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Single-cell RNA sequencing provides unprecedent opportunities to explore the heterogeneity and dynamics inherent in cellular biology. An essential step in the data analysis involves the automatic annotation of cells. Despite development of numerous tools for automated cell annotation, assessing the reliability of predicted annotations remains challenging, particularly for rare and unknown cell types. Here, we introduce VICTOR: Validation and inspection of cell type annotation through optimal regression. VICTOR aims to gauge the confidence of cell annotations by an elastic-net regularized regression with optimal thresholds. We demonstrated that VICTOR performed well in identifying inaccurate annotations, surpassing existing methods in diagnostic ability across various single-cell datasets, including within-platform, cross-platform, cross-studies, and cross-omics settings.

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Near-infrared (NIR) spectroscopy has been widely utilized to predict multi-constituents of corn in agriculture. However, directly extracting constituent information from the NIR spectra is challenging due to many issues such as broad absorption band, overlapping and non-specific nature. To solve these problems and extract implicit features from the raw data of NIR spectra to improve performance of quantitative models, a one-dimensional shallow convolutional neural network (CNN) model based on an eXtreme Gradient Boosting (XGBoost) feature extraction method was proposed in this paper. The leaf node feature information in the XGBoost was encoded and reconstructed to obtain the implicit features of raw data in the NIR spectra. A two-parametric Swish (TSwish or TS) activation function was proposed to improve the performance of CNN, and the elastic net (EN) was also applied to avoid the overfitting problem of the CNN model. Performance of the developed XGBoost-CNN-TS-EN model was evaluated using two public NIR spectroscopy datasets of corn and soil, and the obtained determination coefficients (R2) for moisture, oil, protein, and starch of the corn on test set were 0.993, 0.991, 0.998, and 0.992, respectively, with that of the soil organic matter being 0.992. The XGBoost-CNN-TS-EN model exhibits superior stability, good prediction accuracy, and generalization ability, demonstrating its great potentials for quantitative analysis of multi-constituents in spectroscopic applications.

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Genomic selection (GS) is changing plant breeding by significantly reducing the resources needed for phenotyping. However, its accuracy can be compromised by mismatches between training and testing sets, which impact efficiency when the predictive model does not adequately reflect the genetic and environmental conditions of the target population. To address this challenge, this study introduces a straightforward method using binary-Lasso regression to estimate ß coefficients. In this approach, the response variable assigns 1 to testing set inputs and 0 to training set inputs. Subsequently, Lasso, Ridge, and Elastic Net regression models use the inverse of these ß coefficients (in absolute values) as weights during training (WLasso, WRidge, and WElastic Net). This weighting method gives less importance to features that discriminate more between training and testing sets. The effectiveness of this method is evaluated across six datasets, demonstrating consistent improvements in terms of the normalized root mean square error. Importantly, the model's implementation is facilitated using the glmnet library, which supports straightforward integration for weighting ß coefficients.

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Background: The COVID-19 pandemic has had a profound impact globally, presenting significant social and economic challenges. This study aims to explore the factors affecting mortality among hospitalized COVID-19 patients and construct a machine learning-based model to predict the risk of mortality. Methods: The study examined COVID-19 patients admitted to Imam Reza Hospital in Tabriz, Iran, between March 2020 and November 2021. The Elastic Net method was employed to identify and rank features associated with mortality risk. Subsequently, an artificial neural network (ANN) model was developed based on these features to predict mortality risk. The performance of the model was evaluated by receiver operating characteristic (ROC) curve analysis. Results: The study included 706 patients with 96 features, out of them 26 features were identified as crucial predictors of mortality. The ANN model, utilizing 20 of these features, achieved an area under the ROC curve (AUC) of 98.8 %, effectively stratifying patients by mortality risk. Conclusion: The developed model offers accurate and precipitous mortality risk predictions for COVID-19 patients, enhancing the responsiveness of healthcare systems to high-risk individuals.

