, when an increased amount of glucose substrate is required for the formation of synaptic connections in the human brain. In a second approach, we found that arithmetical skills are associated with alleles of rs133885, a non-synonymous marker in the long isoform of MYO18B. Structural MRI data provided evidence that in contrast to the non-risk group, carriers of the risk allele show a lower depth and volume of the right intraparietal sulcus, a structural entity involved in numerical processing. The new findings presented within this thesis might contribute to a better understanding of dyslexia susceptibility, genetic effects on related endophenotypes and the functional mechanisms that underlie human reading and writing skills

Einsatz der Nahinfrarotspektroskopie zur Qualitätskontrolle ökologischer Produkte am Beispiel von Möhren

Near-infrared reflectance spectroscopy is known for its inexpensiveness, rapidity and accuracy and may become a useful tool for the quality assessment of products of the growing organic food market. The objective of this study was to evaluate the ability of visible and near-infrared reflectance spectroscopy (NIRS) to predict several quality parameters (total nitrogen content and the content of different sugars) of organically grown carrots. Spectra of the VIS-NIR region (400-2500 nm) from 120 dried and milled carrot samples were recorded and transformed in the form of (log[1/reflectance]) values. The samples were randomly separated into two groups for calibration (n=60) and validation (n=60). A modified partial least square method was used to develop an equation over the whole spectrum (1st to 3rd derivation) from the spectra and the laboratory results for total nitrogen and the contents of D-glucose, D-fructose, sucrose and the sum of these three sugars. Calibrations were successful for all constituents. The validation, however, gave differing results: The total nitrogen content was predicted well by NIRS - the regression coefficient (a) of the linear regression (measured against predicted values) was 1.0, the correlation coefficient (r) was 0.9 and the ratio of standard deviation of the laboratory results to standard error of prediction (RDP) was 2.5. A satisfactory prediction was obtained for D-glucose (a=0.8, r=0.8, RDP=1.5) and D-fructose (a=0.8, r=0.8, RDP=1.5). In contrast, the contents of sucrose (a=0.8, r=0.7, RPD=1.4) and the sum of sugars (a=1.2, r=0.6, RPD=1.3) were predicted less satisfactorily. The good and satisfactory results for total nitrogen, glucose and fructose indicate that there is marked potential of NIRS for the quality assessment of organic food products. Studies are now required for a wider spectrum of food products and more constituents

Cortisol and 17-hydroxyprogesterone levels in saliva of healthy neonates - Normative data and relation to body mass index, arterial cord blood pH and time of sampling after birth

The measurement of cortisol and 17-hydroxyprogesterone (17-OHP) in saliva has become a reliable tool for both the scientist and the clinician for studying adrenal cortical function in the adult and the older child. We have now established in parallel normative data for salivary cortisol and 17-OHP levels in healthy neonates. We have asked whether or not there is a circadian rhythm of cortisol and 17-OHP saliva levels in neonates. Furthermore, we have asked whether salivary hormone levels correlated with auxologic and clinical data and time of sampling. Cortisol and 17-OHP levels in saliva samples from 119 healthy neonates (55 girls, 64 boys) were measured using in-house time-resolved fluorescent immunoassays. Saliva samples were obtained using a saliva collecting tube three times a day on the first or second day of life. Gender and gestational age did not influence salivary cortisol and 17-OHP levels. No significant circadian rhythm of salivary hormone levels was detected in this group of newborns. However, body mass index, arterial cord blood pH and time of saliva sampling significantly influenced salivary hormone levels. In conclusion, measurement of cortisol and 17-OHP in saliva is feasible in healthy neonates. The existence of normative data forms the basis for future studies on pathophysiologic states in the newborn period. Copyright (C) 2000 S. Karger AG, Basel

Soybean processing systems

Little is known about professional soybean processing technology in Europe. This brochure describes them by referring to farms or enterprises in Germany and Austria. Through an assessment of advantages and disadvantages, the brochure provides guidance for practitioners including farmers and advisors, with relevance for conventional and organic farming

Properties of permutation-based gene tests and controlling type 1 error using a summary statistic based gene test

