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Support vector machines for separation of mixed plant-pathogen EST collections based on codon usage.

MOTIVATION: Discovery of host and pathogen genes expressed at the plant-pathogen interface often requires the construction of mixed libraries that contain sequences from both genomes. Sequence identification requires high-throughput and reliable classification of genome origin. When using single-pass cDNA sequences difficulties arise from the short sequence length, the lack of sufficient taxonomically relevant sequence data in public databases and ambiguous sequence homology between plant and pathogen genes. RESULTS: A novel method is described, which is independent of the availability of homologous genes and relies on subtle differences in codon usage between plant and fungal genes. We used support vector machines (SVMs) to identify the probable origin of sequences. SVMs were compared to several other machine learning techniques and to a probabilistic algorithm (PF-IND) for expressed sequence tag (EST) classification also based on codon bias differences. Our software (Eclat) has achieved a classification accuracy of 93.1% on a test set of 3217 EST sequences from Hordeum vulgare and Blumeria graminis, which is a significant improvement compared to PF-IND (prediction accuracy of 81.2% on the same test set). EST sequences with at least 50 nt of coding sequence can be classified using Eclat with high confidence. Eclat allows training of classifiers for any host-pathogen combination for which there are sufficient classified training sequences. AVAILABILITY: Eclat is freely available on the Internet (http://mips.gsf.de/proj/est) or on request as a standalone version. CONTACT: friedel@informatik.uni-muenchen.de.

Algorithms↗

Proteomic-based biomarker discovery reveals panels of diagnostic biomarkers for early identification of heart failure subtypes.

BACKGROUND: Limited access to echocardiography can delay the diagnosis of suspected heart failure (HF), which in turn postpones the initiation of optimal guideline-directed medical therapy. Although natriuretic peptides like B-type natriuretic peptide (BNP) are valuable biomarkers for diagnosing and managing HF, the utility of combining BNP with other blood-based biomarkers to predict subtypes of new-onset HF remains underexplored. OBJECTIVES: This study sought to investigate and evaluate the diagnostic significance of adding blood-based biomarkers to BNP for identifying heart failure with preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF), with the goal of enhancing diagnostic assays beyond BNP measurements. METHODS: We identified candidate blood protein biomarkers using untargeted proteomics workflows from a cohort of individuals recruited to the STOP-HF trial who were at risk of HF and subsequently developed either HFpEF or HFrEF over time ("HF progressors"; n = 40). Candidate biomarkers were verified in an independent cohort (n = 52) from a community-based rapid access HF diagnostic clinic. The biological processes associated with these proteins were assessed, and the diagnostic values of biomarker panels were evaluated using a machine learning approach. RESULTS: Within HF progressors, we identified 3 proteins associated with HFpEF development: vascular cell adhesion protein 1 (VCAM1), insulin-like growth factor 2 (IGF2), and inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3). Additionally, 4 proteins were linked to HFrEF development: C-reactive protein (CRP), interleukin-6 receptor subunit beta (IL6RB), phosphatidylinositol-glycan-specific phospholipase D (PHLD), and noelin (NOE1). These findings were verified in an independent cohort to distinguish HF subtypes from controls. Moreover, a random forest algorithm demonstrated that combining these candidate biomarkers with BNP measurement significantly improved the prediction of HF subtypes. CONCLUSIONS: We identified candidate proteins linked to HFpEF and HFrEF in a longitudinal HF progressor cohort and validated them in a community-based cohort. Adding these proteins to BNP led to a significant improvement in HF subtype prediction. Study results have clinical implications for blood-based screening of HF subtypes using panels of biomarkers, particularly in resource-limited settings.

Humans↗

Application of causal discovery of factors driving dissolved oxygen in estuarine environments.