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Spike-and-slab prior distributions are used to impose variable selection in Bayesian regression-style problems with many possible predictors. These priors are a mixture of two zero-centered distributions with differing variances, resulting in different shrinkage levels on parameter estimates based on whether they are relevant to the outcome. The spike-and-slab lasso assigns mixtures of double exponential distributions as priors for the parameters. This framework was initially developed for linear models, later developed for generalized linear models, and shown to perform well in scenarios requiring sparse solutions. Standard formulations of generalized linear models cannot immediately accommodate categorical outcomes with > 2 categories, i.e. multinomial outcomes, and require modifications to model specification and parameter estimation. Such modifications are relatively straightforward in a Classical setting but require additional theoretical and computational considerations in Bayesian settings, which can depend on the choice of prior distributions for the parameters of interest. While previous developments of the spike-and-slab lasso focused on continuous, count, and/or binary outcomes, we generalize the spike-and-slab lasso to accommodate multinomial outcomes, developing both the theoretical basis for the model and an expectation-maximization algorithm to fit the model. To our knowledge, this is the first generalization of the spike-and-slab lasso to allow for multinomial outcomes.

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Artificial intelligence (AI)/deep learning (DL) models that predict molecular phenotypes like gene expression directly from DNA sequences have recently emerged. While these models have proven effective at capturing the variation across genes, their ability to explain inter-individual differences has been limited. We hypothesize that the performance gap can be narrowed through the use of pre-trained embeddings from the Nucleotide Transformer, a large foundation model trained on 3,000+ genomes. We train a transformer model using the pre-trained embeddings and compare its predictive performance to Enformer, the current state-of-the-art model, using genotype and expression data from 290 individuals. Our model significantly outperforms Enformer in terms of correlation across individuals, and narrows the performance gap with an elastic net regression approach that uses just the genetic variants as predictors. Although simple regression models have their advantages in personalized prediction tasks, DL approaches based on foundation models pre-trained on diverse genomes have unique strengths in flexibility and interpretability. With further methodological and computational improvements with more training data, these models may eventually predict molecular phenotypes from DNA sequences with an accuracy surpassing that of regression-based approaches. Our work demonstrates the potential for large pre-trained AI/DL models to advance functional genomics.

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An essential post-translational modification, phosphorylation is intimately related with a wide range of biological activities. The advancement of effective computational methods for correctly recognizing phosphorylation sites is important for in-depth understanding of various physiological phenomena. However, the traditional method of identifying phosphorylation sites experimentally is time-consuming and laborious, which makes it difficult to meet the processing demands of today's big data. This research proposes the use of a novel model, Res-GCN, to recognize the phosphorylation sites of SARS-CoV-2. Firstly, eight feature extraction strategies are utilized to digitize the protein sequence from multiple viewpoints, including amino acid property encodings (AAindex), pseudo-amino acid composition (PseAAC), adapted normal distribution bi-profile Bayes (ANBPB), dipeptide composition (DC), binary encoding (BE), enhanced amino acid composition (EAAC), Word2Vec, and BLOSUM62 matrices. Secondly, elastic net is utilized to eliminate redundant data in the fused matrix. Finally, a combination of graph convolutional network (GCN) and residual network (ResNet) is used to classify the phosphorylated sites and output predictions using a fully connected layer (FC). The performance of Res-GCN is tested by 5-fold cross-validation and independent testing, and excellent results are obtained on S/T and Y datasets. This demonstrates that the Res-GCN model exhibits exceptional predictive performance and generalizability.

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BACKGROUND: Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes - six organochlorine compounds (OCs) and five metals - that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. RESULTS: Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (ß = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (ß = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (ß = 23 g; 95% CI: -25, 71) compared to those with higher educational status (ß = -9 g; 95% CI: -24, 6). CONCLUSIONS: Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

