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Abstract Background Analysis of expression quantitative trait loci (eQTL) aims to identify the genetic loci associated with the expression level of genes. Penalized regression with a proper penalty is suitable for the high-dimensional biological data. Its performance should be enhanced when we incorporate biological knowledge of gene expression network and linkage disequilibrium (LD) structure between loci in high-noise background. Results We propose a network-based group variable selection (NGVS) method for QTL detection. Our method simultaneously maps highly correlated expression traits sharing the same biological function to marker sets formed by LD. By grouping markers, complex joint activity of multiple SNPs can be considered and the dimensionality of eQTL problem is reduced dramatically. In order to demonstrate the power and flexibility of our method, we used it to analyze two simulations and a mouse obesity and diabetes dataset. We considered the gene co-expression network, grouped markers into marker sets and treated the additive and dominant effect of each locus as a group: as a consequence, we were able to replicate results previously obtained on the mouse linkage dataset. Furthermore, we observed several possible sex-dependent loci and interactions of multiple SNPs. Conclusions The proposed NGVS method is appropriate for problems with high-dimensional data and high-noise background. On eQTL problem it outperforms the classical Lasso method, which does not consider biological knowledge. Introduction of proper gene expression and loci correlation information makes detecting causal markers more accurate. With reasonable model settings, NGVS can lead to novel biological findings. more...

Abstract Background Alternative splicing expands transcriptome diversity and plays an important role in regulation of gene expression. Previous studies focus on the regulation of a single cassette exon, but recent experiments indicate that multiple cassette exons within a gene may interact with each other. This interaction can increase the potential to generate various transcripts and adds an extra layer of complexity to gene regulation. Several cases of exon interaction have been discovered. However, the extent to which the cassette exons coordinate with each other remains unknown. Results Based on EST data, we employed a metric of correlation coefficients to describe the interaction between two adjacent cassette exons and then categorized these exon pairs into three different groups by their interaction (correlation) patterns. Sequence analysis demonstrates that strongly-correlated groups are more conserved and contain a higher proportion of pairs with reading frame preservation in a combinatorial manner. Multiple genome comparison further indicates that different groups of correlated pairs have different evolutionary courses: (1) The vast majority of positively-correlated pairs are old, (2) most of the weakly-correlated pairs are relatively young, and (3) negatively-correlated pairs are a mixture of old and young events. Conclusion We performed a large-scale analysis of interactions between adjacent cassette exons. Compared with weakly-correlated pairs, the strongly-correlated pairs, including both the positively and negatively correlated ones, show more evidence that they are under delicate splicing control and tend to be functionally important. Additionally, the positively-correlated pairs bear strong resemblance to constitutive exons, which suggests that they may evolve from ancient constitutive exons, while negatively and weakly correlated pairs are more likely to contain newly emerging exons. more...

Abstract Background MicroRNAs (miRNAs) are a class of endogenous regulatory small RNAs which play an important role in posttranscriptional regulations by targeting mRNAs for cleavage or translational repression. The base-pairing between the 5'-end of miRNA and the target mRNA 3'-UTRs is essential for the miRNA:mRNA recognition. Recent studies show that many seed matches in 3'-UTRs, which are fully complementary to miRNA 5'-ends, are highly conserved. Based on these features, a two-stage strategy can be implemented to achieve the de novo identification of miRNAs by requiring the complete base-pairing between the 5'-end of miRNA candidates and the potential seed matches in 3'-UTRs. Results We presented a new method, which combined multiple pairwise conservation information, to identify the frequently-occurred and conserved 7-mers in 3'-UTRs. A pairwise conservation score (PCS) was introduced to describe the conservation of all 7-mers in 3'-UTRs between any two Drosophila species. Using PCSs computed from 6 pairs of flies, we developed a support vector machine (SVM) classifier ensemble, named Cons-SVM and identified 689 conserved 7-mers including 63 seed matches covering 32 out of 38 known miRNA families in the reference dataset. In the second stage, we searched for 90 nt conserved stem-loop regions containing the complementary sequences to the identified 7-mers and used the previously published miRNA prediction software to analyze these stem-loops. We predicted 47 miRNA candidates in the genome-wide screen. Conclusion Cons-SVM takes advantage of the independent evolutionary information from the 6 pairs of flies and shows high sensitivity in identifying seed matches in 3'-UTRs. Combining the multiple pairwise conservation information by the machine learning approach, we finally identified 47 miRNA candidates in D. melanogaster. more...

