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Background: Conditional logistic regression trees have been proposed as a flexible alternative to the standard method of conditional logistic regression for the analysis of matched case–control studies. While they allow to avoid the strict assumption of linearity and automatically incorporate interactions, conditional logistic regression trees may suffer from a relatively high variability. Further machine learning methods for the analysis of matched case–control studies are missing because conventional machine learning methods cannot handle the matched structure of the data. Results: A random forest method for the analysis of matched case–control studies based on conditional logistic regression trees is proposed, which overcomes the issue of high variability. It provides an accurate estimation of exposure effects while being more flexible in the functional form of covariate effects. The efficacy of the method is illustrated in a simulation study and within an application to real-world data from a matched case–control study on the effect of regular participation in cervical cancer screening on the development of cervical cancer. Conclusions: The proposed random forest method is a promising add-on to the toolbox for the analysis of matched case–control studies and addresses the need for machine-learning methods in this field. It provides a more flexible approach compared to the standard method of conditional logistic regression, but also compared to conditional logistic regression trees. It allows for non-linearity and the automatic inclusion of interaction effects and is suitable both for exploratory and explanatory analyses. [ABSTRACT FROM AUTHOR]

Abstract Background Conditional logistic regression trees have been proposed as a flexible alternative to the standard method of conditional logistic regression for the analysis of matched case–control studies. While they allow to avoid the strict assumption of linearity and automatically incorporate interactions, conditional logistic regression trees may suffer from a relatively high variability. Further machine learning methods for the analysis of matched case–control studies are missing because conventional machine learning methods cannot handle the matched structure of the data. Results A random forest method for the analysis of matched case–control studies based on conditional logistic regression trees is proposed, which overcomes the issue of high variability. It provides an accurate estimation of exposure effects while being more flexible in the functional form of covariate effects. The efficacy of the method is illustrated in a simulation study and within an application to real-world data from a matched case–control study on the effect of regular participation in cervical cancer screening on the development of cervical cancer. Conclusions The proposed random forest method is a promising add-on to the toolbox for the analysis of matched case–control studies and addresses the need for machine-learning methods in this field. It provides a more flexible approach compared to the standard method of conditional logistic regression, but also compared to conditional logistic regression trees. It allows for non-linearity and the automatic inclusion of interaction effects and is suitable both for exploratory and explanatory analyses.

Abstract Background Enzymes play an irreplaceable and important role in maintaining the lives of living organisms. The Enzyme Commission (EC) number of an enzyme indicates its essential functions. Correct identification of the first digit (family class) of the EC number for a given enzyme is a hot topic in the past twenty years. Several previous methods adopted functional domain composition to represent enzymes. However, it would lead to dimension disaster, thereby reducing the efficiency of the methods. On the other hand, most previous methods can only deal with enzymes belonging to one family class. In fact, several enzymes belong to two or more family classes. Results In this study, a fast and efficient multi-label classifier, named PredictEFC, was designed. To construct this classifier, a novel feature extraction scheme was designed for processing functional domain information of enzymes, which counting the distribution of each functional domain entry across seven family classes in the training dataset. Based on this scheme, each training or test enzyme was encoded into a 7-dimenion vector by fusing its functional domain information and above statistical results. Random k-labelsets (RAKEL) was adopted to build the classifier, where random forest was selected as the base classification algorithm. The two tenfold cross-validation results on the training dataset shown that the accuracy of PredictEFC can reach 0.8493 and 0.8370. The independent test on two datasets indicated the accuracy values of 0.9118 and 0.8777. Conclusion The performance of PredictEFC was slightly lower than the classifier directly using functional domain composition. However, its efficiency was sharply improved. The running time was less than one-tenth of the time of the classifier directly using functional domain composition. In additional, the utility of PredictEFC was superior to the classifiers using traditional dimensionality reduction methods and some previous methods, and this classifier can be transplanted for predicting enzyme family classes of other species. Finally, a web-server available at http://124.221.158.221/ was set up for easy usage.

Abstract Background Metabolic syndrome (MetS) is a cluster of metabolic abnormalities (including obesity, insulin resistance, hypertension, and dyslipidemia), which can be used to identify at-risk populations for diabetes and cardiovascular diseases, the main causes of morbidity and mortality worldwide. The achievement of a simple approach for diagnosing MetS without needing biochemical tests is so valuable. The present study aimed to predict MetS using non-invasive features based on a successful random forest learning algorithm. Also, to deal with the problem of data imbalance that naturally exists in this type of data, the effect of two different data balancing approaches, including the Synthetic Minority Over-sampling Technique (SMOTE) and Random Splitting data balancing (SplitBal), on model performance is investigated. Results The most important determinant for MetS prediction was waist circumference. Applying a random forest learning algorithm to imbalanced data, the trained models reach 86.9% and 79.4% accuracies and 37.1% and 38.2% sensitivities in men and women, respectively. However, by applying the SplitBal data balancing technique, the best results were obtained, and despite that the accuracy of the trained models decreased by 7.8% and 11.3%, but their sensitivity improved significantly to 82.3% and 73.7% in men and women, respectively. Conclusions The random forest learning method, along with data balancing techniques, especially SplitBal, could create MetS prediction models with promising results that can be applied as a useful prognostic tool in health screening programs.