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BACKGROUND: Homologous recombination deficiency (HRD) stands as a clinical indicator for discerning responsive outcomes to platinum-based chemotherapy and poly ADP-ribose polymerase (PARP) inhibitors. One of the conventional approaches to HRD prognostication has generally centered on identifying deleterious mutations within the BRCA1/2 genes, along with quantifying the genomic scars, such as Genomic Instability Score (GIS) estimation with scarHRD. However, the scarHRD method has limitations in scenarios involving tumors bereft of corresponding germline data. Although several RNA-seq-based HRD prediction algorithms have been developed, they mainly support cohort-wise classification, thereby yielding HRD status without furnishing an analogous quantitative metric akin to scarHRD. This study introduces the expHRD method, which operates as a novel transcriptome-based framework tailored to n-of-1-style HRD scoring. RESULTS: The prediction model has been established using the elastic net regression method in the Cancer Genome Atlas (TCGA) pan-cancer training set. The bootstrap technique derived the HRD geneset for applying the expHRD calculation. The expHRD demonstrated a notable correlation with scarHRD and superior performance in predicting HRD-high samples. We also performed intra- and extra-cohort evaluations for clinical feasibility in the TCGA-OV and the Genomic Data Commons (GDC) ovarian cancer cohort, respectively. The innovative web service designed for ease of use is poised to extend the realms of HRD prediction across diverse malignancies, with ovarian cancer standing as an emblematic example. CONCLUSIONS: Our novel approach leverages the transcriptome data, enabling the prediction of HRD status with remarkable precision. This innovative method addresses the challenges associated with limited available data, opening new avenues for utilizing transcriptomics to inform clinical decisions.

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The liver is the most common organ for the formation of colorectal cancer metastasis. Non-invasive prognostication of colorectal cancer liver metastasis (CRLM) may better inform clinicians for decision-making. Contrast-enhanced computed tomography images of 180 CRLM cases were included in the final analyses. Radiomics features, including shape, first-order, wavelet, and texture, were extracted with Pyradiomics, followed by feature engineering by penalized Cox regression. Radiomics signatures were constructed for disease-free survival (DFS) by both elastic net (EN) and random survival forest (RSF) algorithms. The prognostic potential of the radiomics signatures was demonstrated by Kaplan-Meier curves and multivariate Cox regression. 11 radiomics features were selected for prognostic modelling for the EN algorithm, with 835 features for the RSF algorithm. Survival heatmap indicates a negative correlation between EN or RSF risk scores and DFS. Radiomics signature by EN algorithm successfully separates DFS of high-risk and low-risk cases in the training dataset (log-rank test: p < 0.01, hazard ratio: 1.45 (1.07-1.96), p < 0.01) and test dataset (hazard ratio: 1.89 (1.17-3.04), p < 0.05). RSF algorithm shows a better prognostic implication potential for DFS in the training dataset (log-rank test: p < 0.001, hazard ratio: 2.54 (1.80-3.61), p < 0.0001) and test dataset (log-rank test: p < 0.05, hazard ratio: 1.84 (1.15-2.96), p < 0.05). Radiomics features have the potential for the prediction of DFS in CRLM cases.

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BACKGROUND: As the important factors in cognitive function, dietary habits and metal exposures are interactive with each other. However, fewer studies have investigated the interaction effect of them on cognitive dysfunction in older adults. METHODS: 2,445 registered citizens aged 60-85 years from 51 community health centers in Luohu District, Shenzhen, were recruited in this study based on the Chinese older adult cohort. All subjects underwent physical examination and Mini-cognitive assessment scale. A semi quantitative food frequency questionnaire was used to obtain their food intake frequency, and 21 metal concentrations in their urine were measured. RESULTS: Elastic-net regression model, a machine learning technique, identified six variables that were significantly associated with cognitive dysfunction in older adults. These variables included education level, gender, urinary concentration of arsenic (As) and cadmium (Cd), and the frequency of monthly intake of egg and bean products. After adjusting for multiple factors, As and Cd concentrations were positively associated with increased risk of mild cognitive impairment (MCI) in the older people, with OR values of 1.19 (95% CI: 1.05-1.42) and 1.32 (95% CI: 1.01-1.74), respectively. In addition, older adults with high frequency of egg intake (≥30 times/month) and bean products intake (≥8 times/month) had a reduced risk of MCI than those with low protein egg intake (<30 times/month) and low bean products intake (<8 times/month), respectively. Furthermore, additive interaction were observed between the As exposure and egg products intake, as well as bean products. Cd exposure also showed additive interactions with egg and bean products intake. CONCLUSIONS: The consumption of eggs and bean products, as well as the levels of exposure to the heavy metals Cd and As, have been shown to have a substantial influence on cognitive impairment in the elderly population.

