The genetic and environmental etiology of novel frequency-driven regional parcellations of abnormal white matter.

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (rg = 0.57-0.85), although two were small (rg = 0.35-0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration.

Bayesian Approach to Disease Risk Evaluation Based on Air Pollution and Weather Conditions.

BACKGROUND: Environmental factors such as meteorological conditions and air pollutants are recognized as important for human health, where mortality and morbidity of certain diseases may be related to abrupt climate change or air pollutant concentration. In the literature, environmental factors have been identified as risk factors for chronic diseases such as ischemic heart disease. However, the likelihood evaluation of the disease occurrence probability due to environmental factors is missing. METHOD: We defined people aged 51-90 years who were free from ischemic heart disease (ICD9: 410-414) in 1996-2002 as the susceptible group. A Bayesian conditional logistic regression model based on a case-crossover design was utilized to construct a risk information system and applied to data from three databases in Taiwan: air quality variables from the Environmental Protection Administration (EPA), meteorological parameters from the Central Weather Bureau (CWB), and subject information from the National Health Insurance Research Database (NHIRD). RESULTS: People living in different geographic regions in Taiwan were found to have different risk factors; thus, disease risk alert intervals varied in the three regions. CONCLUSIONS: Disease risk alert intervals can be a reference for weather bureaus to issue health warnings. With early warnings, susceptible groups can take measures to avoid exacerbation of disease when meteorological conditions and air pollution become hazardous to their health.

Polygenic resilience scores capture protective genetic effects for Alzheimer's disease.

Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer's disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast "resilient" unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.

Network hub-node prioritization of gene regulation with intra-network association.

BACKGROUND: To identify and prioritize the influential hub genes in a gene-set or biological pathway, most analyses rely on calculation of marginal effects or tests of statistical significance. These procedures may be inappropriate since hub nodes are common connection points and therefore may interact with other nodes more often than non-hub nodes do. Such dependence among gene nodes can be conjectured based on the topology of the pathway network or the correlation between them. RESULTS: Here we develop a pathway activity score incorporating the marginal (local) effects of gene nodes as well as intra-network affinity measures. This score summarizes the expression levels in a gene-set/pathway for each sample, with weights on local and network information, respectively. The score is next used to examine the impact of each node through a leave-one-out evaluation. To illustrate the procedure, two cancer studies, one involving RNA-Seq from breast cancer patients with high-grade ductal carcinoma in situ and one microarray expression data from ovarian cancer patients, are used to assess the performance of the procedure, and to compare with existing methods, both ones that do and do not take into consideration correlation and network information. The hub nodes identified by the proposed procedure in the two cancer studies are known influential genes; some have been included in standard treatments and some are currently considered in clinical trials for target therapy. The results from simulation studies show that when marginal effects are mild or weak, the proposed procedure can still identify causal nodes, whereas methods relying only on marginal effect size cannot. CONCLUSIONS: The NetworkHub procedure proposed in this research can effectively utilize the network information in combination with local effects derived from marker values, and provide a useful and complementary list of recommendations for prioritizing causal hubs.

Probabilistic prioritization of candidate pathway association with pathway score.

BACKGROUND: Current methods for gene-set or pathway analysis are usually designed to test the enrichment of a single gene-set. Once the analysis is carried out for each of the sets under study, a list of significant sets can be obtained. However, if one wishes to further prioritize the importance or strength of association of these sets, no such quantitative measure is available. Using the magnitude of p-value to rank the pathways may not be appropriate because p-value is not a measure for strength of significance. In addition, when testing each pathway, these analyses are often implicitly affected by the number of differentially expressed genes included in the set and/or affected by the dependence among genes. RESULTS: Here we propose a two-stage procedure to prioritize the pathways/gene-sets. In the first stage we develop a pathway-level measure with three properties. First, it contains all genes (differentially expressed or not) in the same set, and summarizes the collective effect of all genes per sample. Second, this pathway score accounts for the correlation between genes by synchronizing their correlation directions. Third, the score includes a rank transformation to enhance the variation among samples as well as to avoid the influence of extreme heterogeneity among genes. In the second stage, all scores are included simultaneously in a Bayesian logistic regression model which can evaluate the strength of association for each set and rank the sets based on posterior probabilities. Simulations from Gaussian distributions and human microarray data, and a breast cancer study with RNA-Seq are considered for demonstration and comparison with other existing methods. CONCLUSIONS: The proposed summary pathway score provides for each sample an overall evaluation of gene expression in a gene-set. It demonstrates the advantages of including all genes in the set and the synchronization of correlation direction. The simultaneous utilization of all pathway-level scores in a Bayesian model not only offers a probabilistic evaluation and ranking of the pathway association but also presents good accuracy in identifying the top-ranking pathways. The resulting recommendation list of ranked pathways can be a reference for potential target therapy or for future allocation of research resources.

Manipulation of micro-particles by flexible polymer-based optically-induced dielectrophoretic devices.

This study presents a novel technology to manipulate micro-particles with the assistance from flexible polymer-based optically-induced dielectrophoretic (ODEP) devices. Bending the flexible ODEP devices downwards or upwards to create convex or concave curvatures, respectively, enables the more effective separation or collection of micro-particles with different diameters. The travel distances of the polystyrene beads of 40 µm diameter, as induced by the projected light in a given time period was increased by ~100%, which were 43.0 ± 5.0 and 84.6 ± 4.0 µm for flat and convex ODEP devices, respectively. A rapid separation or collection of micro-particles can be achieved with the assistance of gravity because the falling polystyrene beads followed the inclination of the downward and upward bent ODEP devices.