The global spread of the SARS-CoV-2 pandemic, originating in Wuhan, China, has had profound consequences on both health and the economy. Traditional alignment-based phylogenetic tree methods for tracking epidemic dynamics demand substantial computational power due to the growing number of sequenced strains. Consequently, there is a pressing need for an alignment-free approach to characterize these strains and monitor the dynamics of various variants. In this work, we introduce a swift and straightforward tool named GenoSig, implemented in C++. The tool exploits the Di and Tri nucleotide frequency signatures to delineate the taxonomic lineages of SARS-CoV-2 by employing diverse machine learning (ML) and deep learning (DL) models. Our approach achieved a tenfold cross-validation accuracy of 87.88% (± 0.013) for DL and 86.37% (± 0.0009) for Random Forest (RF) model, surpassing the performance of other ML models. Validation using an additional unexposed dataset yielded comparable results. Despite variations in architectures between DL and RF, it was observed that later clades, specifically GRA, GRY, and GK, exhibited superior performance compared to earlier clades G and GH. As for the continental origin of the virus, both DL and RF models exhibited lower performance than in predicting clades. However, both models demonstrated relatively higher accuracy for Europe, North America, and South America compared to other continents, with DL outperforming RF. Both models consistently demonstrated a preference for cytosine and guanine over adenine and thymine in both clade and continental analyses, in both Di and Tri nucleotide frequencies signatures. Our findings suggest that GenoSig provides a straightforward approach to address taxonomic, epidemiological, and biological inquiries, utilizing a reductive method applicable not only to SARS-CoV-2 but also to similar research questions in an alignment-free context. [ABSTRACT FROM AUTHOR]

Background: Enzymes play an irreplaceable and important role in maintaining the lives of living organisms. The Enzyme Commission (EC) number of an enzyme indicates its essential functions. Correct identification of the first digit (family class) of the EC number for a given enzyme is a hot topic in the past twenty years. Several previous methods adopted functional domain composition to represent enzymes. However, it would lead to dimension disaster, thereby reducing the efficiency of the methods. On the other hand, most previous methods can only deal with enzymes belonging to one family class. In fact, several enzymes belong to two or more family classes. Results: In this study, a fast and efficient multi-label classifier, named PredictEFC, was designed. To construct this classifier, a novel feature extraction scheme was designed for processing functional domain information of enzymes, which counting the distribution of each functional domain entry across seven family classes in the training dataset. Based on this scheme, each training or test enzyme was encoded into a 7-dimenion vector by fusing its functional domain information and above statistical results. Random k-labelsets (RAKEL) was adopted to build the classifier, where random forest was selected as the base classification algorithm. The two tenfold cross-validation results on the training dataset shown that the accuracy of PredictEFC can reach 0.8493 and 0.8370. The independent test on two datasets indicated the accuracy values of 0.9118 and 0.8777. Conclusion: The performance of PredictEFC was slightly lower than the classifier directly using functional domain composition. However, its efficiency was sharply improved. The running time was less than one-tenth of the time of the classifier directly using functional domain composition. In additional, the utility of PredictEFC was superior to the classifiers using traditional dimensionality reduction methods and some previous methods, and this classifier can be transplanted for predicting enzyme family classes of other species. Finally, a web-server available at http://124.221.158.221/ was set up for easy usage. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is a cluster of metabolic abnormalities (including obesity, insulin resistance, hypertension, and dyslipidemia), which can be used to identify at-risk populations for diabetes and cardiovascular diseases, the main causes of morbidity and mortality worldwide. The achievement of a simple approach for diagnosing MetS without needing biochemical tests is so valuable. The present study aimed to predict MetS using non-invasive features based on a successful random forest learning algorithm. Also, to deal with the problem of data imbalance that naturally exists in this type of data, the effect of two different data balancing approaches, including the Synthetic Minority Over-sampling Technique (SMOTE) and Random Splitting data balancing (SplitBal), on model performance is investigated. Results: The most important determinant for MetS prediction was waist circumference. Applying a random forest learning algorithm to imbalanced data, the trained models reach 86.9% and 79.4% accuracies and 37.1% and 38.2% sensitivities in men and women, respectively. However, by applying the SplitBal data balancing technique, the best results were obtained, and despite that the accuracy of the trained models decreased by 7.8% and 11.3%, but their sensitivity improved significantly to 82.3% and 73.7% in men and women, respectively. Conclusions: The random forest learning method, along with data balancing techniques, especially SplitBal, could create MetS prediction models with promising results that can be applied as a useful prognostic tool in health screening programs. [ABSTRACT FROM AUTHOR]

Abstract Background Correlation metrics are widely utilized in genomics analysis and often implemented with little regard to assumptions of normality, homoscedasticity, and independence of values. This is especially true when comparing values between replicated sequencing experiments that probe chromatin accessibility, such as assays for transposase-accessible chromatin via sequencing (ATAC-seq). Such data can possess several regions across the human genome with little to no sequencing depth and are thus non-normal with a large portion of zero values. Despite distributed use in the epigenomics field, few studies have evaluated and benchmarked how correlation and association statistics behave across ATAC-seq experiments with known differences or the effects of removing specific outliers from the data. Here, we developed a computational simulation of ATAC-seq data to elucidate the behavior of correlation statistics and to compare their accuracy under set conditions of reproducibility. Results Using these simulations, we monitored the behavior of several correlation statistics, including the Pearson’s R and Spearman’s $$\rho$$ ρ coefficients as well as Kendall’s $$\tau$$ τ and Top–Down correlation. We also test the behavior of association measures, including the coefficient of determination R $$^2$$ 2 , Kendall’s W, and normalized mutual information. Our experiments reveal an insensitivity of most statistics, including Spearman’s $$\rho$$ ρ , Kendall’s $$\tau$$ τ , and Kendall’s W, to increasing differences between simulated ATAC-seq replicates. The removal of co-zeros (regions lacking mapped sequenced reads) between simulated experiments greatly improves the estimates of correlation and association. After removing co-zeros, the R $$^2$$ 2 coefficient and normalized mutual information display the best performance, having a closer one-to-one relationship with the known portion of shared, enhanced loci between simulated replicates. When comparing values between experimental ATAC-seq data using a random forest model, mutual information best predicts ATAC-seq replicate relationships. Conclusions Collectively, this study demonstrates how measures of correlation and association can behave in epigenomics experiments. We provide improved strategies for quantifying relationships in these increasingly prevalent and important chromatin accessibility assays.