Dissolved oxygen (DO) concentrations in estuarine bottom waters are a manifestation of multiple, interacting physical and biogeochemical processes, yet identifying their independent contributions remains challenging. Here, we analyze monthly water quality monitoring data from eight stations across Long Island Sound from 1994 to 2022 using a causal discovery framework (PCMCI+) and transformation of forcing variables. Our goal is to identify and isolate variables that causally influence bottom DO and improve predictive models by minimizing overfitting and multicollinearity. PCMCI+ reveals surface-layer temperature as the most important and consistent negative driver of bottom DO, followed by stratification. Wind events exhibit only brief relief by advection and mixing, while river discharge shows no direct causal link to DO, making it less influential than previously thought. Biogeochemical variables, including chlorophyll-a (Chl-a), nitrate and nitrite, and particulate carbon, influence DO through both contemporaneous and time-lagged pathways, often with signs that shift depending on the process. The derived models were evaluated by comparing skill scores, mean squared error, and Akaike Information Criterion. Both model types perform well, with coefficient of determination values exceeding 0.90 at multiple stations using only 3-5 predictors. Our analysis reveals that the best causal predictors are surface-layer temperature, stratification, Chl-a, and particle carbon. This approach provides a scalable framework for improving prediction models and understanding the mechanistic links that control the seasonal variability of DO in estuarine systems.

Estuaries↗

Stratifying lung adenocarcinoma: a novel prognostic model based on mitochondrial outer membrane permeabilization activity.

UNLABELLED: Mitochondrial outer membrane permeabilization (MOMP) is a core apoptotic regulatory event that dictates mitochondrial integrity, where full activation drives cell death and sublethal dysregulation contributes to tumor genomic instability. We used the Cancer Genome Atlas lung adenocarcinoma cohort (TCGA-LUAD) as the training cohort and the Gene Expression Omnibus dataset GSE42127 as the validation cohort to identify prognostic genes related to MOMP activity in lung adenocarcinoma (LUAD) and to evaluate their potential biological significance. By intersecting MOMP-related genes with differentially expressed genes, combined with survival analysis, Mendelian randomization analysis, and 101 machine-learning algorithm combinations, seven prognostic genes, namely BIRC5, PSMD11, TNFRSF13C, YWHAZ, YWHAG, CYCS, and LTB, were identified. Next, an optimal prognostic model was constructed based on the gradient boosting machine (GBM) algorithm. Based on the risk score, LUAD patients were stratified into high- and low-risk groups, and patients in the high-risk group exhibited poorer overall survival in both the training and validation cohorts. Furthermore, a nomogram integrating the risk score and clinicopathological factors was developed and showed favorable predictive performance for 1-, 3-, and 5-year survival. Meanwhile, functional and immune analyses revealed that the high-risk group was enriched in DNA replication-related pathways and demonstrated a higher tumor mutation burden (TMB). Correlation analysis indicated that TNFRSF13C was positively correlated with activated B cells, whereas BIRC5 was negatively correlated with eosinophils, suggesting that MOMP-related genes might be involved in remodeling the immune microenvironment of LUAD. Drug sensitivity analysis showed differences in predicted half-maximal inhibitory concentration (IC50) values between the risk groups, suggesting the potential value of this model in assisting therapeutic stratification. Single-cell RNA sequencing (scRNA-seq) further identified T lymphocytes as a key cell type, with numerous prognostic genes exhibiting differential expression in T cells or dynamic changes during differentiation. We suggest that the MOMP-related signature established in this study may provide a reference for prognostic stratification in LUAD and offers candidate prognostic genes for subsequent experimental and clinical validation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05058-6.

Lung adenocarcinoma↗

FiberID--a technique to identify fibrous protein subclasses.

Fibrous proteins such as collagen, silk, and elastin play critical biological roles, yet they have been the subject of few projects that use computational techniques to predict either their class or their structure. In this article, we present FiberID, a simple yet effective method for identifying and distinguishing three fibrous protein subclasses from their primary sequences. Using a combination of amino acid composition and fast Fourier measurements, FiberID can classify fibrous proteins belonging to these subclasses with high accuracy by using two standard machine learning techniques (decision trees and Naïve Bayesian classifiers). After presenting our results, we present several fibrous sequences that are regularly misclassified by FiberID as sequences of potential interest for further study. Finally, we analyze the decision trees developed by FiberID for potential insights regarding the structure of these proteins.

Algorithms↗

Discriminating different classes of toxicants by transcript profiling.