Abstract Background Like microarray-based investigations, high-throughput proteomics techniques require machine learning algorithms to identify biomarkers that are informative for biological classification problems. Feature selection and classification algorithms need to be robust to noise and outliers in the data. Results We developed a recursive support vector machine (R-SVM) algorithm to select important genes/biomarkers for the classification of noisy data. We compared its performance to a similar, state-of-the-art method (SVM recursive feature elimination or SVM-RFE), paying special attention to the ability of recovering the true informative genes/biomarkers and the robustness to outliers in the data. Simulation experiments show that a 5 %-~20 % improvement over SVM-RFE can be achieved regard to these properties. The SVM-based methods are also compared with a conventional univariate method and their respective strengths and weaknesses are discussed. R-SVM was applied to two sets of SELDI-TOF-MS proteomics data, one from a human breast cancer study and the other from a study on rat liver cirrhosis. Important biomarkers found by the algorithm were validated by follow-up biological experiments. Conclusion The proposed R-SVM method is suitable for analyzing noisy high-throughput proteomics and microarray data and it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features. The multivariate SVM-based method outperforms the univariate method in the classification performance, but univariate methods can reveal more of the differentially expressed features especially when there are correlations between the features. more...

Abstract Background MicroRNAs (miRNAs) are a group of short (~22 nt) non-coding RNAs that play important regulatory roles. MiRNA precursors (pre-miRNAs) are characterized by their hairpin structures. However, a large amount of similar hairpins can be folded in many genomes. Almost all current methods for computational prediction of miRNAs use comparative genomic approaches to identify putative pre-miRNAs from candidate hairpins. Ab initio method for distinguishing pre-miRNAs from sequence segments with pre-miRNA-like hairpin structures is lacking. Being able to classify real vs. pseudo pre-miRNAs is important both for understanding of the nature of miRNAs and for developing ab initio prediction methods that can discovery new miRNAs without known homology. Results A set of novel features of local contiguous structure-sequence information is proposed for distinguishing the hairpins of real pre-miRNAs and pseudo pre-miRNAs. Support vector machine (SVM) is applied on these features to classify real vs. pseudo pre-miRNAs, achieving about 90% accuracy on human data. Remarkably, the SVM classifier built on human data can correctly identify up to 90% of the pre-miRNAs from other species, including plants and virus, without utilizing any comparative genomics information. Conclusion The local structure-sequence features reflect discriminative and conserved characteristics of miRNAs, and the successful ab initio classification of real and pseudo pre-miRNAs opens a new approach for discovering new miRNAs. more...

Abstract Background There is recently great interest in haplotype block structure and haplotype tagging SNPs (htSNPs) in the human genome for its implication on htSNPs-based association mapping strategy for complex disease. Different definitions have been used to characterize the haplotype block structure in the human genome, and several different performance criteria and algorithms have been suggested on htSNPs selection. Results A heuristic algorithm, generalized branch-and-bound algorithm, is applied to the searching of minimal set of haplotype tagging SNPs (htSNPs) according to different htSNPs performance criteria. We develop a software htSNPer1.0 to implement the algorithm, and integrate three htSNPs performance criteria and four haplotype block definitions for haplotype block partitioning. It is a software with powerful Graphical User Interface (GUI), which can be used to characterize the haplotype block structure and select htSNPs in the candidate gene or interested genomic regions. It can find the global optimization with only a fraction of the computing time consumed by exhaustive searching algorithm. Conclusion htSNPer1.0 allows molecular geneticists to perform haplotype block analysis and htSNPs selection using different definitions and performance criteria. The software is a powerful tool for those focusing on association mapping based on strategy of haplotype block and htSNPs. more...