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This study aimed to develop and validate prediction models to estimate the risk of death and intensive care unit admission in COVID-19 inpatients. All RT-PCR-confirmed adult COVID-19 inpatients admitted to Fujian Provincial Hospital from October 2022 to April 2023 were considered. Elastic Net Regression was used to derive the risk prediction models. Potential risk factors were considered, which included demographic characteristics, clinical symptoms, comorbidities, laboratory results, treatment process, prognosis. A total of 1906 inpatients were included finally by inclusion/exclusion criteria and were divided into derivation and test cohorts in a ratio of 8:2, where 1526 (80%) samples were used to develop prediction models under a repeated cross-validation framework and the remaining 380 (20%) samples were used for performance evaluation. Overall performance, discrimination and calibration were evaluated in the validation set and test cohort and quantified by accuracy, scaled Brier score (SbrS), the area under the ROC curve (AUROC), and Spiegelhalter-Z statistics. The models performed well, with high levels of discrimination (AUROCICU [95%CI]: 0.858 [0.803,0.899]; AUROCdeath [95%CI]: 0.906 [0.850,0.948]); and good calibrations (Spiegelhalter-ZICU: - 0.821 (p-value: 0.412); Spiegelhalter-Zdeath: 0.173) in the test set. We developed and validated prediction models to help clinicians identify high risk patients for death and ICU admission after COVID-19 infection.

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Most epidemiological studies on the associations between pesticides exposure and semen quality have been based on a single pesticide, with inconsistent major results. In contrast, there was limited human evidence on the potential effect of pesticides mixture on semen quality. Our study aimed to investigate the relationship of pesticide profiles with semen quality parameters among 299 non-occupationally exposed males aged 25-50 without any clinical abnormalities. Serum concentrations of 21 pesticides were quantified by gas chromatography-tandem mass spectrometry (GC-MS/MS). Semen quality parameters were abstracted from medical records. Generalized linear regression models (GLMs) and three mixture approaches, including weighted quantile sum regression (WQS), elastic net regression (ENR) and Bayesian kernel machine regression (BKMR), were applied to explore the single and mixed effects of pesticide exposure on semen quality. In GLMs, as the serum levels of Bendiocarb, ß-BHC, Clomazone, Dicrotophos, Dimethenamid, Paclobutrazole, Pentachloroaniline and Pyrimethanil increased, the straight-line velocity (VSL), linearity (LIN) and straightness (STR) decreased. This negative association also occurred between the concentration of ß-BHC, Pentachloroaniline, Pyrimethanil and progressive motility, total motility. In the WQS models, pesticides mixture was negatively associated with total motility and several sperm motility parameters (ß: -3.07∼-1.02 per decile, FDR-P<0.05). After screening the important pesticides derived from the mixture by ENR model, the BKMR models showed that the decreased qualities for VSL, LIN, and STR were also observed when pesticide mixtures were at ≥ 70th percentiles. Clomazone, Dimethenamid, and Pyrimethanil (Posterior inclusion probability, PIP: 0.2850-0.8900) were identified as relatively important contributors. The study provides evidence that exposure to single or mixed pesticide was associated with impaired semen quality.

