Journal of Bioinformatics and Computational Biology最新文献

{"title":"A dual-level sparsity Bayesian framework for rare-variant association analysis using integrated nested laplace approximation.","authors":"Caixia Li, Bujun Mei","doi":"10.1142/S0219720026500125","DOIUrl":"https://doi.org/10.1142/S0219720026500125","url":null,"abstract":"<p><p><i>Background</i>. Rare genetic variants (minor allele frequency, MAF <1%) carry a substantial share of the unexplained heritability of complex human traits, yet set-based association tests lose power precisely in the regime in which rare variation is most informative - when only a small minority of the variants inside a gene is causal and the aggregate contribution to phenotypic variance is well below one per cent. Burden tests dilute a genuine signal across neutral polymorphisms because they impose a common effect direction, whereas variance-component tests such as the optimal unified sequence kernel association test (SKAT-O) estimate a single dispersion parameter shared by every variant in the set and therefore cannot isolate the few variants that actually drive the association. <i>Methods</i>. We present a Bayesian INLA Model (BIM), a hierarchical Bayesian framework that couples the Integrated Nested Laplace Approximation (INLA) with a <i>dual-level sparsity</i> prior. At the gene level, a bimodal mixture prior on the log-precision of the gene-specific variance component performs explicit model selection between an associated and a null state. At the variant level, a horseshoe prior supplies adaptive, variant-specific shrinkage whose posterior shrinkage factor admits a closed-form characterization, so that individual pathogenic variants escape penalization while neutral effects are driven towards zero. Functional annotations enter as hierarchical covariates that modulate both the location and the scale of the variant-effect prior. Gene-level evidence is summarized by marginal-likelihood Bayes factors and posterior inclusion probabilities, and discoveries are declared by a Bayesian false-discovery-rate (FDR) rule that controls the average local FDR of the selected set. Posterior uncertainty is decomposed into parametric, structural, internal (genotype uncertainty) and external (population structure) components through an explicit application of the law of total variance. <i>Results</i>. Across 100 replicated simulations calibrated on 1000 Genomes Project Phase 3 European haplotypes, BIM attained 75.2% power (95% confidence interval [CI] 69.5-81.0%) to detect causal genes in the most demanding scenario of 0.5% variance explained, against 58.0% for BATI, 38.0% for MiST, 22.0% (95% CI 16.9-27.1%) for SKAT-O and 9.0% (95% CI 5.4-12.6%) for the burden test (paired <i>t</i>-test [Formula: see text] for every pairwise comparison). The realized FDR was 3.8%, below the nominal 5% level, and gene-level posterior inclusion probabilities were well calibrated against the empirical frequency of true association. In a whole-exome sequencing analysis of 500 chronic lymphocytic leukemia (CLL) cases and 1300 ancestry-matched controls, BIM returned a Bayesian FDR 5% discovery set of 12 genes, including the established susceptibility genes <i>BRCA2</i> (Bayes factor, BF [Formula: see text] 50.3) and <i>CHEK2</i> (BF [Formula: see text] 30.1) and the novel c","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":" ","pages":"2650012"},"PeriodicalIF":0.8,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-cycle-interferon coordination changes across proliferative states in TNBC/basal-like breast cancer.","authors":"Fatih Dikbaş","doi":"10.1142/S0219720026500137","DOIUrl":"https://doi.org/10.1142/S0219720026500137","url":null,"abstract":"<p><p>Cohort-wide pathway correlations can hide strong relationships that differ across tumor states. We asked whether this occurs in TNBC/basal-like breast cancer by ordering tumors on prespecified Hallmark pathway axes and comparing pathway correlations in fixed low and high states under complete-family error control. The dominant result was a recurrent proliferation-interferon pattern: three independently replicated relationships showed weaker or reversed cell-cycle/interferon correlation at higher E2F or G2/M state. Two additional, biologically distinct patient relationships also replicated, linking IL-6/JAK/STAT3 state to apoptosis-cholesterol coordination and IFN-gamma state to EMT-IFN-alpha coordination, without implying a shared molecular mechanism. Thirty-two patient relationships survived structural checks and five replicated in the same direction. Cell-line analyses provided complementary constraints: CRISPR tested selective single-gene dependency associations, whereas GDSC tested preclinical drug-response associations. None of 895,224 valid CRISPR axis-gene tests survived global correction, whereas four of 31,610 GDSC axis-drug tests did, on NOTCH, Complement, or Apoptosis axes; three involved MEK1/2 inhibitors. These drug-response associations do not validate the patient correlations, but they motivate prospective testing of pathway states as preclinical stratification variables. Practically, a weak pooled correlation should not be read as no association when a biologically defensible ordering axis exists.