Background: The advent of genome-wide association studies has led to many novel disease-SNP associations, opening the door to focused study on their biological underpinnings. Because of the importance of analyzing these associations, numerous statistical methods have been devoted to them. However, fewer methods have attempted to associate entire genes or genomic regions with outcomes, which is potentially more useful knowledge from a biological perspective and those methods currently implemented are often permutation-based. Results: One property of some permutation-based tests is that their power varies as a function of whether significant markers are in regions of linkage disequilibrium (LD) or not, which we show from a theoretical perspective. We therefore develop two methods for quantifying the degree of association between a genomic region and outcome, both of whose power does not vary as a function of LD structure. One method uses dimension reduction to “filter” redundant information when significant LD exists in the region, while the other, called the summary-statistic test, controls for LD by scaling marker Z-statistics using knowledge of the correlation matrix of markers. An advantage of this latter test is that it does not require the original data, but only their Z-statistics from univariate regressions and an estimate of the correlation structure of markers, and we show how to modify the test to protect the type 1 error rate when the correlation structure of markers is misspecified. We apply these methods to sequence data of oral cleft and compare our results to previously proposed gene tests, in particular permutation-based ones. We evaluate the versatility of the modification of the summary-statistic test since the specification of correlation structure between markers can be inaccurate. Conclusion: We find a significant association in the sequence data between the 8q24 region and oral cleft using our dimension reduction approach and a borderline significant association using the summary-statistic based approach. We also implement the summary-statistic test using Z-statistics from an already-published GWAS of Chronic Obstructive Pulmonary Disorder (COPD) and correlation structure obtained from HapMap. We experiment with the modification of this test because the correlation structure is assumed imperfectly known

Neural Correlates of Recognition Memory in Children with Febrile Seizures: Evidence from Functional Magnetic Resonance Imaging

Febrile seizures (FS) are assumed to not have adverse long-term effects on cognitive development. Nevertheless, FS are often associated with hippocampal sclerosis which can imply episodic memory deficits. This interrelation has hardly been studied so far. In the current study 13 children who had suffered from FS during infancy and 14 control children (7 to 9-years-old) were examined for episodic and semantic memory with standardized neuropsychological tests. Furthermore, using functional magnetic resonance imaging (fMRI) we studied neuronal activation while the children performed a continuous recognition memory task. The analysis of the behavioral data of the neuropsychological tests and the recognition memory experiment did not reveal any between-group differences in memory performance. Consistent with other studies fMRI revealed repetition enhancement effects for both groups in a variety of brain regions (e.g., right middle frontal gyrus, left parahippocampal gyrus) and a repetition suppression effect in the right superior temporal gyrus. Different neural activation patterns between both groups were obtained selectively within the right supramarginal gyrus (BA 40). In the control group correct rejections of new items were associated with stronger activation than correctly identified old items (HITs) whereas in the FS group no difference occurred. On the background that the right supramarginal gyrus is assumed to mediate a top-down process to internally direct attention toward recollected information, the results could indicate that control children used strategic recollection in order to reject new items (recall-to-reject). In contrast, the missing effect in the FS group could reflect a lack of strategy use, possibly due to impaired recollective processing. This study demonstrates that FS, even with mainly benign courses, can be accompanied by selective modifications in the neural structures underlying recognition memory

Comparison of uptake and prices of biosimilars in the US, Germany, and Switzerland

Importance: Biologics account for a substantial proportion of health care expenditures. Their costs have been projected to reach US $452 billion in global spending by 2022. Given recent expiration of patent protection of biologics, a shift toward greater follow-on competition among biosimilars would be expected that would allow greater uptake and lower drug costs. Objective: To assess uptake and prices of biosimilars in the US compared with 2 European countries (Germany and Switzerland) with national mechanisms for drug price negotiation. Design, Setting, and Participants: In this cohort study, biologics and biosimilars that were approved in the US, Germany, and Switzerland until August 2020 were identified. Prices and sales data were extracted from public and commercial databases for the years 2011 to 2020. Data were analyzed from August 1, 2021, to February 28, 2022. Main Outcomes and Measures: Descriptive statistics were used to show temporal trends in the uptake of biosimilars and relative prices compared with those of reference products (ie, biologic agents) for each country. Descriptive analysis was also performed to compare the uptake of biosimilars between the 3 countries limited to biologics that have biosimilars on the market in all countries. To test if biosimilar awareness in each country increased over the last decade, a linear least squares regression was applied. Results: The study cohort included 15 biosimilars and 6 biologics for the US, 52 biosimilars and 15 biologics for Germany, and 28 biosimilars and 13 biologics for Switzerland. Uptake of biosimilars increased over time in all countries. On average, the biosimilar market share at launch was highest in Germany; however, it increased at the fastest rate in the US. Monthly treatment costs of biosimilars in the US were a median of 1.94 (IQR, 1.78-2.44) and 2.74 (IQR, 1.91-3.46) higher than corresponding costs in Germany and Switzerland, respectively. Conclusions and Relevance: The findings of this cohort study suggest that more biosimilars have been marketed in Germany and Switzerland than in the US. Policies that counter anticompetitive practices in the US could allow biosimilars to enter the market sooner and could also lower health care costs with improved access. Awareness of biosimilars should be promoted to increase uptake of biosimilars globally