Male rats were treated with various model compounds or the appropriate vehicle controls. Most substances were either well-known hepatotoxicants or showed hepatotoxicity during preclinical testing. The aim of the present study was to determine if biological samples from rats treated with various compounds can be classified based on gene expression profiles. In addition to gene expression analysis using microarrays, a complete serum chemistry profile and liver and kidney histopathology were performed. We analyzed hepatic gene expression profiles using a supervised learning method (support vector machines; SVMs) to generate classification rules and combined this with recursive feature elimination to improve classification performance and to identify a compact subset of probe sets with potential use as biomarkers. Two different SVM algorithms were tested, and the models obtained were validated with a compound-based external cross-validation approach. Our predictive models were able to discriminate between hepatotoxic and nonhepatotoxic compounds. Furthermore, they predicted the correct class of hepatotoxicant in most cases. We provide an example showing that a predictive model built on transcript profiles from one rat strain can successfully classify profiles from another rat strain. In addition, we demonstrate that the predictive models identify nonresponders and are able to discriminate between gene changes related to pharmacology and toxicity. This work confirms the hypothesis that compound classification based on gene expression data is feasible.

Algorithms↗

Can host genetics transform the sustainable control of tropical theileriosis? Insights from the Tick-Theileria interface.

Tropical theileriosis, caused by the tick-transmitted apicomplexan parasite Theileria annulata, remains a major constraint on cattle production across North Africa, the Mediterranean basin, the Middle East and South Asia. Current control depends on acaricides, the theilericidal drug buparvaquone and live attenuated schizont vaccines, but acaricide resistance, buparvaquone-resistance mutations and the logistical demands of vaccination are eroding the sustainability of these tools. Host genetics offers a complementary and durable alternative. Indigenous Bos indicus breeds are consistently more resistant to ticks and tolerate T. annulata infection better than exotic Bos taurus cattle, and this advantage has a measurable heritable component. Unlike previous reviews, which treat tick resistance, T. annulata immunobiology and livestock genomic selection as separate subjects, we integrate all three and assess host genetics specifically against the failure modes of current control. We review the tick, parasite and host interface, the evidence for natural resistance, and the genetic and immunological mechanisms involved, including signal-regulatory protein, bovine major histocompatibility complex class II and inflammatory pathway genes. We then assess whether genomic selection, multi-omics, machine learning and gene editing can translate these mechanisms into resistant cattle, and we weigh the biological, economic and infrastructural barriers to implementation. The evidence indicates that host genetics will not replace existing control but could reduce reliance on acaricides and chemotherapy. That contribution remains prospective rather than demonstrated: no resistance marker for T. annulata has yet been validated, prediction accuracies are moderate and transfer poorly between breeds, and no endemic production system has implemented selection for resistance.

Animals↗

Plant promoter prediction with confidence estimation.

Accurate prediction of promoters is fundamental to understanding gene expression patterns, where confidence estimation is one of the main requirements. Using recently developed transductive confidence machine (TCM) techniques, we developed a new program TSSP-TCM for the prediction of plant promoters that also provides confidence of the prediction. The program was trained on 132 and 104 sequences and tested on 40 and 25 sequences (containing TATA and TATA-less promoters, respectively) with known transcription start sites (TSSs). As negative training samples for TCM learning we used coding and intron sequences of plant genes annotated in the GenBank. In the test set of TATA promoters, the program correctly predicted TSS for 35 out of 40 (87.5%) genes with a median deviation of several base pairs from the true site location. For 25 TATA-less promoters, TSSs were predicted for 21 out of 25 (84%) genes, including 14 cases of 5 bp distance between annotated and predicted TSSs. Using TSSP-TCM program we annotated promoters in the whole Arabidopsis genome. The predicted promoters were in good agreement with the start position of known Arabidopsis mRNAs. Thus, TCM technique has produced a plant-oriented promoter prediction tool of high accuracy. TSSP-TCM program and annotated promoters are available at http://mendel.cs.rhul.ac.uk/mendel.php?topic=fgen.

Arabidopsis↗

Identifying wrist fracture patients with high accuracy by automatic categorization of X-ray reports.

The authors performed this study to determine the accuracy of several text classification methods to categorize wrist x-ray reports. We randomly sampled 751 textual wrist x-ray reports. Two expert reviewers rated the presence (n = 301) or absence (n = 450) of an acute fracture of wrist. We developed two information retrieval (IR) text classification methods and a machine learning method using a support vector machine (TC-1). In cross-validation on the derivation set (n = 493), TC-1 outperformed the two IR based methods and six benchmark classifiers, including Naive Bayes and a Neural Network. In the validation set (n = 258), TC-1 demonstrated consistent performance with 93.8% accuracy; 95.5% sensitivity; 92.9% specificity; and 87.5% positive predictive value. TC-1 was easy to implement and superior in performance to the other classification methods.