Background: Correlation metrics are widely utilized in genomics analysis and often implemented with little regard to assumptions of normality, homoscedasticity, and independence of values. This is especially true when comparing values between replicated sequencing experiments that probe chromatin accessibility, such as assays for transposase-accessible chromatin via sequencing (ATAC-seq). Such data can possess several regions across the human genome with little to no sequencing depth and are thus non-normal with a large portion of zero values. Despite distributed use in the epigenomics field, few studies have evaluated and benchmarked how correlation and association statistics behave across ATAC-seq experiments with known differences or the effects of removing specific outliers from the data. Here, we developed a computational simulation of ATAC-seq data to elucidate the behavior of correlation statistics and to compare their accuracy under set conditions of reproducibility. Results: Using these simulations, we monitored the behavior of several correlation statistics, including the Pearson's R and Spearman's ρ coefficients as well as Kendall's τ and Top–Down correlation. We also test the behavior of association measures, including the coefficient of determination R 2 , Kendall's W, and normalized mutual information. Our experiments reveal an insensitivity of most statistics, including Spearman's ρ , Kendall's τ , and Kendall's W, to increasing differences between simulated ATAC-seq replicates. The removal of co-zeros (regions lacking mapped sequenced reads) between simulated experiments greatly improves the estimates of correlation and association. After removing co-zeros, the R 2 coefficient and normalized mutual information display the best performance, having a closer one-to-one relationship with the known portion of shared, enhanced loci between simulated replicates. When comparing values between experimental ATAC-seq data using a random forest model, mutual information best predicts ATAC-seq replicate relationships. Conclusions: Collectively, this study demonstrates how measures of correlation and association can behave in epigenomics experiments. We provide improved strategies for quantifying relationships in these increasingly prevalent and important chromatin accessibility assays. [ABSTRACT FROM AUTHOR]

Abstract Background and objective Diabetes is a life-threatening chronic disease with a growing global prevalence, necessitating early diagnosis and treatment to prevent severe complications. Machine learning has emerged as a promising approach for diabetes diagnosis, but challenges such as limited labeled data, frequent missing values, and dataset imbalance hinder the development of accurate prediction models. Therefore, a novel framework is required to address these challenges and improve performance. Methods In this study, we propose an innovative pipeline-based multi-classification framework to predict diabetes in three classes: diabetic, non-diabetic, and prediabetes, using the imbalanced Iraqi Patient Dataset of Diabetes. Our framework incorporates various pre-processing techniques, including duplicate sample removal, attribute conversion, missing value imputation, data normalization and standardization, feature selection, and k-fold cross-validation. Furthermore, we implement multiple machine learning models, such as k-NN, SVM, DT, RF, AdaBoost, and GNB, and introduce a weighted ensemble approach based on the Area Under the Receiver Operating Characteristic Curve (AUC) to address dataset imbalance. Performance optimization is achieved through grid search and Bayesian optimization for hyper-parameter tuning. Results Our proposed model outperforms other machine learning models, including k-NN, SVM, DT, RF, AdaBoost, and GNB, in predicting diabetes. The model achieves high average accuracy, precision, recall, F1-score, and AUC values of 0.9887, 0.9861, 0.9792, 0.9851, and 0.999, respectively. Conclusion Our pipeline-based multi-classification framework demonstrates promising results in accurately predicting diabetes using an imbalanced dataset of Iraqi diabetic patients. The proposed framework addresses the challenges associated with limited labeled data, missing values, and dataset imbalance, leading to improved prediction performance. This study highlights the potential of machine learning techniques in diabetes diagnosis and management, and the proposed framework can serve as a valuable tool for accurate prediction and improved patient care. Further research can build upon our work to refine and optimize the framework and explore its applicability in diverse datasets and populations.

Abstract Background Cancer subtype classification is helpful for personalized cancer treatment. Although, some approaches have been developed to classifying caner subtype based on high dimensional gene expression data, it is difficult to obtain satisfactory classification results. Meanwhile, some cancers have been well studied and classified to some subtypes, which are adopt by most researchers. Hence, this priori knowledge is significant for further identifying new meaningful subtypes. Results In this paper, we present a combined parallel random forest and autoencoder approach for cancer subtype identification based on high dimensional gene expression data, ForestSubtype. ForestSubtype first adopts the parallel RF and the priori knowledge of cancer subtype to train a module and extract significant candidate features. Second, ForestSubtype uses a random forest as the base module and ten parallel random forests to compute each feature weight and rank them separately. Then, the intersection of the features with the larger weights output by the ten parallel random forests is taken as our subsequent candidate features. Third, ForestSubtype uses an autoencoder to condenses the selected features into a two-dimensional data. Fourth, ForestSubtype utilizes k-means++ to obtain new cancer subtype identification results. In this paper, the breast cancer gene expression data obtained from The Cancer Genome Atlas are used for training and validation, and an independent breast cancer dataset from the Molecular Taxonomy of Breast Cancer International Consortium is used for testing. Additionally, we use two other cancer datasets for validating the generalizability of ForestSubtype. ForestSubtype outperforms the other two methods in terms of the distribution of clusters, internal and external metric results. The open-source code is available at https://github.com/lffyd/ForestSubtype . Conclusions Our work shows that the combination of high-dimensional gene expression data and parallel random forests and autoencoder, guided by a priori knowledge, can identify new subtypes more effectively than existing methods of cancer subtype classification.