Anwendbarkeit der Nah- Infrarotspektroskopie zur Qualitätsbeurteilung von Komposten

Die Verwendung hochwertiger Komposte als organische Dünger hat positive Effekte auf den Boden und das Pflanzenwachstum. Komposte können beispielsweise die Stickstoffumsetzung und die Bildung von organischer Substanz erhöhen. Zudem sind viele Komposte in der Lage Pflanzen-krankheiten zu unterdrücken (Hoitink et al., 2006). Die Kompostqualität ist dabei von entscheidender Bedeutung. Die Einteilung erfolgt durch die Analyse von ausgewählten physikalischen, chemischen und bio-logischen Parametern, die zur Güte-klassifizierung herangezogen werden. Bislang werden sämtliche Parameter kostenintensiv und unter hohem Zeitaufwand, meist mit einer aufwendigen Probenvorbereitung, nasschemisch untersucht. Die Nahinfrarot-Spektroskopie (NIRS), ist eine präzise Messtechnik, die mehrere Analysen in einem Arbeitsgang durchführen kann, welches den Zeit- und Kostenaufwand von Analysen deutlich reduzieren könnte. Ziel der vorliegenden Arbeit war es, die Anwendbarkeit der NIRS zur Beurteilung der Kompostqualität, insbesondere biologischer Parameter, zu untersuchen. Die folgenden Fragestellungen wurden bearbeitet: • Können Basisparameter, biologische Parameter, Keim- und Suppressivitäts-tests mit NIRS vorhergesagt werden? • Wie hoch ist der Einfluss der Homogenität der Proben auf die Abschätzungsgenauigkeit der NIRS

‘Location, Location, Location’: a spatial approach for rare variant analysis and an application to a study on non-syndromic cleft lip with or without cleft palate

Motivation: For the analysis of rare variants in sequence data, numerous approaches have been suggested. Fixed and flexible threshold approaches collapse the rare variant information of a genomic region into a test statistic with reduced dimensionality. Alternatively, the rare variant information can be combined in statistical frameworks that are based on suitable regression models, machine learning, etc. Although the existing approaches provide powerful tests that can incorporate information on allele frequencies and prior biological knowledge, differences in the spatial clustering of rare variants between cases and controls cannot be incorporated. Based on the assumption that deleterious variants and protective variants cluster or occur in different parts of the genomic region of interest, we propose a testing strategy for rare variants that builds on spatial cluster methodology and that guides the identification of the biological relevant segments of the region. Our approach does not require any assumption about the directions of the genetic effects. Results: In simulation studies, we assess the power of the clustering approach and compare it with existing methodology. Our simulation results suggest that the clustering approach for rare variants is well powered, even in situations that are ideal for standard methods. The efficiency of our spatial clustering approach is not affected by the presence of rare variants that have opposite effect size directions. An application to a sequencing study for non-syndromic cleft lip with or without cleft palate (NSCL/P) demonstrates its practical relevance. The proposed testing strategy is applied to a genomic region on chromosome 15q13.3 that was implicated in NSCL/P etiology in a previous genome-wide association study, and its results are compared with standard approaches. Availability: Source code and documentation for the implementation in R will be provided online. Currently, the R-implementation only supports genotype data. We currently are working on an extension for VCF files. Contact: [email protected]