</p>","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":"24 4","pages":"2650013"},"PeriodicalIF":0.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anchors for homology-based scaffolding.","authors":"Karl K Käther, Thomas Gatter, Steffen Lemke, Peter F Stadler","doi":"10.1142/S0219720026500101","DOIUrl":"https://doi.org/10.1142/S0219720026500101","url":null,"abstract":"<p><p>Homology-based scaffolding orders contigs based on conserved collinearity of homologous sequences across related species. Existing methods often rely on costly whole-genome alignments or show limited robustness when integrating multiple references. Here, we introduce an anchor-based scaffolding framework that adapts synteny anchors to efficiently infer contig order and orientation relative to one or more reference genomes. Our approach leverages precomputed, sufficiently unique anchors and their respective high-confidence homology matches in a greedy approach, combining single-reference to multi-reference scaffolds using a maximum matching. Across simulated and real datasets, anchor-based scaffolding achieves accuracy comparable to state-of-the-art methods. Notably, the approach shows particular strengths in multi-reference settings. These results demonstrate that synteny-anchor-based scaffolding provides an additional tool for homology-based scaffolding with robust accuracy and superior performance in multi-reference scenarios.</p>","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":"24 4","pages":"2650010"},"PeriodicalIF":0.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When current taxids make historical taxa look new.","authors":"Habib Mahjoubi","doi":"10.1142/S0219720026710046","DOIUrl":"https://doi.org/10.1142/S0219720026710046","url":null,"abstract":"<p><p>A taxon can keep its biological identity while its numeric identifier changes over time. Reconstructing a past taxonomy state by resolving each sequence to its current-day identifier ignores this and can make an already-existing taxon look newly created. Among 56 viral sequences flagged as newly created between two NCBI taxonomy snapshots one year apart, only 17 (30.4%) were genuinely absent from the earlier snapshot; the remaining 39 (69.6%) already existed there under a predecessor identifier later merged into today's. The same mechanism recovers 222-272 identifiers per snapshot across an independently drawn library-wide population of 14,607 identifiers, for 10 of 13 dated snapshots studied (2014-2022). An illustrative classification experiment shows the practical consequence: retagging the 39 artifacts with their period-valid identifier restores correct classification. Since correction relies on identifier-merge history alone, it establishes apparent novelty caused by identifier evolution, not biological novelty. We give five recommendations to avoid this artifact.</p>","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":"24 4","pages":"2671004"},"PeriodicalIF":0.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A scalable pan-genomic pipeline for annotation-free discovery of species-specific markers: Application to <i>Staphylococcus aureus</i>.","authors":"Yuyang Zhou, Jiayi Wang, Junhua Xiao, Yuxun Zhou, Kai Li","doi":"10.1142/S0219720026500095","DOIUrl":"https://doi.org/10.1142/S0219720026500095","url":null,"abstract":"<p><p>Current bioinformatics approaches for bacterial diagnostic target discovery remain constrained by their reliance on gene annotations and fixed-boundary genome segmentation, which overlook unannotated intergenic regions and introduce sequence-truncation artifacts. Here, we developed an open-source, annotation-independent pan-genomic pipeline featuring an overlapping sliding-window algorithm (500-bp window, 100-bp step) and a three-tier subtractive screening funnel. Using <i>Staphylococcus aureus</i> as a model, the pipeline screened 1629 genomes against 852 non-<i>S. aureus Staphylococcus</i> genomes and >20,000 background bacterial genomes. Seven highly conserved, unannotated targets (SA-1-SA-7) were identified, with all seven translated into qPCR primer sets (SAP-1-SAP-7), among which three (SAP-1-SAP-3) were further characterized by <i>in vitro</i> experiments. Multi-layer <i>in silico</i> evaluation demonstrated 100% intraspecific sensitivity and zero cross-reactivity against background genomes, including the <i>S. aureus</i> complex. <i>In vitro</i> testing using crude cell lysates confirmed specific amplification of <i>S. aureus</i> DNA without non-target cross-reactivity, establishing a qualitative limit of detection (LOD) of 10⁵ CFU/mL. Additional computational validation on draft genomes, raw sequencing reads, near-neighbor species, and a clinical truth set corroborated marker robustness under realistic conditions. This framework successfully circumvents conventional gene-centric limitations, providing a generalizable computational strategy for target discovery across other high-priority bacterial pathogens.