Abstract All the time, pancreatic cancer is a problem worldwide because of its high degree of malignancy and increased mortality. Neural network model analysis is an efficient and accurate machine learning method that can quickly and accurately predict disease feature genes. The aim of our research was to build a neural network model that would help screen out feature genes for pancreatic cancer diagnosis and prediction of prognosis. Our study confirmed that the neural network model is a reliable way to predict feature genes of pancreatic cancer, and immune cells infiltrating play an essential role in the development of pancreatic cancer, especially neutrophils. ANO1, AHNAK2, and ADAM9 were eventually identified as feature genes of pancreatic cancer, helping to diagnose and predict prognosis. Neural network model analysis provides us with a new idea for finding new intervention targets for pancreatic cancer.

Background: Cancer subtype classification is helpful for personalized cancer treatment. Although, some approaches have been developed to classifying caner subtype based on high dimensional gene expression data, it is difficult to obtain satisfactory classification results. Meanwhile, some cancers have been well studied and classified to some subtypes, which are adopt by most researchers. Hence, this priori knowledge is significant for further identifying new meaningful subtypes. Results: In this paper, we present a combined parallel random forest and autoencoder approach for cancer subtype identification based on high dimensional gene expression data, ForestSubtype. ForestSubtype first adopts the parallel RF and the priori knowledge of cancer subtype to train a module and extract significant candidate features. Second, ForestSubtype uses a random forest as the base module and ten parallel random forests to compute each feature weight and rank them separately. Then, the intersection of the features with the larger weights output by the ten parallel random forests is taken as our subsequent candidate features. Third, ForestSubtype uses an autoencoder to condenses the selected features into a two-dimensional data. Fourth, ForestSubtype utilizes k-means++ to obtain new cancer subtype identification results. In this paper, the breast cancer gene expression data obtained from The Cancer Genome Atlas are used for training and validation, and an independent breast cancer dataset from the Molecular Taxonomy of Breast Cancer International Consortium is used for testing. Additionally, we use two other cancer datasets for validating the generalizability of ForestSubtype. ForestSubtype outperforms the other two methods in terms of the distribution of clusters, internal and external metric results. The open-source code is available at https://github.com/lffyd/ForestSubtype. Conclusions: Our work shows that the combination of high-dimensional gene expression data and parallel random forests and autoencoder, guided by a priori knowledge, can identify new subtypes more effectively than existing methods of cancer subtype classification. [ABSTRACT FROM AUTHOR]

Background: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) displays significant potential for applications in cancer research, especially in tumor typing and subtyping. Lung cancer is the primary cause of tumor-related deaths, where the most lethal entities are adenocarcinoma (ADC) and squamous cell carcinoma (SqCC). Distinguishing between these two common subtypes is crucial for therapy decisions and successful patient management. Results: We propose a new algebraic topological framework, which obtains intrinsic information from MALDI data and transforms it to reflect topological persistence. Our framework offers two main advantages. Firstly, topological persistence aids in distinguishing the signal from noise. Secondly, it compresses the MALDI data, saving storage space and optimizes computational time for subsequent classification tasks. We present an algorithm that efficiently implements our topological framework, relying on a single tuning parameter. Afterwards, logistic regression and random forest classifiers are employed on the extracted persistence features, thereby accomplishing an automated tumor (sub-)typing process. To demonstrate the competitiveness of our proposed framework, we conduct experiments on a real-world MALDI dataset using cross-validation. Furthermore, we showcase the effectiveness of the single denoising parameter by evaluating its performance on synthetic MALDI images with varying levels of noise. Conclusion: Our empirical experiments demonstrate that the proposed algebraic topological framework successfully captures and leverages the intrinsic spectral information from MALDI data, leading to competitive results in classifying lung cancer subtypes. Moreover, the framework's ability to be fine-tuned for denoising highlights its versatility and potential for enhancing data analysis in MALDI applications. [ABSTRACT FROM AUTHOR]

BACKGROUND: Moonlighting proteins (MPs) are a subclass of multifunctional proteins in which more than one independent or usually distinct function occurs in a single polypeptide chain. Identification of unknown cellular processes, understanding novel protein mechanisms, improving the prediction of protein functions, and gaining information about protein evolution are the main reasons to study MPs. They also play an important role in disease pathways and drug-target discovery. Since detecting MPs experimentally is quite a challenge, most of them are detected randomly. Therefore, introducing an appropriate computational approach to predict MPs seems reasonable. RESULTS: In this study, we introduced a competent model for detecting moonlighting and non-MPs through extracted features from protein sequences. We attempted to set up a well-judged scheme for detecting outlier proteins. Consequently, 37 distinct feature vectors were utilized to study each proteins impact on detecting MPs. Furthermore, 8 different classification methods were assessed to find the best performance. To detect outliers, each one of the classifications was executed 100 times by tenfold cross-validation on feature vectors; proteins which misclassified 90 times or more were grouped. This process was applied to every single feature vector and eventually the intersection of these groups was determined as the outlier proteins. The results of tenfold cross-validation on a dataset of 351 samples (containing 215 moonlighting and 136 non-moonlighting proteins) reveal that the SVM method on all feature vectors has the highest performance among all methods in this study and other available methods. Besides, the study of outliers showed that 57 of 351 proteins in the dataset could be an appropriate candidate for the outlier. Among the outlier proteins, there were non-MPs (such as P69797) that have been misclassified in 8 different classification methods with 16 different feature vectors. Because these proteins have been obtained by computational methods, the results of this study could reduce the likelihood of hypothesizing whether these proteins are non-moonlighting at all. CONCLUSIONS: MPs are difficult to be identified through experimentation. Using distinct feature vectors, our method enabled identification of novel moonlighting proteins. The study also pinpointed that a number of non-MPs are likely to be moonlighting.

