q-bio.GN

arXiv:2405.05734v2 Announce Type: replace Abstract: Repeat content and heterozygosity rate of the target genome are crucial factors in determining the ability to generate a complete telomere-to-telomere assembly. The mathematical relationship between the required coverage and read length for the purpose of unique reconstruction remains unexplored for diploid genomes. We investigate the information-theoretic conditions that the given set of sequencing reads must satisfy to achieve the complete reconstruction of the true sequence of a diploid genome. We also analyze the standard greedy and de-Bruijn graph-based assembly algorithms. Our results show that the coverage and read length requirements of the assembly algorithms are considerably higher than the lower bound because both algorithms require the double repeats in the genome to be bridged. Finally, we derive the necessary conditions for the overlap graph-based assembly paradigm.

arXiv:2501.06805v1 Announce Type: new Abstract: Accurately identifying cancer samples is crucial for precise diagnosis and effective patient treatment. Traditional methods falter with high-dimensional and high feature-to-sample count ratios, which are critical for classifying cancer samples. This study aims to develop a novel feature selection framework specifically for transcriptome data and propose two ensemble classifiers. For feature selection, we partition the transcriptome dataset vertically based on feature types. Then apply the Boruta feature selection process on each of the partitions, combine the results, and apply Boruta again on the combined result. We repeat the process with different parameters of Boruta and prepare the final feature set. Finally, we constructed two ensemble ML models based on LR, SVM and XGBoost classifiers with max voting and averaging probability approach. We used 10-fold cross-validation to ensure robust and reliable classification performance. With 97.11\% accuracy and 0.9996 AUC value, our approach performs better compared to existing state-of-the-art methods to classify 33 types of cancers. A set of 12 types of cancer is traditionally challenging to differentiate between each other due to their similarity in tissue of origin. Our method accurately identifies over 90\% of samples from these 12 types of cancers, which outperforms all known methods presented in existing literature. The gene set enrichment analysis reveals that our framework's selected features have enriched the pathways highly related to cancers. This study develops a feature selection framework to select features highly related to cancer development and leads to identifying different types of cancer samples with higher accuracy.

arXiv:2412.07051v2 Announce Type: replace-cross Abstract: Classifying genome sequences based on metadata has been an active area of research in comparative genomics for decades with many important applications across the life sciences. Established methods for classifying genomes can be broadly grouped into sequence alignment-based and alignment-free models. Conventional alignment-based models rely on genome similarity measures calculated based on local sequence alignments or consistent ordering among sequences. However, such methods are computationally expensive when dealing with large ensembles of even moderately sized genomes. In contrast, alignment-free (AF) approaches measure genome similarity based on summary statistics in an unsupervised setting and are efficient enough to analyze large datasets. However, both alignment-based and AF methods typically assume fixed scoring rubrics that lack the flexibility to assign varying importance to different parts of the sequences based on prior knowledge. In this study, we integrate AI and network science approaches to develop a comparative genomic analysis framework that addresses these limitations. Our approach, termed the Genome Misclassification Network Analysis (GMNA), simultaneously leverages misclassified instances, a learned scoring rubric, and label information to classify genomes based on associated metadata and better understand potential drivers of misclassification. We evaluate the utility of the GMNA using Naive Bayes and convolutional neural network models, supplemented by additional experiments with transformer-based models, to construct SARS-CoV-2 sampling location classifiers using over 500,000 viral genome sequences and study the resulting network of misclassifications. We demonstrate the global health potential of the GMNA by leveraging the SARS-CoV-2 genome misclassification networks to investigate the role human mobility played in structuring geographic clustering of SARS-CoV-2.

