GxGrare: gene-gene interaction analysis method for rare variants from high-throughput sequencing data

Background

With the rapid advancement of array-based genotyping techniques, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with common complex diseases. However, it has been shown that only a small proportion of the genetic etiology of complex diseases could be explained by the genetic factors identified from GWAS. This missing heritability could possibly be explained by gene-gene interaction (epistasis) and rare variants. There has been an exponential growth of gene-gene interaction analysis for common variants in terms of methodological developments and practical applications. Also, the recent advancement of high-throughput sequencing technologies makes it possible to conduct rare variant analysis. However, little progress has been made in gene-gene interaction analysis for rare variants.

Results

Here, we propose GxGrare which is a new gene-gene interaction method for the rare variants in the framework of the multifactor dimensionality reduction (MDR) analysis. The proposed method consists of three steps; 1) collapsing the rare variants, 2) MDR analysis for the collapsed rare variants, and 3) detect top candidate interaction pairs. GxGrare can be used for the detection of not only gene-gene interactions, but also interactions within a single gene. The proposed method is illustrated with 1080 whole exome sequencing data of the Korean population in order to identify causal gene-gene interaction for rare variants for type 2 diabetes.

Conclusion

The proposed GxGrare performs well for gene-gene interaction detection with collapsing of rare variants. GxGrare is available at http://bibs.snu.ac.kr/software/gxgrare which contains simulation data and documentation. Supported operating systems include Linux and OS X.

     

arrayQCplot: software for checking the quality of microarray data

SUMMARY: arrayQCplot is a software for the exploratory analysis of microarray data. This software focuses on quality control and generates newly developed plots for quality and reproducibility checks. It is developed using R and provides a user-friendly graphical interface for graphics and statistical analysis. Therefore, novice users will find arrayQCplot as an easy-to-use software for checking the quality of their data by a simple mouse click. AVAILABILITY: arrayQCplot software is available from Bioconductor at http://www.bioconductor.org. A more detailed manual is available at http://bibs.snu.ac.kr/software/arrayQCplot CONTACT: tspark@stats.snu.ac.kr.     

NABIC SNP: an integrated database for SNP markers

AvailabilityThe database is available online for free at http://nabic.rda.go.kr/SNP     

Bis-class: a new classification tool of methylation status using bayes classifier and local methylation information

Background

Whole genome sequencing of bisulfite converted DNA (‘methylC-seq’) method provides comprehensive information of DNA methylation. An important application of these whole genome methylation maps is classifying each position as a methylated versus non-methylated nucleotide. A widely used current method for this purpose, the so-called binomial method, is intuitive and straightforward, but lacks power when the sequence coverage and the genome-wide methylation level are low. These problems present a particular challenge when analyzing sparsely methylated genomes, such as those of many invertebrates and plants.

Results

We demonstrate that the number of sequence reads per position from methylC-seq data displays a large variance and can be modeled as a shifted negative binomial distribution. We also show that DNA methylation levels of adjacent CpG sites are correlated, and this similarity in local DNA methylation levels extends several kilobases. Taking these observations into account, we propose a new method based on Bayesian classification to infer DNA methylation status while considering the neighborhood DNA methylation levels of a specific site. We show that our approach has higher sensitivity and better classification performance than the binomial method via multiple analyses, including computational simulations, Area Under Curve (AUC) analyses, and improved consistencies across biological replicates. This method is especially advantageous in the analyses of sparsely methylated genomes with low coverage.

Conclusions

Our method improves the existing binomial method for binary methylation calls by utilizing a posterior odds framework and incorporating local methylation information. This method should be widely applicable to the analyses of methylC-seq data from diverse sparsely methylated genomes. Bis-Class and example data are provided at a dedicated website (http://bibs.snu.ac.kr/software/Bisclass).

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-608) contains supplementary material, which is available to authorized users.     

Riboflavin as an independent and accurate biomarker for adherence in a randomized double-blind and placebo-controlled clinical trial

Background: Medication adherence is critical for success of clinical trials.

Objective: To assess oral riboflavin is an adherence marker.

Methods: Riboflavin was incorporated into active treatment and placebo pills for a clinical trial lasting for 2 years.

Results: The accuracy (area under the receiver operating curve) of urinary riboflavin was 0.91 as a binary classifier of adherence, and was similar or better than for two active study ingredients daidzein (0.92) and genistein (0.87) (all p?<?0.0001). Decreased adherence over time was similar in the two study groups.

Conclusion: Riboflavin is an accurate and useful biomarker for study pill ingestion.     

Starvation Driven Diffusion as a Survival Strategy of Biological Organisms

The purpose of this article is to introduce a diffusion model for biological organisms that increase their motility when food or other resource is insufficient. It is shown in this paper that Fick’s diffusion law does not explain such a starvation driven diffusion correctly. The diffusion model for nonuniform Brownian motion in Kim (Einstein’s random walk and thermal diffusion, preprint http://amath.kaist.ac.kr/papers/Kim/31.pdf, 2013) is employed in this paper and a Fokker–Planck type diffusion law is obtained. Lotka–Volterra type competition systems with spatial heterogeneity are tested, where one species follows the starvation driven diffusion and the other follows the linear diffusion. In heterogeneous environments, the starvation driven diffusion turns out to be a better survival strategy than the linear one. Various issues such as the global asymptotic stability, convergence to an ideal free distribution, the extinction and coexistence of competing species are discussed.     