Abstract Background Acute oral toxicity of drug candidates can lead to drug development failure; thus, predicting the acute oral toxicity of small compounds is important for successful drug development. However, evaluation of the acute oral toxicity of small compounds considered in the early stages of drug discovery is limited because of cost and time. Here, we developed a computational framework, PredAOT, that predicts the acute oral toxicity of small compounds in mice and rats. Methods PredAOT is based on multiple random forest models for the accurate prediction of acute oral toxicity. A total of 6226 and 6238 compounds evaluated in mice and rats, respectively, were used to train the models. Results PredAOT has the advantage of predicting acute oral toxicity in mice and rats simultaneously, and its prediction performance is similar to or better than that of existing tools. Conclusion PredAOT will be a useful tool for the quick and accurate prediction of the acute oral toxicity of small compounds in mice and rats during drug development.

Abstract Background In individuals or animals suffering from genetic or acquired diseases, it is important to identify which clinical or phenotypic variables can be used to discriminate between disease and non-disease states, the response to treatments or sexual dimorphism. However, the data often suffers from low number of samples, high number of variables or unbalanced experimental designs. Moreover, several parameters can be recorded in the same test. Thus, correlations should be assessed, and a more complex statistical framework is necessary for the analysis. Packages already exist that provide analysis tools, but they are not found together, rendering the decision method and implementation difficult for non-statisticians. Result We present Gdaphen, a fast joint-pipeline allowing the identification of most important qualitative and quantitative predictor variables to discriminate between genotypes, treatments, or sex. Gdaphen takes as input behavioral/clinical data and uses a Multiple Factor Analysis (MFA) to deal with groups of variables recorded from the same individuals or anonymize genotype-based recordings. Gdaphen uses as optimized input the non-correlated variables with 30% correlation or higher on the MFA-Principal Component Analysis (PCA), increasing the discriminative power and the classifier’s predictive model efficiency. Gdaphen can determine the strongest variables that predict gene dosage effects thanks to the General Linear Model (GLM)-based classifiers or determine the most discriminative not linear distributed variables thanks to Random Forest (RF) implementation. Moreover, Gdaphen provides the efficacy of each classifier and several visualization options to fully understand and support the results as easily readable plots ready to be included in publications. We demonstrate Gdaphen capabilities on several datasets and provide easily followable vignettes. Conclusions Gdaphen makes the analysis of phenotypic data much easier for medical or preclinical behavioral researchers, providing an integrated framework to perform: (1) pre-processing steps as data imputation or anonymization; (2) a full statistical assessment to identify which variables are the most important discriminators; and (3) state of the art visualizations ready for publication to support the conclusions of the analyses. Gdaphen is open-source and freely available at https://github.com/munizmom/gdaphen , together with vignettes, documentation for the functions and examples to guide you in each own implementation.

Background: Acute oral toxicity of drug candidates can lead to drug development failure; thus, predicting the acute oral toxicity of small compounds is important for successful drug development. However, evaluation of the acute oral toxicity of small compounds considered in the early stages of drug discovery is limited because of cost and time. Here, we developed a computational framework, PredAOT, that predicts the acute oral toxicity of small compounds in mice and rats. Methods: PredAOT is based on multiple random forest models for the accurate prediction of acute oral toxicity. A total of 6226 and 6238 compounds evaluated in mice and rats, respectively, were used to train the models. Results: PredAOT has the advantage of predicting acute oral toxicity in mice and rats simultaneously, and its prediction performance is similar to or better than that of existing tools. Conclusion: PredAOT will be a useful tool for the quick and accurate prediction of the acute oral toxicity of small compounds in mice and rats during drug development. [ABSTRACT FROM AUTHOR]