Machine learning (ML) and Natural Language Processing (NLP) have achieved remarkable success in many fields and have brought new opportunities and high expectation in the analyses of medical data, of which the most common type is the massive free-text electronic medical records (EMR). However, the free EMR texts are lacking consistent standards, rich of private information, and limited in availability. Also, it is often hard to have a balanced number of samples for the types of diseases under study. These problems hinder the development of ML and NLP methods for EMR data analysis. To tackle these problems, we developed a model called Medical Text Generative Adversarial Network or mtGAN, to generate synthetic EMR text. It is based on the GAN framework and is trained by the REINFORCE algorithm. It takes disease tags as inputs and generates synthetic texts as EMRs for the corresponding diseases. We evaluate the model from micro-level, macro-level and application-level on a Chinese EMR text dataset. The results show that the method has a good capacity to fit real data and can generate realistic and diverse EMR samples. This provides a novel way to avoid potential leakage of patient privacy while still supply sufficient well-controlled cohort data for developing downstream ML and NLP methods. [ABSTRACT FROM AUTHOR] more...

The development of gastritis is associated with an increased risk of gastric cancer. Current invasive gastritis diagnostic methods are not suitable for monitoring progress. In this work based on 78 gastritis patients and 50 healthy individuals, we observed that the variation of tongue-coating microbiota was associated with the occurrence and development of gastritis. Twenty-one microbial species were identified for differentiating tongue-coating microbiomes of gastritis and healthy individuals. Pathways such as microbial metabolism in diverse environments, biosynthesis of antibiotics and bacterial chemotaxis were up-regulated in gastritis patients. The abundance of Campylobacter concisus was found associated with the gastric precancerous cascade. Furthermore, Campylobacter concisus could be detected in tongue coating and gastric fluid in a validation cohort containing 38 gastritis patients. These observations provided biological evidence of tongue diagnosis in traditional Chinese medicine, and indicated that tongue-coating microbiome could be a potential non-invasive biomarker, which might be suitable for long-term monitoring of gastritis. [ABSTRACT FROM AUTHOR] more...

Background: Reproducibility is a defining feature of a scientific discovery. Reproducibility can be at different levels for different types of study. The purpose of the Human Cell Atlas (HCA) project is to build maps of molecular signatures of all human cell types and states to serve as references for future discoveries. Constructing such a complex reference atlas must involve the assembly and aggregation of data from multiple labs, probably generated with different technologies. It has much higher requirements on reproducibility than individual research projects. To add another layer of complexity, the bioinformatics procedures involved for single-cell data have high flexibility and diversity. There are many factors in the processing and analysis of single-cell RNA-seq data that can shape the final results in different ways. Methods: To study what levels of reproducibility can be reached in current practices, we conducted a detailed reproduction study for a well-documented recent publication on the atlas of human blood dendritic cells as an example to break down the bioinformatics steps and factors that are crucial for the reproducibility at different levels. Results: We found that the major scientific discovery can be well reproduced after some efforts, but there are also some differences in some details that may cause uncertainty in the future reference. This study provides a detailed case observation on the on-going discussions of the type of standards the HCA community should take when releasing data and publications to guarantee the reproducibility and reliability of the future atlas. Conclusion: Current practices of releasing data and publications may not be adequate to guarantee the reproducibility of HCA. We propose building more stringent guidelines and standards on the information that needs to be provided along with publications for projects that evolved in the HCA program. [ABSTRACT FROM AUTHOR] more...

Atrial fibrillation significantly impacts individual health, public wellness, and healthcare expenditure. The primary tool for its detection is the Electrocardiograph (ECG), a non-invasive test that generates abundant data requiring expert human analysis. This task becomes exceedingly complex when interpreting ECG signals with cyclical patterns, fluctuating lengths, and vulnerability to noise. Despite these challenges, there exists a significant gap in the research focusing on further differentiating persistent and paroxysmal atrial fibrillation, a task akin to multi-class discrimination, and pinpointing the exact start and end of abnormal episodes, a process central to localization. We present the Multi-level Multi-task Attention-based Recurrent Neural Network (MMA-RNN), a solution founded on a hierarchical structure that leverages Bidirectional Long and Short-Term Memory Networks (Bi-LSTM) and attention layers to discern three-level sequential features. This framework enhances information synergy and reduces error accumulation by deploying a multi-head classifier that concurrently tackles both previously mentioned critical tasks, facilitating a more streamlined and accurate analysis. We affirm the proficiency of our model through rigorous testing on the CPSC 2021 dataset, where it achieved 0.9437 out of 1 in discrimination and 1.3538 out of 1.6479 in localization. Our method also exhibited superior performance in line with official evaluation benchmarks. Our innovative algorithm holds the potential for real-time AF monitoring through wearable technology, promoting proactive healthcare and early intervention. [ABSTRACT FROM AUTHOR] more...