</p>","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":"24 4","pages":"2650009"},"PeriodicalIF":0.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CNV-ECOD: A copy number variation detection method based on ECOD algorithm using next-generation sequencing data.","authors":"Ranran Sun, Jinxin Dong, Hua Jiang, Ruchao Du, Yuxi Zhang","doi":"10.1142/S0219720026500083","DOIUrl":"https://doi.org/10.1142/S0219720026500083","url":null,"abstract":"<p><p>Copy number variation (CNV), as a major type of DNA structural variations (SVs), plays a key role in causing human diseases and contributing to genetic diversity. Accurate identification of CNVs is significant for disease mechanism analysis, personalized diagnosis and treatment, and drug development. Although next-generation sequencing (NGS) technology has greatly promoted the development of CNV detection methods, the existing methods generally have problems such as high false positives and inaccurate boundaries. Therefore, a new method is proposed for detecting CNVs in a single sample of NGS data, called CNV-ECOD. The method first employs the empirical-cumulative-distribution-based outlier detection (ECOD) algorithm to identify abnormal signals of read depth (RD) for preliminary detection of CNVs. To correct false positives and refine CNV boundaries further, it integrates paired-end mapping (PEM) and split read (SR) strategies. The integration of the RD-PEM-SR hierarchical progressive framework and the anomaly scoring mechanism based on ECOD can effectively improve the accuracy of CNV detection. Comparing our approach to four peer methods, simulation results demonstrate that it achieves the best balance between precision and sensitivity. Also, the proposed method has the best <i>F</i>1-scores and the highest overlap density scores (ODSs) in real-sample experiments. Therefore, CNV-ECOD is expected to develop into an efficient and robust CNV detection tool.</p>","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":"24 3","pages":"2650008"},"PeriodicalIF":0.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative benchmarking of template-based, evolutionary-diffusion, and generative language models for IsPETase structure prediction.","authors":"Berkay Orçun Yener, Şurhan Göl, Bora Kutlu, Özgür Öztürk","doi":"10.1142/S0219720026510029","DOIUrl":"https://doi.org/10.1142/S0219720026510029","url":null,"abstract":"<p><p>Accurate protein structure prediction is critical for rational enzyme engineering, which requires high-fidelity models. This study benchmarks three distinct structure prediction paradigms against the experimental crystal structure of IsPETase, serving as a diagnostic case study. The evaluated approaches include classical homology modeling (SWISS-MODEL), MSA-conditioned diffusion (AlphaFold 3), and generative language modeling (ESM-3). Predicted models were evaluated using stereochemical validation, molecular docking with a PET dimer analogue, and molecular dynamics simulations. While all approaches reproduced the overall fold and preserved the catalytic triad geometry, notable differences were observed in atomic clashes and hydrogen bonding patterns. ESM-3 showed elevated steric clashes and reduced hydrogen bond counts. Molecular dynamics indicated that the experimental structure maintained the highest stability, with SWISS-MODEL closely following, while ESM-3 displayed greater fluctuations, particularly in loop regions. Crucially, blind docking simulations revealed that the ESM-3 active site was sterically occluded, rendering it inaccessible to the PET dimer. This inaccessibility persisted even after targeted energy minimization. These findings suggest that while generative language models represent a powerful capability for rapid scaffold exploration, they do not yet achieve the thermodynamic precision of established homology and evolutionary approaches required for functional active site engineering.</p>","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":"24 3","pages":"2651002"},"PeriodicalIF":0.