arXiv:2501.03923v1 Announce Type: cross Abstract: Neurodegenerative diseases (NDDs) are complex and lack effective treatment due to their poorly understood mechanism. The increasingly used data analysis from Single nucleus RNA Sequencing (snRNA-seq) allows to explore transcriptomic events at a single cell level, yet face challenges in interpreting the mechanisms underlying a disease. On the other hand, Neural Network (NN) models can handle complex data to offer insights but can be seen as black boxes with poor interpretability. In this context, explainable AI (XAI) emerges as a solution that could help to understand disease-associated mechanisms when combined with efficient NN models. However, limited research explores XAI in single-cell data. In this work, we implement a method for identifying disease-related genes and the mechanistic explanation of disease progression based on NN model combined with SHAP. We analyze available Huntington's disease (HD) data to identify both HD-altered genes and mechanisms by adding Gene Set Enrichment Analysis (GSEA) comparing two methods, differential gene expression analysis (DGE) and NN combined with SHAP approach. Our results show that DGE and SHAP approaches offer both common and differential sets of altered genes and pathways, reinforcing the usefulness of XAI methods for a broader perspective of disease.

arXiv:2311.02029v4 Announce Type: replace-cross Abstract: Metagenomics, the study of genome sequences of diverse organisms cohabiting in a shared environment, has experienced significant advancements across various medical and biological fields. Metagenomic analysis is crucial, for instance, in clinical applications such as infectious disease screening and the diagnosis and early detection of diseases such as cancer. A key task in metagenomics is to determine the species present in a sample and their relative abundances. Currently, the field is dominated by either alignment-based tools, which offer high accuracy but are computationally expensive, or alignment-free tools, which are fast but lack the needed accuracy for many applications. In response to this dichotomy, we introduce MetaTrinity, a tool based on heuristics, to achieve a fundamental improvement in accuracy-runtime tradeoff over existing methods. We benchmark MetaTrinity against two leading metagenomic classifiers, each representing different ends of the performance-accuracy spectrum. On one end, Kraken2, a tool optimized for performance, shows modest accuracy yet a rapid runtime. The other end of the spectrum is governed by Metalign, a tool optimized for accuracy. Our evaluations show that MetaTrinity achieves an accuracy comparable to Metalign while gaining a 4x speedup without any loss in accuracy. This directly equates to a fourfold improvement in runtime-accuracy tradeoff. Compared to Kraken2, MetaTrinity requires a 5x longer runtime yet delivers a 17x improvement in accuracy. This demonstrates a 3.4x enhancement in the accuracy-runtime tradeoff for MetaTrinity. This dual comparison positions MetaTrinity as a broadly applicable solution for metagenomic classification, combining advantages of both ends of the spectrum: speed and accuracy. MetaTrinity is publicly available at https://github.com/CMU-SAFARI/MetaTrinity.

arXiv:2501.01462v1 Announce Type: new Abstract: Host-response-based diagnostics can improve the accuracy of diagnosing bacterial and viral infections, thereby reducing inappropriate antibiotic prescriptions. However, the existing cohorts with limited sample size and coarse infections types are unable to support the exploration of an accurate and generalizable diagnostic model. Here, we curate the largest infection host-response transcriptome data, including 11,247 samples across 89 blood transcriptome datasets from 13 countries and 21 platforms. We build a diagnostic model for pathogen prediction starting from a pan-infection model as foundation (AUC = 0.97) based on the pan-infection dataset. Then, we utilize knowledge distillation to efficiently transfer the insights from this "teacher" model to four lightweight pathogen "student" models, i.e., staphylococcal infection (AUC = 0.99), streptococcal infection (AUC = 0.94), HIV infection (AUC = 0.93), and RSV infection (AUC = 0.94), as well as a sepsis "student" model (AUC = 0.99). The proposed knowledge distillation framework not only facilitates the diagnosis of pathogens using pan-infection data, but also enables an across-disease study from pan-infection to sepsis. Moreover, the framework enables high-degree lightweight design of diagnostic models, which is expected to be adaptively deployed in clinical settings.

