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Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.
Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (\(\kappa\))] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.
Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (\(\kappa\) = 0.66 and \(\kappa\) = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (\(ICC_1 = 0.71\) and \(ICC_2 = 0.75\), respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).
Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
Einleitung: Unter dem Begriff exekutive Funktionen (EF) werden häufig die Komponenten Inhibition, kognitive Flexibilität und Aktualisierung von Arbeitsgedächtnisrepräsentationen subsumiert. EF sind bereichsübergreifende Prädiktoren schulischer Leistungen. Verschiedene Operationalisierungen derselben Komponente, z.B. Performanztests und Elterneinschätzungen, zeigen häufig nur geringe Interkorrelationen. Die Methoden scheinen unterschiedliche Aspekte einer Komponente zu erfassen, daher könnte eine Kombination zur Vorhersage schulischer Leistungen sinnvoll sein. Methode: N = 96 Erst- und Zweitklässler_innen mit und ohne Entwicklungsauffälligkeiten wurden mittels EF-Performanztests und Schulleistungstests zu Mathematik und Lesen untersucht. Per Fragebogen wurden elternbeurteilte EF und als Kontrollvariablen der sozioökonomische Status (SÖS) und das Vorliegen von Merkmalen einer Aufmerksamkeitsdefizit-Hyperaktivitätsstörung (ADHS) erfasst. Ergebnisse: Elternbeurteilungen hatten über die Performanztests hinaus einen bedeutsamen Vorhersagewert für die Mathematik- und Leseleistung. Der Einfluss von Alter, SÖS und ADHS-Merkmalen wurde kontrolliert. Diskussion: Die kombinierte Anwendung beider Erfassungsmethoden scheint somit vorteilhaft für die Prognose schulischer Leistungen und die Prävention von Schulleistungsproblemen.
We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.