Artificial Intelligence↗

Modeling unknowns: A vision for uncertainty-aware machine learning in healthcare.

The integration of machine learning (ML) into healthcare is accelerating, driven by the proliferation of biomedical data and the promise of data-driven clinical support. A key challenge in this context is managing the pervasive uncertainty inherent in medical reasoning and decision-making. Despite its recognized importance, uncertainty is often underrepresented in the design and evaluation of clinical AI systems. Here we report an editorial overview of a special issue dedicated to uncertainty modeling in medical AI, which gathers theoretical, methodological, and practical contributions addressing this critical gap. Across these works, authors reveal that fewer than 4% of studies address uncertainty explicitly, and propose alternative design principles-such as optimizing for clinical net benefit or embedding explainability with confidence estimates. Notable contributions include the RelAI system for real-time prediction reliability, empirical findings on how uncertainty communication shapes clinical interpretation, and benchmarks for out-of-distribution detection in tabular data. Furthermore, this issue highlights the use of causal reasoning and anomaly detection to enhance system robustness and accountability. Together, these studies argue that representing, communicating, and operationalizing uncertainty are essential not only for clinical safety but also for building trust in AI-driven care. This special issue thus repositions uncertainty from a limitation to a foundational asset in the responsible deployment of ML in healthcare.

Machine Learning↗

The machine-learning classifier ALLCatchR2 identifies 20 T-ALL subtypes across cohorts and age groups.

T-cell acute lymphoblastic leukemia (T-ALL) comprises molecularly diverse subtypes, but robust cross-cohort validations and operational gene-expression definitions are lacking. To establish a gene-expression-anchored framework for T-ALL subtyping, we aggregated 2314 transcriptomes (15 cohorts, age: 0.8-90.8 years). An extended unsupervised approach defined 17 main clusters and 3 subclusters in samples with high blast fractions. Supervised analyses added an overarching immature T-ALL (early T cell precursor [ETP]-like) definition and resolved the LMO2 &#x3b3;&#x3b4;-like subtype. All clusters contained samples from at least two cohorts. Characteristic genomic driver enrichments were consistent across cohorts, while gene-expression clusters did not correspond exclusively to single driver events but also reflected developmental origins. A machine-learning classifier based on ALLCatchR, our B-cell acute lymphoblastic leukemia (B-ALL) classifier, identified these 20 transcriptomic subtypes and the immature T-ALL (ETP-like) signature with 0.995-1.0 accuracy in a validation set (n&#x2009;=&#x2009;203). Testing the classifier on a second hold-out data set (n&#x2009;=&#x2009;265 samples) showed that 92.7% of predictions matched with corresponding driver alterations. Across all samples, 83.2% of cases received high-confidence predictions, 7.3% candidate predictions, and 9.5% remained unclassified, largely because of low blast fractions. We identified a novel gene-expression cluster markedly enriched (P&#x2009;<&#x2009;0.001) for clonal hematopoiesis mutations (IDH2 R140Q, DNMT3A) and a stem-/progenitor cell-like gene expression. This novel clonal hematopoiesis-related T-ALL subtype was observed in six cohorts and accounted for 8.9% of adults and 39.5% of patients aged >50 years. We extended&#xa0;ALLCatchR into ALLCatchR2, a free R package that now enables B-/T-lineage separation, gene-expression subtyping, blast estimation, and developmental annotation to harmonize T-ALL classification across studies and clinical contexts.

Journal Article↗

An accurate QSPR study of O-H bond dissociation energy in substituted phenols based on support vector machines.

The support vector machine (SVM), as a novel type of learning machine, was used to develop a Quantitative Structure-Property Relationship (QSPR) model of the O-H bond dissociation energy (BDE) of 78 substituted phenols. The six descriptors calculated solely from the molecular structures of compounds selected by forward stepwise regression were used as inputs for the SVM model. The root-mean-square (rms) errors in BDE predictions for the training, test, and overall data sets were 3.808, 3.320, and 3.713 BDE units (kJ mol(-1)), respectively. The results obtained by Gaussian-kernel SVM were much better than those obtained by multiple linear regression, radial basis function neural networks, linear-kernel SVM, and other QSPR approaches.