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As the most abundant mRNA modification, m6A controls and influences many aspects of mRNA metabolism including the mRNA stability and degradation. However, the role of specific m6A sites in regulating gene expression still remains unclear. In additional, the multicollinearity problem caused by the correlation of methylation level of multiple m6A sites in each gene could influence the prediction performance. To address the above challenges, we propose an elastic-net regularized negative binomial regression model (called m6Aexpress-enet) to predict which m6A site could potentially regulate its gene expression. Comprehensive evaluations on simulated datasets demonstrate that m6Aexpress-enet could achieve the top prediction performance. Applying m6Aexpress-enet on real MeRIP-seq data from human lymphoblastoid cell lines, we have uncovered the complex regulatory pattern of predicted m6A sites and their unique enrichment pathway of the constructed co-methylation modules. m6Aexpress-enet proves itself as a powerful tool to enable biologists to discover the mechanism of m6A regulatory gene expression. Furthermore, the source code and the step-by-step implementation of m6Aexpress-enet is freely accessed at https://github.com/tengzhangs/m6Aexpress-enet.

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Depression is an incapacitating psychiatric disorder with increased risk through adolescence. Among other factors, children with family history of depression have significantly higher risk of developing depression. Early identification of pre-adolescent children who are at risk of depression is crucial for early intervention and prevention. In this study, we used a large longitudinal sample from the Adolescent Brain Cognitive Development (ABCD) Study (2658 participants after imaging quality control, between 9-10 years at baseline), we applied advanced machine learning methods to predict depression risk at the two-year follow-up from the baseline assessment, using a set of comprehensive multimodal neuroimaging features derived from structural MRI, diffusion tensor imaging, and task and rest functional MRI. Prediction performance underwent a rigorous cross-validation method of leave-one-site-out. Our results demonstrate that all brain features had prediction scores significantly better than expected by chance, with brain features from rest-fMRI showing the best classification performance in the high-risk group of participants with parental history of depression (N = 625). Specifically, rest-fMRI features, which came from functional connectomes, showed significantly better classification performance than other brain features. This finding highlights the key role of the interacting elements of the connectome in capturing more individual variability in psychopathology compared to measures of single brain regions. Our study contributes to the effort of identifying biological risks of depression in early adolescence in population-based samples.

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There is an increasing demand for navigation capability for space vehicles. The exploitation of the so-called Space Service Volume (SSV), and hence the extension of the Global Navigation Satellite System (GNSS) from terrestrial to space users, is currently considered a fundamental step. Knowledge of the constellation antenna pattern, including the side lobe signals, is the main input for assessing the expected GNSS signal availability and navigation performance, especially for high orbits. The best way to define and share this information with the final GNSS user is still an open question. This paper proposes a novel methodology for the definition of a high-fidelity and easy-to-use statistical model to represent GNSS constellation antenna patterns. The reconstruction procedure, based on antenna characterization techniques and statistical learning, is presented here through its successful implementation for the "Galileo Reference Antenna Pattern (GRAP)" model, which has been proposed as the reference model for the Galileo programme. The GRAP represents the expected Equivalent Isotropic Radiated Power (EIRP) variation for the Galileo FOC satellites, and it is obtained by processing the measurements retrieved during the characterization campaign performed on the Galileo FOC antennas. The mathematical background of the model is analyzed in depth in order to better assess the GRAP with respect to different objectives such as improved resolution, smoothness and proper representation of the antenna pattern statistical distribution. The analysis confirms the enhanced GRAP properties and envisages the possibility of extending the approach to other GNSSs. The discussion is complemented by a preliminary use case characterization of the Galileo performance in SSV. The accessibility, a novel indicator, is defined in order to represent in a quick and compact manner, the expected Galileo SSV quality for different altitudes and target mission requirements. The SSV characterization is performed to demonstrate how simply and effectively the GRAP model can be inserted into user analysis. The work creates the basis for an improved capability for assessing Galileo-based navigation in SSV according to the current knowledge of the antenna pattern.