A method for comparing multiple bacterial community structures from 16S rDNA clone library sequences

Culture-independent approaches, based on 16S rDNA sequences, are extensively used in modern microbial ecology. Sequencing of the clone library generated from environmental DNA has advantages over fingerprint-based methods, such as denaturing gradient gel electrophoresis, as it provides precise identification and quantification of the phylotypes present in samples. However, to date, no method exists for comparing multiple bacterial community structures using clone library sequences. In this study, an automated method to achieve this has been developed, by applying pair wise alignment, hierarchical clustering and principle component analysis. The method has been demonstrated to be successful in comparing samples from various environments. The program, named CommCluster, was written in JAVA, and is now freely available, at http://chunlab.snu.ac.kr/commcluster/.     

ModuleSearch: finding functional modules in a protein–protein interaction network

Many biological processes are performed by a group of proteins rather than by individual proteins. Proteins involved in the same biological process often form a densely connected sub-graph in a protein–protein interaction network. Therefore, finding a dense sub-graph provides useful information to predict the function or protein complex of uncharacterised proteins in the sub-graph. We developed a heuristic algorithm that finds functional modules in a protein–protein interaction network and visualises the modules. The algorithm has been implemented in a platform-independent, standalone program called ModuleSearch. In an interaction network of yeast proteins, ModuleSearch found 366 overlapping modules. Of the modules, 71% have a function shared by more than half the proteins in the module and 58% have a function shared by all proteins in the module. Comparison of ModuleSearch with other programs shows that ModuleSearch finds more sub-graphs than most other programs, yet a higher proportion of the sub-graphs correspond to known functional modules. ModuleSearch and sample data are freely available to academics at http://bclab.inha.ac.kr/ModuleSearch.     

InfarctSizer: computing infarct volume from brain images of a stroke animal model

Many computational methods for determining the infarct volume from the image of 2,3,5-triphenyltetrazolium chloride-stained brain slices rely on the discretion of the user to determine the infarct region by visual inspection. Once the user determines the infarct boundary by visual inspection, the methods compute the area within the boundary with the assumption that all the spots within the boundary have been infarcted at the same level. However, in the same brain image, partially infarcted spots often tend to appear pinkish whereas fully or severely infarcted spots appear white. We developed a program called InfarctSizer, which automatically detects the infarct region and computes the infarct volume proportional to infarction levels. Comparison of InfarctSizer with other methods shows that InfarctSizer computes the infarct volume more accurately and efficiently than other methods. InfarctSizer and sample brain images are available at http://wilab.inha.ac.kr/brainimage.     

Lipoprotein-associated phospholipase A2, and subsequent cardiovascular events and mortality among patients with coronary heart disease

Objective: The objective of this study is to evaluate the relevance of Lp-PLA₂ to risk prediction among coronary heart disease (CHD) patients.

Methods: Lp-PLA₂ activity was measured in 2538 CHD patients included in the Bezafibrate Infarction Prevention (BIP) study.

Results: Adjusting for patient characteristics and traditional risk factors, 1 standard deviation of Lp-PLA₂ was associated with a hazard ratio (HR) of 1.12 (95% confidence interval (CI): 1.00–1.25) for mortality and 1.03 (0.93–1.14) for cardiovascular events. Lp-PLA₂ did not significantly improve model discrimination, or calibration nor result in noteworthy reclassification.

Conclusions: Our results do not support added value of Lp-PLA₂ for predicting cardiovascular events or mortality among CHD patients beyond traditional risk factor.     

Pregnancy associated plasma protein-A as a prognostic biomarker of all-cause mortality and cardiovascular events in patients presenting with chest pain: a systematic review

Aim: Novel biomarkers have been proposed for identification of patients at greater risk of future adverse events among those presenting with chest pain. In this review, we aim to elucidate the ability of pregnancy associated plasma protein-A (PAPP-A) to predict mortality and other cardiovascular events in this patient population.

Methods: A literature search of the electronic databases Medline, Scopus, Cochrane Library and ClinicalTrials.gov was performed in order to identify studies investigating the utility of PAPP-A to predict mortality and adverse cardiovascular events in patients with chest pain.

Results: Eight studies met our inclusion criteria. Five of these studies pertained to patients with confirmed ischemic chest pain, while the rest included patients presenting with chest pain possibly due to acute coronary syndrome, irrespectively of the underlying cause. Although the results for long-term events were inconclusive in both groups of patients, higher PAPP-A concentrations were found to be a significant predictor of short-term adverse events in patients with confirmed ischemic chest pain.

Conclusions: PAPP-A appears to be a potentially useful biomarker for short-term risk stratification of patients presenting with chest pain of ischemic origin. However, there is an eminent need for more standardized clinical studies investigating the prognostic value of this biomarker.     