Journal Article↗

Classification of a diverse set of Tetrahymena pyriformis toxicity chemical compounds from molecular descriptors by statistical learning methods.

Toxicity of various compounds has been measured in many studies by their toxic effects against Tetrahymena pyriformis. Efforts have also been made to use computational quantitative structure-activity relationship (QSAR) and statistical learning methods (SLMs) for predicting Tetrahymena pyriformis toxicity (TPT) at impressive accuracies. Because of the diversity of compounds and toxicity mechanisms, it is desirable to explore additional methods and to examine if these methods are applicable to more diverse sets of compounds. We tested several SLMs (logistic regression, C4.5 decision tree, k-nearest neighbor, probabilistic neural network, support vector machines) for their capability in predicting TPT by using 1129 compounds (841 TPT and 288 non-TPT agents) which are more diverse than those in other studies. A feature selection method was used for improving prediction performance and selecting molecular descriptors responsible for distinguishing TPT and non-TPT agents. The prediction accuracies are 86.9% approximately 94.2% for TPT and 71.2% approximately 87.5% for non-TPT agents based on 5-fold cross-validation studies, which are comparable to some of earlier studies despite the use of more diverse sets of compounds. The selected molecular descriptors are consistent with those used in other studies and experimental findings. These suggest that SLMs are useful for predicting TPT potential of diverse sets of compounds and for characterizing the molecular descriptors associated with TPT.

Animals↗

Subsystem identification through dimensionality reduction of large-scale gene expression data.

The availability of parallel, high-throughput biological experiments that simultaneously monitor thousands of cellular observables provides an opportunity for investigating cellular behavior in a highly quantitative manner at multiple levels of resolution. One challenge to more fully exploit new experimental advances is the need to develop algorithms to provide an analysis at each of the relevant levels of detail. Here, the data analysis method non-negative matrix factorization (NMF) has been applied to the analysis of gene array experiments. Whereas current algorithms identify relationships on the basis of large-scale similarity between expression patterns, NMF is a recently developed machine learning technique capable of recognizing similarity between subportions of the data corresponding to localized features in expression space. A large data set consisting of 300 genome-wide expression measurements of yeast was used as sample data to illustrate the performance of the new approach. Local features detected are shown to map well to functional cellular subsystems. Functional relationships predicted by the new analysis are compared with those predicted using standard approaches; validation using bioinformatic databases suggests predictions using the new approach may be up to twice as accurate as some conventional approaches.

Algorithms↗

Efficient Detection and Characterization of Targets of Natural Selection Using Transfer Learning.

Natural selection leaves detectable patterns of altered spatial diversity within genomes, and identifying affected regions is crucial for understanding species evolution. Recently, machine learning approaches applied to raw population genomic data have been developed to uncover these adaptive signatures. Convolutional neural networks (CNNs) are particularly effective for this task, as they handle large data arrays while maintaining element correlations. However, shallow CNNs may miss complex patterns due to their limited capacity, while deep CNNs can capture these patterns but require extensive data and computational power. Transfer learning addresses these challenges by utilizing a deep CNN pretrained on a large dataset as a feature extraction tool for downstream classification and evolutionary parameter prediction. This approach reduces extensive training data generation requirements and computational needs while maintaining high performance. In this study, we developed TrIdent, a tool that uses transfer learning to enhance detection of adaptive genomic regions from image representations of multilocus variation. We evaluated TrIdent across various genetic, demographic, and adaptive settings, in addition to unphased data and other confounding factors. TrIdent demonstrated improved detection of adaptive regions compared to recent methods using similar data representations. We further explored model interpretability through class activation maps and adapted TrIdent to infer selection parameters for identified adaptive candidates. Using whole-genome haplotype data from European and African populations, TrIdent effectively recapitulated known sweep candidates and identified novel cancer, and other disease-associated genes as potential sweeps.

Selection, Genetic↗

Foundations of Artificial Intelligence in Hepatology: What a Clinician Needs to Know.

