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Biology subjects

Koenig, I. R.

Publications and source records attributed to Koenig, I. R..

3 recordsLinked to original sources

Identification of representative trees in random forests based on a new tree-based distance measure

In life sciences random forests are often used to train predictive models. However, gaining any explanatory insight into the mechanics leading to a specific outcome is rather complex, which impedes the implementation of random forests into clinical practice. By simplifying a complex ensemble of decision trees to a single most representative tree, it is assumed to be possible to observe common tree structures, the importance of specific features and variable interactions. Thus, representative trees could also help to understand interactions between genetic variants. Intuitively, representative trees are those with the minimal distance to all other trees, which requires a proper definition of the distance between two trees. Thus, we developed a new tree-based distance measure, which incorporates more of the underlying tree structure than other metrics. We compared our new method with the existing metrics in an extensive simulation study and applied it to predict the age at onset based on a set of genetic risk factors in a clinical data set. In our simulation study we were able to show the advantages of our weighted splitting variable approach. Our real data application revealed that representative trees are not only able to replicate the results from a recent genome-wide association study, but also can give additional explanations of the genetic mechanisms. Finally, we implemented all compared distance measures in R and made them publicly available in the R package timbR (https://github.com/imbs-hl/timbR).

bioinformatics↗

Maternally inherited differences within mitochondrial Complex I control murine healthspan.

Mitochondrial complex I, the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery, has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA-encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in the mitochondrially encoded complex I gene mt-Nd2 modulates lifespan by altering cellular tryptophan levels and, consequently, ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C>A in mt-Nd2 lived significantly shorter than the controls did. The same mutation led to a higher susceptibility to glucose intolerance induced by high-fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA-encoded complex I gene, mt-Nd5, suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases.

genetics↗

Risky behaviors and Parkinson’s disease: A Mendelian randomization study in up to 1 million study participants

ObjectiveDopaminergic neurotransmission is known to be a potential modulator of risky behaviors including substance abuse, promiscuity, and gambling. Furthermore, observational studies have shown associations between risky behaviors and Parkinsons disease; however, the causal nature of these associations remains unclear. Thus, in this study, we examine causal associations between risky behavior phenotypes on Parkinsons disease using a Mendelian randomization approach.\n\nMethodsWe used two-sample Mendelian randomization to generate unconfounded estimates using summary statistics from two independent, large meta-analyses of genome-wide association studies on risk taking behaviors (n=370,771-939,908) and Parkinsons disease (cases: n=9581, controls: n = 33,245). We used inverse variance weighted as the main method for judging causality.\n\nResultsOur results support a strong protective association between the tendency to smoke and Parkinsons disease (OR=0.714 per log odds of ever smoking; 95% CI=0.568-0.897; p-value=0.0041; Cochran Q test; p-value=0.238; I2 index=6.3%). Furthermore, we observed risk association trends between automobile speed propensity as well as the number of sexual partners and Parkinsons disease after removal of overlapping loci with other risky traits (OR=1.986 for each standard deviation increase in normalized automobile speed propensity; 95% CI=1.215-3.243; p-value=0.0066, OR=1.635 for each standard deviation increase in number of sexual partners; 95% CI=1.165-2.293; p-value=0.0049).\n\nInterpretationThese findings provide support for a causal relationship between general risk tolerance and Parkinsons disease and may provide new insights in the pathogenic mechanisms leading to the development of Parkinsons disease.

genetics↗