BcSNPdb: bovine coding region single nucleotide polymorphisms located proximal to quantitative trait loci

Bovine coding region single nucleotide polymorphisms located proximal to quantitative trait loci were identified to facilitate bovine QTL fine mapping research. A total of 692,763 bovine SNPs was extracted from 39,432 UniGene clusters, and 53,446 candidate SNPs were found to be a depth >3. In order to validate the in silico SNPs experimentally, 186 animals representing 14 breeds and 100 mixed breeds were analyzed. Genotyping of 40 randomly selected candidate SNPs revealed that 43% of these SNPs ranged in frequency from 0.009 to 0.498. To identify non-synonymous SNPs and to correct for possible frameshift errors in the ESTs at the predicted SNP positions, we designed a program that determines coding regions by protein-sequence referencing, and identified 17,735 nsSNPs. The SNPs and bovine quantitative traits loci informations were integrated into a bovine SNP data: BcSNPdb (http://snugenome.snu.ac.kr/BtcSNP/). Currently there are 43 different kinds of quantitative traits available. Thus, these SNPs would serve as valuable resources for exploiting genomic variation that influence economically and agriculturally important traits in cows.     

Soluble CD40 ligand in haemodialysis patients: survival impact and cardiovascular prognostic role

Context: Soluble CD40 ligand (sCD40l) can predict cardiovascular events (CVE) and mortality in haemodialysis (HD) patients (short-, medium-term follow-up studies).

Objective: To evaluate the relationship between sCD40l and survival, CVE and mortality in HD patients on long-term follow-up.

Methods: We registered 46?HD patients’ baseline characteristics, mortality and CVE for 108 months.

Results: SCD40l correlated positively with C-reactive protein, was higher in survivors, but had no impact on survival and was not predictive for CVE or CV mortality.

Conclusion: The levels of sCD40l have no influence on survival or CVE and mortality in HD patients in a long-term follow-up.     

GPS tracking reveals rafting behaviour of Northern Gannets (Morus bassanus): implications for foraging ecology and conservation

Capsule Three quarters of tracked Northern Gannets (Morus bassanus) at Grassholm gathered in rafts around the colony, concentrated within a recently designated at-sea Special Protection Area (SPA), but rafting was not correlated with foraging effort.

Aims To investigate the incidence, distribution and foraging implications of Northern Gannet rafting behaviour in waters adjacent to a large colony.

Methods Using bird-borne global positioning system (GPS) loggers we reconstructed at-sea movement and used a speed filter to identify rafting behaviour within 10?km of the colony. We mapped the spatial distribution of rafting events from 160 breeding individuals over 5 years, and investigated the relationship between foraging effort (trip duration and total distance travelled) and the presence/absence of rafting.

Results On average, 74% of tracked birds engaged in rafting. Of the 381 foraging trips analysed, rafting was recorded on 237 (62%). Birds were more likely to raft on outbound (224 trips, 59%), than inbound journeys (38 trips, 10%). Presence/absence of rafting did not correlate significantly with foraging trip distance or duration nor with duration of nest attendance. The majority of rafting was concentrated in a 2-km radius around the colony within a recently designated seaward SPA extension. Birds showed low individual repeatability in rafting, although there was lower variation within, than among, individuals.

Conclusion Our results show that rafting is important for breeding gannets on Grassholm, and a recently designated at-sea SPA encapsulates the core distribution of rafting. Rafting did not appear to be correlated with foraging behaviour. Given the dearth of literature on rafting and the wealth of GPS tracking data for seabirds, we suggest that similar research be conducted elsewhere to further elucidate the ecological and applied significance of this behaviour.     

Early signatures of bleeding and mortality in patients on left ventricular assist device support: novel methods for personalized risk-stratification

Background: Left ventricular assist devices (LVADs) provide support for patients with end-stage heart failure. The aims of this study were to determine whether baseline analysis and early trends in routine laboratory data, platelet activity, and thromboinflammatory biomarkers following LVAD implantation reveal trends that predict personalized risks of one-year gastrointestinal (GI) bleeding, stroke, pump thrombosis, drive-line infections and mortality in patients on LVAD support.

Methods: We performed an observational study at the University of Kentucky with 61 participants who underwent first-time LVAD implantation. Blood was collected at baseline and post-op days 0, 1, 3 and 6 as well as clinical follow-up. Demographics, clinical characteristics, one-year adverse events and routine laboratory data were collected from electronic medical records. Platelet function and plasma biomarkers were profiled.

Results: Evaluation of routine laboratory results revealed that sustained thrombocytopenia and increased mean platelet volume (MPV) were associated with development of GI bleeding and mortality. Platelet function at follow-up visit predicted one-year bleeding events. Thrombotic biomarker sCD40L strongly predicted one-year GI bleeding at baseline before implantation and within the first week following LVAD implant.

Conclusions: Early trends in routine bloodwork and platelet function may serve as novel signatures of patients at risk to experience adverse events.