Background: In individuals or animals suffering from genetic or acquired diseases, it is important to identify which clinical or phenotypic variables can be used to discriminate between disease and non-disease states, the response to treatments or sexual dimorphism. However, the data often suffers from low number of samples, high number of variables or unbalanced experimental designs. Moreover, several parameters can be recorded in the same test. Thus, correlations should be assessed, and a more complex statistical framework is necessary for the analysis. Packages already exist that provide analysis tools, but they are not found together, rendering the decision method and implementation difficult for non-statisticians. Result: We present Gdaphen, a fast joint-pipeline allowing the identification of most important qualitative and quantitative predictor variables to discriminate between genotypes, treatments, or sex. Gdaphen takes as input behavioral/clinical data and uses a Multiple Factor Analysis (MFA) to deal with groups of variables recorded from the same individuals or anonymize genotype-based recordings. Gdaphen uses as optimized input the non-correlated variables with 30% correlation or higher on the MFA-Principal Component Analysis (PCA), increasing the discriminative power and the classifier's predictive model efficiency. Gdaphen can determine the strongest variables that predict gene dosage effects thanks to the General Linear Model (GLM)-based classifiers or determine the most discriminative not linear distributed variables thanks to Random Forest (RF) implementation. Moreover, Gdaphen provides the efficacy of each classifier and several visualization options to fully understand and support the results as easily readable plots ready to be included in publications. We demonstrate Gdaphen capabilities on several datasets and provide easily followable vignettes. Conclusions: Gdaphen makes the analysis of phenotypic data much easier for medical or preclinical behavioral researchers, providing an integrated framework to perform: (1) pre-processing steps as data imputation or anonymization; (2) a full statistical assessment to identify which variables are the most important discriminators; and (3) state of the art visualizations ready for publication to support the conclusions of the analyses. Gdaphen is open-source and freely available at https://github.com/munizmom/gdaphen, together with vignettes, documentation for the functions and examples to guide you in each own implementation. [ABSTRACT FROM AUTHOR]

Abstract Background The human body is inhabited by a diverse community of commensal non-pathogenic bacteria, many of which are essential for our health. By contrast, pathogenic bacteria have the ability to invade their hosts and cause a disease. Characterizing the differences between pathogenic and commensal non-pathogenic bacteria is important for the detection of emerging pathogens and for the development of new treatments. Previous methods for classification of bacteria as pathogenic or non-pathogenic used either raw genomic reads or protein families as features. Using protein families instead of reads provided a better interpretability of the resulting model. However, the accuracy of protein-families-based classifiers can still be improved. Results We developed a wide scope pathogenicity classifier (WSPC), a new protein-content-based machine-learning classification model. We trained WSPC on a newly curated dataset of 641 bacterial genomes, where each genome belongs to a different species. A comparative analysis we conducted shows that WSPC outperforms existing models on two benchmark test sets. We observed that the most discriminative protein-family features in WSPC are widely spread among bacterial species. These features correspond to proteins that are involved in the ability of bacteria to survive and replicate during an infection, rather than proteins that are directly involved in damaging or invading the host.

Abstract Background There is a growing body of evidence from biological experiments suggesting that microRNAs (miRNAs) play a significant regulatory role in both diverse cellular activities and pathological processes. Exploring miRNA-disease associations not only can decipher pathogenic mechanisms but also provide treatment solutions for diseases. As it is inefficient to identify undiscovered relationships between diseases and miRNAs using biotechnology, an explosion of computational methods have been advanced. However, the prediction accuracy of existing models is hampered by the sparsity of known association network and single-category feature, which is hard to model the complicated relationships between diseases and miRNAs. Results In this study, we advance a new computational framework (GATMDA) to discover unknown miRNA-disease associations based on graph attention network with multi-source information, which effectively fuses linear and non-linear features. In our method, the linear features of diseases and miRNAs are constructed by disease-lncRNA correlation profiles and miRNA-lncRNA correlation profiles, respectively. Then, the graph attention network is employed to extract the non-linear features of diseases and miRNAs by aggregating information of each neighbor with different weights. Finally, the random forest algorithm is applied to infer the disease-miRNA correlation pairs through fusing linear and non-linear features of diseases and miRNAs. As a result, GATMDA achieves impressive performance: an average AUC of 0.9566 with five-fold cross validation, which is superior to other previous models. In addition, case studies conducted on breast cancer, colon cancer and lymphoma indicate that 50, 50 and 48 out of the top fifty prioritized candidates are verified by biological experiments. Conclusions The extensive experimental results justify the accuracy and utility of GATMDA and we could anticipate that it may regard as a utility tool for identifying unobserved disease-miRNA relationships.

Abstract Background Transcription factors (TFs) bind regulatory DNA regions with sequence specificity, form complexes and regulate gene expression. In cooperative TF-TF binding, two transcription factors bind onto a shared DNA binding site as a pair. Previous work has demonstrated pairwise TF-TF-DNA interactions with position weight matrices (PWMs), which may however not sufficiently take into account the complexity and flexibility of pairwise binding. Results We propose two random forest (RF) methods for joint TF-TF binding site prediction: ComBind and JointRF. We train models with previously published large-scale CAP-SELEX DNA libraries, which comprise DNA sequences enriched for binding of a selected TF pair. JointRF builds a random forest with sub-sequences selected from CAP-SELEX DNA reads with previously proposed pairwise PWM. JointRF outperforms (area under receiver operating characteristics curve, AUROC, 0.75) the current state-of-the-art method i.e. orientation and spacing specific pairwise PWMs (AUROC 0.59). Thus, JointRF may be utilized to improve prediction accuracy for pre-determined binding preferences. However, pairwise TF binding is currently considered flexible; a pair may bind DNA with different orientations and amounts of dinucleotide gaps or overlap between the two motifs. Thus, we developed ComBind, which utilizes random forests by considering simultaneously multiple orientations and spacings of the two factors. Our approach outperforms (AUROC 0.78) PWMs, as well as JointRF (p

Abstract Background Human protein kinases play important roles in cancers, are highly co-regulated by kinase families rather than a single kinase, and complementarily regulate signaling pathways. Even though there are > 100,000 protein kinase inhibitors, only 67 kinase drugs are currently approved by the Food and Drug Administration (FDA). Results In this study, we used “merged moiety-based interpretable features (MMIFs),” which merged four moiety-based compound features, including Checkmol fingerprint, PubChem fingerprint, rings in drugs, and in-house moieties as the input features for building random forest (RF) models. By using > 200,000 bioactivity test data, we classified inhibitors as kinase family inhibitors or non-inhibitors in the machine learning. The results showed that our RF models achieved good accuracy (> 0.8) for the 10 kinase families. In addition, we found kinase common and specific moieties across families using the Shapley Additive exPlanations (SHAP) approach. We also verified our results using protein kinase complex structures containing important interactions of the hinges, DFGs, or P-loops in the ATP pocket of active sites. Conclusions In summary, we not only constructed highly accurate prediction models for predicting inhibitors of kinase families but also discovered common and specific inhibitor moieties between different kinase families, providing new opportunities for designing protein kinase inhibitors.