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Background: The X chromosome is often omitted in disease association studies despite containing thousands of genes that may provide insight into well-known sex differences in the risk of Alzheimer's disease (AD). Objective: To model the expression of X chromosome genes and evaluate their impact on AD risk in a sex-stratified manner. Methods: Using elastic net, we evaluated multiple modeling strategies in a set of 175 whole blood samples and 126 brain cortex samples, with whole genome sequencing and RNA-seq data. SNPs (MAF > 0.05) within the cis-regulatory window were used to train tissue-specific models of each gene. We apply the best models in both tissues to sex-stratified summary statistics from a meta-analysis of Alzheimer's Disease Genetics Consortium (ADGC) studies to identify AD-related genes on the X chromosome. Results: Across different model parameters, sample sex, and tissue types, we modeled the expression of 217 genes (95 genes in blood and 135 genes in brain cortex). The average model R2 was 0.12 (range from 0.03 to 0.34). We also compared sex-stratified and sex-combined models on the X chromosome. We further investigated genes that escaped X chromosome inactivation (XCI) to determine if their genetic regulation patterns were distinct. We found ten genes associated with AD at p < 0.05, with only ARMCX6 in female brain cortex (p = 0.008) nearing the significance threshold after adjusting for multiple testing (α = 0.002). Conclusions: We optimized the expression prediction of X chromosome genes, applied these models to sex-stratified AD GWAS summary statistics, and identified one putative AD risk gene, ARMCX6.

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A novel regularized elastic net regression model was developed to predict processing factor (PF) for pesticide residues, which represents a change in the residue levels during food processing. The PF values for tomato juice, wet pomace and dry pomace in the evaluations and reports published by the Joint FAO/WHO Meeting on Pesticide Residues significantly correlated with the physicochemical properties of pesticides, and subsequently the correlation was observed in the present tomato processing study. The elastic net regression model predicted the PF values using the physicochemical properties as predictor variables for both training and test data within a 2-fold range for 80-100% of the pesticides tested in the tomato processing study while overcoming multicollinearity. These results suggest that the PF values are predictable at a certain degree of accuracy from the unique sets of physicochemical properties of pesticides using the developed model based on a processing study with representative pesticides.

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Age at sexual maturity is a key life history trait that can be used to predict population growth rates and develop life history models. In many wild animal species, the age at sexual maturity is not accurately quantified. This results in a reduced ability to accurately model demography of wild populations. Recent studies have indicated the potential for CpG density within gene promoters to be predictive of other life history traits, specifically maximum lifespan. Here, we have developed a machine learning model using gene promoter CpG density to predict the mean age at sexual maturity in mammalian species. In total, 91 genomes were used to identify 101 unique gene promoters predictive of age at sexual maturity across males and females. We found these gene promoters to be most predictive of age at sexual maturity in females (R 2 = 0.881) compared to males (R 2 = 0.758). The median absolute error rate was also found to be lower in females (0.427 years) compared to males (0.785 years). This model provides a novel method for species-level age at sexual maturity prediction without the need for long-term monitoring. This study also highlights a potential epigenetic mechanism for the onset of sexual maturity, indicating the possibility of using epigenetic biomarkers for this important life history trait.

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BACKGROUND: The impact of the gut microbiota on neuropsychiatric disorders has gained much attention in recent years; however, comprehensive data on the relationship between the gut microbiome and its metabolites and resistance to treatment for depression and anxiety is lacking. Here, we investigated intestinal metabolites in patients with depression and anxiety disorders, and their possible roles in treatment resistance. RESULTS: We analyzed fecal metabolites and microbiomes in 34 participants with depression and anxiety disorders. Fecal samples were obtained three times for each participant during the treatment. Propensity score matching led us to analyze data from nine treatment responders and nine non-responders, and the results were validated in the residual sample sets. Using elastic net regression analysis, we identified several metabolites, including N-ε-acetyllysine; baseline levels of the former were low in responders (AUC = 0.86; 95% confidence interval, 0.69-1). In addition, fecal levels of N-ε-acetyllysine were negatively associated with the abundance of Odoribacter. N-ε-acetyllysine levels increased as symptoms improved with treatment. CONCLUSION: Fecal N-ε-acetyllysine levels before treatment may be a predictive biomarker of treatment-refractory depression and anxiety. Odoribacter may play a role in the homeostasis of intestinal L-lysine levels. More attention should be paid to the importance of L-lysine metabolism in those with depression and anxiety.