arXiv:2410.22452v2 Announce Type: replace-cross Abstract: Identifying mutations of SARS-CoV-2 strains associated with their phenotypic changes is critical for pandemic prediction and prevention. We compared an explainable convolutional neural network (CNN) approach and the traditional genome-wide association study (GWAS) on the mutations associated with WHO labels of SARS-CoV-2, a proxy for virulence phenotypes. We trained a CNN classification model that can predict genomic sequences into Variants of Concern (VOCs) and then applied Shapley Additive explanations (SHAP) model to identify mutations that are important for the correct predictions. For comparison, we performed traditional GWAS to identify mutations associated with VOCs. Comparison of the two approaches shows that the explainable neural network approach can more effectively reveal known nucleotide substitutions associated with VOCs, such as those in the spike gene regions. Our results suggest that explainable neural networks for genomic sequences offer a promising alternative to the traditional genome wide analysis approaches.

arXiv:2412.18154v1 Announce Type: cross Abstract: Emerging topics in biomedical research are continuously expanding, providing a wealth of information about genes and their function. This rapid proliferation of knowledge presents unprecedented opportunities for scientific discovery and formidable challenges for researchers striving to keep abreast of the latest advancements. One significant challenge is navigating the vast corpus of literature to extract vital gene-related information, a time-consuming and cumbersome task. To enhance the efficiency of this process, it is crucial to address several key challenges: (1) the overwhelming volume of literature, (2) the complexity of gene functions, and (3) the automated integration and generation. In response, we propose GeneSUM, a two-stage automated gene summary extractor utilizing a large language model (LLM). Our approach retrieves and eliminates redundancy of target gene literature and then fine-tunes the LLM to refine and streamline the summarization process. We conducted extensive experiments to validate the efficacy of our proposed framework. The results demonstrate that LLM significantly enhances the integration of gene-specific information, allowing more efficient decision-making in ongoing research.

arXiv:2412.18156v1 Announce Type: cross Abstract: Large language models (LLMs) have demonstrated remarkable advancements, primarily due to their capabilities in modeling the hidden relationships within text sequences. This innovation presents a unique opportunity in the field of life sciences, where vast collections of single-cell omics data from multiple species provide a foundation for training foundational models. However, the challenge lies in the disparity of data scales across different species, hindering the development of a comprehensive model for interpreting genetic data across diverse organisms. In this study, we propose an innovative hybrid approach that integrates the general knowledge capabilities of LLMs with domain-specific representation models for single-cell omics data interpretation. We begin by focusing on genes as the fundamental unit of representation. Gene representations are initialized using functional descriptions, leveraging the strengths of mature language models such as LLaMA-2. By inputting single-cell gene-level expression data with prompts, we effectively model cellular representations based on the differential expression levels of genes across various species and cell types. In the experiments, we constructed developmental cells from humans and mice, specifically targeting cells that are challenging to annotate. We evaluated our methodology through basic tasks such as cell annotation and visualization analysis. The results demonstrate the efficacy of our approach compared to other methods using LLMs, highlighting significant improvements in accuracy and interoperability. Our hybrid approach enhances the representation of single-cell data and offers a robust framework for future research in cross-species genetic analysis.

arXiv:2411.03871v2 Announce Type: replace Abstract: A common step at the core of many RNA transcript assembly tools is to find a set of weighted paths that best explain the weights of a DAG. While such problems easily become NP-hard, scalable solvers exist only for a basic error-free version of this problem, namely minimally decomposing a network flow into weighted paths. The main result of this paper is to show that we can achieve speedups of two orders of magnitude also for path-finding problems in the realistic setting (i.e., the weights do not induce a flow). We obtain these by employing the safety information that is encoded in the graph structure inside Integer Linear Programming (ILP) solvers for these problems. We first characterize the paths that appear in all path covers of the DAG, generalizing a graph reduction commonly used in the error-free setting (e.g. by Kloster et al. [ALENEX~2018]). Secondly, following the work of Ma, Zheng and Kingsford [RECOMB 2021], we characterize the \emph{sequences} of arcs that appear in all path covers of the DAG. We experiment with a path-finding ILP model (least squares) and with a more recent and accurate one. We use a variety of datasets originally created by Shao and Kingsford [TCBB, 2017], as well as graphs built from sequencing reads by the state-of-the-art tool for long-read transcript discovery, IsoQuant [Prjibelski et al., Nat.~Biotechnology~2023]. The ILPs armed with safe paths or sequences exhibit significant speed-ups over the original ones. On graphs with a large width, average speed-ups are in the range $50-160\times$ in the latter ILP model and in the range $100-1000\times$ in the least squares model. Our scaling techniques apply to any ILP whose solution paths are a path cover of the arcs of the DAG. As such, they can become a scalable building block of practical RNA transcript assembly tools, avoiding heuristic trade-offs currently needed on complex graphs.