Abstract Background SNARE proteins play an important role in different biological functions. This study aims to investigate the contribution of a new class of molecular descriptors (called SNARER) related to the chemical-physical properties of proteins in order to evaluate the performance of binary classifiers for SNARE proteins. Results We constructed a SNARE proteins balanced dataset, D128, and an unbalanced one, DUNI, on which we tested and compared the performance of the new descriptors presented here in combination with the feature sets (GAAC, CTDT, CKSAAP and 188D) already present in the literature. The machine learning algorithms used were Random Forest, k-Nearest Neighbors and AdaBoost and oversampling and subsampling techniques were applied to the unbalanced dataset. The addition of the SNARER descriptors increases the precision for all considered ML algorithms. In particular, on the unbalanced DUNI dataset the accuracy increases in parallel with the increase in sensitivity while on the balanced dataset D128 the accuracy increases compared to the counterpart without the addition of SNARER descriptors, with a strong improvement in specificity. Our best result is the combination of our descriptors SNARER with CKSAAP feature on the dataset D128 with 92.3% of accuracy, 90.1% for sensitivity and 95% for specificity with the RF algorithm. Conclusions The performed analysis has shown how the introduction of molecular descriptors linked to the chemical-physical and structural characteristics of the proteins can improve the classification performance. Additionally, it was pointed out that performance can change based on using a balanced or unbalanced dataset. The balanced nature of training can significantly improve forecast accuracy.

Abstract Background Long non-coding RNAs (lncRNAs) play a crucial role in diverse biological processes and have been confirmed to be concerned with various diseases. Largely uncharacterized of the physiological role and functions of lncRNA remains. MicroRNAs (miRNAs), which are usually 20–24 nucleotides, have several critical regulatory parts in cells. LncRNA can be regarded as a sponge to adsorb miRNA and indirectly regulate transcription and translation. Thus, the identification of lncRNA-miRNA associations is essential and valuable. Results In our work, we present DWLMI to infer the potential associations between lncRNAs and miRNAs by representing them as vectors via a lncRNA-miRNA-disease-protein-drug graph. Specifically, DeepWalk can be used to learn the behavior representation of vertices. The methods of fingerprint, k-mer and MeSH descriptors were mainly used to learn the attribute representation of vertices. By combining the above two kinds of information, unknown lncRNA-miRNA associations can be predicted by the random forest classifier. Under the five-fold cross-validation, the proposed DWLMI model obtained an average prediction accuracy of 95.22% with a sensitivity of 94.35% at the AUC of 98.56%. Conclusions The experimental results demonstrated that DWLMI can effectively predict the potential lncRNA-miRNA associated pairs, and the results can provide a new insight for related non-coding RNA researchers in the field of combing biology big data with deep learning.

Abstract Background Amyloids are insoluble fibrillar aggregates that are highly associated with complex human diseases, such as Alzheimer’s disease, Parkinson’s disease, and type II diabetes. Recently, many studies reported that some specific regions of amino acid sequences may be responsible for the amyloidosis of proteins. It has become very important for elucidating the mechanism of amyloids that identifying the amyloidogenic regions. Accordingly, several computational methods have been put forward to discover amyloidogenic regions. The majority of these methods predicted amyloidogenic regions based on the physicochemical properties of amino acids. In fact, position, order, and correlation of amino acids may also influence the amyloidosis of proteins, which should be also considered in detecting amyloidogenic regions. Results To address this problem, we proposed a novel machine-learning approach for predicting amyloidogenic regions, called ReRF-Pred. Firstly, the pseudo amino acid composition (PseAAC) was exploited to characterize physicochemical properties and correlation of amino acids. Secondly, tripeptides composition (TPC) was employed to represent the order and position of amino acids. To improve the distinguishability of TPC, all possible tripeptides were analyzed by the binomial distribution method, and only those which have significantly different distribution between positive and negative samples remained. Finally, all samples were characterized by PseAAC and TPC of their amino acid sequence, and a random forest-based amyloidogenic regions predictor was trained on these samples. It was proved by validation experiments that the feature set consisted of PseAAC and TPC is the most distinguishable one for detecting amyloidosis. Meanwhile, random forest is superior to other concerned classifiers on almost all metrics. To validate the effectiveness of our model, ReRF-Pred is compared with a series of gold-standard methods on two datasets: Pep-251 and Reg33. The results suggested our method has the best overall performance and makes significant improvements in discovering amyloidogenic regions. Conclusions The advantages of our method are mainly attributed to that PseAAC and TPC can describe the differences between amyloids and other proteins successfully. The ReRF-Pred server can be accessed at http://106.12.83.135:8080/ReRF-Pred/.