This review focuses on foundational knowledge about artificial intelligence (AI) in hepatology, exploring how AI, including machine learning and deep learning, leverages large-scale clinical data to transform the diagnosis, risk assessment, prognostication, and management of liver diseases. Online resources are described to offer fundamental AI knowledge and essential technical skills and to facilitate clinician participation across the entire AI lifecycle, ensuring they contribute not only as end users but also in development and deployment. Unlike traditional statistical approaches that prioritize interpretable parameters and clinical insight, AI focuses on maximizing predictive accuracy by identifying complex, often non-linear patterns using high-dimensional data, albeit often at the cost of model interpretability. AI is demonstrating clinical utility in liver histopathology and radiological imaging, significantly improving detection accuracy for cirrhosis, clinically significant portal hypertension, and hepatocellular carcinoma. Beyond diagnostics, AI-driven prediction models are emerging to provide personalized risk stratification for the development of liver-related complications and treatment guidance, based on complex data including longitudinal laboratory results, comorbidities, and co-medication use to monitor disease progression and therapy response. The field is rapidly expanding into novel areas such as analyzing patient-reported outcomes, genomic data, and real-time liver function monitoring, offering deeper mechanistic insights alongside clinical tools. Despite the potential to revolutionize hepatology practice and research, successful integration into routine care faces challenges. These include seamless workflow integration with existing electronic health records, establishing clear liability frameworks, and guaranteeing protection of patient privacy. Addressing these hurdles requires collaborative efforts from clinicians, researchers, and regulators to develop best practices and governance. Understanding the transformative capabilities, current applications, emerging frontiers, and essential implementation considerations is crucial for clinicians navigating the evolving AI landscape and responsibly utilizing its power for improved patient outcomes.

PROBAST+AI↗

Homology induction: the use of machine learning to improve sequence similarity searches.

BACKGROUND: The inference of homology between proteins is a key problem in molecular biology The current best approaches only identify approximately 50% of homologies (with a false positive rate set at 1/1000). RESULTS: We present Homology Induction (HI), a new approach to inferring homology. HI uses machine learning to bootstrap from standard sequence similarity search methods. First a standard method is run, then HI learns rules which are true for sequences of high similarity to the target (assumed homologues) and not true for general sequences, these rules are then used to discriminate sequences in the twilight zone. To learn the rules HI describes the sequences in a novel way based on a bioinformatic knowledge base, and the machine learning method of inductive logic programming. To evaluate HI we used the PDB40D benchmark which lists sequences of known homology but low sequence similarity. We compared the HI methodology with PSI-BLAST alone and found HI performed significantly better. In addition, Receiver Operating Characteristic (ROC) curve analysis showed that these improvements were robust for all reasonable error costs. The predictive homology rules learnt by HI by can be interpreted biologically to provide insight into conserved features of homologous protein families. CONCLUSIONS: HI is a new technique for the detection of remote protein homology--a central bioinformatic problem. HI with PSI-BLAST is shown to outperform PSI-BLAST for all error costs. It is expect that similar improvements would be obtained using HI with any sequence similarity method.

Algorithms↗

Robust diagnosis of non-Hodgkin lymphoma phenotypes validated on gene expression data from different laboratories.

A major challenge in cancer diagnosis from microarray data is the need for robust, accurate, classification models which are independent of the analysis techniques used and can combine data from different laboratories. We propose such a classification scheme originally developed for phenotype identification from mass spectrometry data. The method uses a robust multivariate gene selection procedure and combines the results of several machine learning tools trained on raw and pattern data to produce an accurate meta-classifier. We illustrate and validate our method by applying it to gene expression datasets: the oligonucleotide HuGeneFL microarray dataset of Shipp et al. (www.genome.wi.mit.du/MPR/lymphoma) and the Hu95Av2 Affymetrix dataset (DallaFavera's laboratory, Columbia University). Our pattern-based meta-classification technique achieves higher predictive accuracies than each of the individual classifiers , is robust against data perturbations and provides subsets of related predictive genes. Our techniques predict that combinations of some genes in the p53 pathway are highly predictive of phenotype. In particular, we find that in 80% of DLBCL cases the mRNA level of at least one of the three genes p53, PLK1 and CDK2 is elevated, while in 80% of FL cases, the mRNA level of at most one of them is elevated.

Biomarkers, Tumor↗