arXiv:2406.06969v2 Announce Type: replace-cross Abstract: Background: Understanding cellular diversity throughout the body is essential for elucidating the complex functions of biological systems. Recently, large-scale single-cell omics datasets, known as omics atlases, have become available. These atlases encompass data from diverse tissues and cell-types, providing insights into the landscape of cell-type-specific gene expression. However, the isolated effect of the tissue environment has not been thoroughly investigated. Evaluating this isolated effect is challenging due to statistical confounding with cell-type effects, arising from significant biases in the combinations of tissues and cell-types within the body. Results: This study introduces a novel data analysis framework, named the Combinatorial Sub-dataset Extraction for Confounding Reduction (COSER), which addresses statistical confounding by using graph theory to enumerate appropriate sub-datasets. COSER enables the assessment of isolated effects of discrete variables in single cells. Applying COSER to the Tabula Muris Senis single-cell transcriptome atlas, we characterized the isolated impact of tissue environments. Our findings demonstrate that some of genes are markedly affected by the tissue environment, particularly in modulating intercellular diversity in immune responses and their age-related changes. Conclusion: COSER provides a robust, general-purpose framework for evaluating the isolated effects of discrete variables from large-scale data mining. This approach reveals critical insights into the interplay between tissue environments and gene expression.

arXiv:2410.19236v2 Announce Type: replace Abstract: With the rapid growth of large-scale machine learning models in genomics, Shapley values have emerged as a popular method for model explanations due to their theoretical guarantees. While Shapley values explain model predictions locally for an individual input query sequence, extracting biological knowledge requires global explanation across thousands of input sequences. This demands exponential model evaluations per sequence, resulting in significant computational cost and carbon footprint. Herein, we develop SHAP zero, a method that estimates Shapley values and interactions with a near-zero marginal cost for future queried sequences after paying a one-time fee for model sketching. SHAP zero achieves this by establishing a surprisingly underexplored connection between the Shapley values and interactions and the Fourier transform of the model. Explaining two genomic models, one trained to predict guide RNA binding and the other to predict DNA repair outcome, we demonstrate that SHAP zero achieves orders of magnitude reduction in amortized computational cost compared to state-of-the-art algorithms, revealing almost all predictive motifs -- a finding previously inaccessible due to the combinatorial space of possible interactions.

arXiv:2412.16074v1 Announce Type: new Abstract: DNA data storage is rapidly gaining traction as a long-term data archival solution, primarily due to its exceptional durability. Retrieving stored data relies on DNA sequencing, which involves a process called basecalling -- a typically costly and slow task that uses machine learning to map raw sequencing signals back to individual DNA bases (which are then translated into digital bits to recover the data). Current models for basecalling have been optimized for reading individual bases. However, with the advent of novel DNA synthesis methods tailored for data storage, there is significant potential for optimizing the reading process. In this paper, we focus on Motif-based DNA synthesis, where sequences are constructed from motifs -- groups of bases -- rather than individual bases. To enable efficient reading of data stored in DNA using Motif-based DNA synthesis, we designed Motif Caller, a machine learning model built to detect entire motifs within a DNA sequence, rather than individual bases. Motifs can also be detected from individually identified bases using a basecaller and then searching for motifs, however, such an approach is unnecessarily complex and slow. Building a machine learning model that directly identifies motifs allows to avoid the additional step of searching for motifs. It also makes use of the greater amount of features per motif, thus enabling finding the motifs with higher accuracy. Motif Caller significantly enhances the efficiency and accuracy of data retrieval in DNA storage based on Motif-Based DNA synthesis.