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum - DDINet: Drug-drug interaction prediction network based on multi-molecular fingerprint features and multi-head attention centered weighted autoencoder.","authors":"K Soni Sharmila, S Thanga Revathi, Pokkuluri Kiran Sree","doi":"10.1142/S0219720026920022","DOIUrl":"10.1142/S0219720026920022","url":null,"abstract":"","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":" ","pages":"2692002"},"PeriodicalIF":0.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148200686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trap spaces as labelled ideals of SCC posets: A structural-functional theory of reachability in asynchronous boolean networks.","authors":"Belayneh Yibeltal Yizengaw","doi":"10.1142/S0219720026500071","DOIUrl":"https://doi.org/10.1142/S0219720026500071","url":null,"abstract":"<p><p>Boolean networks provide a qualitative framework for modelling regulatory systems when kinetic parameters are unavailable, with cellular phenotypes represented as attractors of the induced dynamics [J. D. Schwab <i>et al.</i>, Concepts in Boolean network modeling, <i>Comput. Struct. Biotechnol. J.</i> <b>18</b>:571-582, 2020]. A central challenge is <i>phenotypic reachability</i>: determining whether asynchronous dynamics can connect invariant regions of the state space, a problem that becomes computationally intractable in large networks [L. Cifuentes-Fontanals, M. Noual, and E. Remy, Revisiting trap spaces in Boolean networks, <i>Theor. Comput. Sci.</i> <b>915</b>:1-20, 2022; K. Perrot and C. Paulevé, Complexity of asynchronous reachability in Boolean networks, <i>Theor. Comput. Sci.</i> <b>1000</b>:114650, 2024.]. We develop a structural theory of reachability in which trap spaces are identified with labelled order ideals of SCC-posets. The SCC-poset determines the order of commitment events, while admissible evaluations encode branching within regulatory modules, so that multistability appears as an intrinsic feature of the theory. Within this framework, we establish necessary and sufficient conditions for reachability, introduce the commitment depth, and show that deciding non-trivial branching is computationally intractable. We further demonstrate that effective interaction structure is jointly determined by topology and Boolean logic. We validate the framework on a Boolean model of CD4[Formula: see text] T-cell differentiation, where refinement chains recover the observed ordering of cytokine response, lineage commitment, and phenotypic branching. In the absence of multistability the structure collapses to a distributive lattice, a non-generic limiting regime.</p>","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":"24 3","pages":"2650007"},"PeriodicalIF":0.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148297062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When pipelines run but coordinates fail: A simple spatial specificity check for false locality in post-GWAS analysis.","authors":"Zheng Han, Hongcheng Zhu, Changzai Li","doi":"10.1142/S0219720026710034","DOIUrl":"https://doi.org/10.1142/S0219720026710034","url":null,"abstract":"<p><p>Some post-GWAS analysis software can run to completion without reporting an error while producing results that are not biologically valid. We call this failure false locality: a result appears to be local to a gene or protein because it was produced from a regional window, but the window or its metadata points to the wrong genomic address. We identify three mechanisms. First, a genome-build address mismatch occurs when GRCh38 protein-QTL coordinates are used with GRCh37 outcome files; in our 91-sentinel audit, 66 coordinates moved by more than 100[Formula: see text]kb and 54 moved by more than 200[Formula: see text]kb after remapping. Second, non-specific regional noise occurs when significant <i>P</i> values persist after the analysis window is deliberately moved to a zero-overlap variant set. Third, location-label blindness occurs when software returns the same output after the declared coordinate label is changed while the SNP table is unchanged; in an official SMR/HEIDI CXCL10 test, the top SNP, SMR <i>P</i> value, and HEIDI <i>P</i> value remained identical across correct, wrong, and shifted labels. We propose a simple Change Test: a result should not be treated as local evidence unless the numerical output changes, weakens, or disappears when the analysis window or coordinate label is intentionally moved to a biologically wrong location. This standard turns software execution from a passive success signal into an explicit spatial-specificity check.</p>","PeriodicalId":48910,"journal":{"name":"Journal of Bioinformatics and Computational Biology","volume":"24 3","pages":"2671003"},"PeriodicalIF":0.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148297026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}