Biology subjects

Ziegler, A.

Publications and source records attributed to Ziegler, A..

3 recordsLinked to original sources

bioRxiv2018

Evaluating predictive biomarkers for a binary outcome with linear versus logistic regression - Practical recommendations for the choice of the model

A predictive biomarker can forecast whether a patient benefits from a specific treatment under study. To establish predictiveness of a biomarker, a statistical interaction between the biomarker status and the treatment group concerning the clinical outcome needs to be shown. In clinical trials looking at a binary outcome, linear or logistic regression models may be used to evaluate the interaction, but the effects in the two models are different and differently interpreted. Specifically, the effects are estimated as absolute risk reductions (ARRs) and odds ratios (ORs) in the linear and logistic model, thus measuring the effect on an additive and multiplicative scale, respectively.\n\nWe derived the relationship between the effects of the linear and the logistic regression model allowing for translations between the effect estimates between both models. In addition, we performed a comprehensive simulation study to compare the power of the two models under a variety of scenarios in different study designs. In general, the differences in power to detect interaction were minor, and visible differences were detected in rather unrealistic scenarios of effect size combinations and were usually in favor of the logistic model.\n\nBased on our results and theoretical considerations, we recommend to 1) estimate logistic regression models because of their statistical properties, 2) test for interaction effects and 3) calculate and report both ARRs and ORs from these using the formulae provided.

epidemiology↗

bioRxiv2018

Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development

De novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuronal generation and migration. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity and induce ectopic RNA-protein granules and aberrant translation in neural progenitors and neurons. Together, our study demonstrates novel mechanisms underlying DDX3X syndrome, and highlights roles for RNA-protein aggregates in the pathogenesis of neurodevelopmental disease.

genetics↗

bioRxiv2017

Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e. the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally-arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of a AKR/J mouse strain (B6-mtAKR) together with a C57BL/6J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to wild-type C57BL/6J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair metabolic health and lifespan in mice.\n\nHighlightsO_LIWe identify heteroplasmy of the adenine-repeat variation (9 to 13A) in nt5172 in the origin of light-strand DNA replication (OriL) in inbred mice.\nC_LIO_LIB6-mtAKR mice carry >20% 12A heteroplasmy in the OriL, while B6 mice carry only [~] 10% heteroplasmy.\nC_LIO_LIThe level of 12A heteroplasmy correlates to mtDNA copy number, glucose metabolism, and lifespan in mice.\nC_LIO_LIGiven the established role of mtDNA heteroplasmy in regards to endurance exercise performance in athletes, these findings may impact our understanding of metabolism and aging in humans.\nC_LI

genetics↗