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Genetic and environmental factors both contribute to cognitive test performance. A substantial increase in average intelligence test results in the second half of the previous century within one generation is unlikely to be explained by genetic changes. One possible explanation for the strong malleability of cognitive performance measure is that environmental factors modify gene expression via epigenetic mechanisms. Epigenetic factors may help to understand the recent observations of an association between dopamine-dependent encoding of reward prediction errors and cognitive capacity, which was modulated by adverse life events. The possible manifestation of malleable biomarkers contributing to variance in cognitive test performance, and thus possibly contributing to the "missing heritability" between estimates from twin studies and variance explained by genetic markers, is still unclear. Here we show in 1475 healthy adolescents from the IMaging and GENetics (IMAGEN) sample that general IQ (gIQ) is associated with (1) polygenic scores for intelligence, (2) epigenetic modification of DRD2 gene, (3) gray matter density in striatum, and (4) functional striatal activation elicited by temporarily surprising reward-predicting cues. Comparing the relative importance for the prediction of gIQ in an overlapping subsample, our results demonstrate neurobiological correlates of the malleability of gIQ and point to equal importance of genetic variance, epigenetic modification of DRD2 receptor gene, as well as functional striatal activation, known to influence dopamine neurotransmission. Peripheral epigenetic markers are in need of confirmation in the central nervous system and should be tested in longitudinal settings specifically assessing individual and environmental factors that modify epigenetic structure.
Background
High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called 'omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods.
Methods
We took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up). We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS), and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort.
Results
We found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis.
Conclusions
We demonstrate that metabolites identified using a high-throughput method (GC-MS) perform well in predicting the development of fasting plasma glucose over several years. Notably, not single, but a complex pattern of metabolites propels the prediction and therefore reflects the complexity of the underlying molecular mechanisms. This result could only be captured by application of multivariate statistical approaches. Therefore, we highly recommend the usage of statistical methods that seize the complexity of the information given by high-throughput methods.
The Limpopo Basin in southern Africa is prone to droughts which affect the livelihood of millions of people in South Africa, Botswana, Zimbabwe and Mozambique. Seasonal drought early warning is thus vital for the whole region. In this study, the predictability of hydrological droughts during the main runoff period from December to May is assessed using statistical approaches. Three methods (multiple linear models, artificial neural networks, random forest regression trees) are compared in terms of their ability to forecast streamflow with up to 12 months of lead time. The following four main findings result from the study.
1. There are stations in the basin at which standardised streamflow is predictable with lead times up to 12 months. The results show high inter-station differences of forecast skill but reach a coefficient of determination as high as 0.73 (cross validated).
2. A large range of potential predictors is considered in this study, comprising well-established climate indices, customised teleconnection indices derived from sea surface temperatures and antecedent streamflow as a proxy of catchment conditions. El Nino and customised indices, representing sea surface temperature in the Atlantic and Indian oceans, prove to be important teleconnection predictors for the region. Antecedent streamflow is a strong predictor in small catchments (with median 42% explained variance), whereas teleconnections exert a stronger influence in large catchments.
3. Multiple linear models show the best forecast skill in this study and the greatest robustness compared to artificial neural networks and random forest regression trees, despite their capabilities to represent nonlinear relationships.
4. Employed in early warning, the models can be used to forecast a specific drought level. Even if the coefficient of determination is low, the forecast models have a skill better than a climatological forecast, which is shown by analysis of receiver operating characteristics (ROCs). Seasonal statistical forecasts in the Limpopo show promising results, and thus it is recommended to employ them as complementary to existing forecasts in order to strengthen preparedness for droughts.