Abstract Background A thermal face recognition under different conditions is proposed in this article. The novelty of the proposed method is applying temperature information in the recognition of thermal face. The physiological information is obtained from the face using a thermal camera, and a machine learning classifier is utilized for thermal face recognition. The steps of preprocessing, feature extraction and classification are incorporated in training phase. First of all, by using Bayesian framework, the human face can be extracted from thermal face image. Several thermal points are selected as a feature vector. These points are utilized to train Random Forest (RF). Random Forest is a supervised learning algorithm. It is an ensemble of decision trees. Namely, RF merges multiple decision trees together to obtain a more accurate classification. Feature vectors from the testing image are fed into the classifier for face recognition. Results Experiments were conducted under different conditions, including normal, adding noise, wearing glasses, face mask, and glasses with mask. To compare the performance with the convolutional neural network-based technique, experimental results of the proposed method demonstrate its robustness against different challenges. Conclusions Comparisons with other techniques demonstrate that the proposed method is robust under less feature points, which is around one twenty-eighth to one sixtieth of those by other classic methods.

Abstract Background The study of drug–target interactions (DTIs) affinity plays an important role in safety assessment and pharmacology. Currently, quantitative structure–activity relationship (QSAR) and molecular docking (MD) are most common methods in research of DTIs affinity. However, they often built for a specific target or several targets, and most QSAR and MD methods were based either on structure of drug molecules or on structure of receptors with low accuracy and small scope of application. How to construct quantitative prediction models with high accuracy and wide applicability remains a challenge. To this end, this paper screened molecular descriptors based on molecular vibrations and took molecule-target as a whole system to construct prediction models with high accuracy-wide applicability based on dissociation constant (Kd) and concentration for 50% of maximal effect (EC50), and to provide reference for quantifying affinity of DTIs. Results After comprehensive comparison, the results showed that RF models are optimal models to analyze and predict DTIs affinity with coefficients of determination (R2) are all greater than 0.94. Compared to the quantitative models reported in literatures, the RF models developed in this paper have higher accuracy and wide applicability. In addition, E-state molecular descriptors associated with molecular vibrations and normalized Moreau-Broto autocorrelation (G3), Moran autocorrelation (G4), transition-distribution (G7) protein descriptors are of higher importance in the quantification of DTIs. Conclusion Through screening molecular descriptors based on molecular vibrations and taking molecule-target as whole system, we obtained optimal models based on RF with more accurate-widely applicable, which indicated that selection of molecular descriptors associated with molecular vibrations and the use of molecular-target as whole system are reliable methods for improving performance of models. It can provide reference for quantifying affinity of DTIs.

Background: The human body is inhabited by a diverse community of commensal non-pathogenic bacteria, many of which are essential for our health. By contrast, pathogenic bacteria have the ability to invade their hosts and cause a disease. Characterizing the differences between pathogenic and commensal non-pathogenic bacteria is important for the detection of emerging pathogens and for the development of new treatments. Previous methods for classification of bacteria as pathogenic or non-pathogenic used either raw genomic reads or protein families as features. Using protein families instead of reads provided a better interpretability of the resulting model. However, the accuracy of protein-families-based classifiers can still be improved. Results: We developed a wide scope pathogenicity classifier (WSPC), a new protein-content-based machine-learning classification model. We trained WSPC on a newly curated dataset of 641 bacterial genomes, where each genome belongs to a different species. A comparative analysis we conducted shows that WSPC outperforms existing models on two benchmark test sets. We observed that the most discriminative protein-family features in WSPC are widely spread among bacterial species. These features correspond to proteins that are involved in the ability of bacteria to survive and replicate during an infection, rather than proteins that are directly involved in damaging or invading the host. [ABSTRACT FROM AUTHOR]

Background: There is a growing body of evidence from biological experiments suggesting that microRNAs (miRNAs) play a significant regulatory role in both diverse cellular activities and pathological processes. Exploring miRNA-disease associations not only can decipher pathogenic mechanisms but also provide treatment solutions for diseases. As it is inefficient to identify undiscovered relationships between diseases and miRNAs using biotechnology, an explosion of computational methods have been advanced. However, the prediction accuracy of existing models is hampered by the sparsity of known association network and single-category feature, which is hard to model the complicated relationships between diseases and miRNAs. Results: In this study, we advance a new computational framework (GATMDA) to discover unknown miRNA-disease associations based on graph attention network with multi-source information, which effectively fuses linear and non-linear features. In our method, the linear features of diseases and miRNAs are constructed by disease-lncRNA correlation profiles and miRNA-lncRNA correlation profiles, respectively. Then, the graph attention network is employed to extract the non-linear features of diseases and miRNAs by aggregating information of each neighbor with different weights. Finally, the random forest algorithm is applied to infer the disease-miRNA correlation pairs through fusing linear and non-linear features of diseases and miRNAs. As a result, GATMDA achieves impressive performance: an average AUC of 0.9566 with five-fold cross validation, which is superior to other previous models. In addition, case studies conducted on breast cancer, colon cancer and lymphoma indicate that 50, 50 and 48 out of the top fifty prioritized candidates are verified by biological experiments. Conclusions: The extensive experimental results justify the accuracy and utility of GATMDA and we could anticipate that it may regard as a utility tool for identifying unobserved disease-miRNA relationships. [ABSTRACT FROM AUTHOR]

Background: Precision medicine for cancer treatment relies on an accurate pathological diagnosis. The number of known tumor classes has increased rapidly, and reliance on traditional methods of histopathologic classification alone has become unfeasible. To help reduce variability, validation costs, and standardize the histopathological diagnostic process, supervised machine learning models using DNA-methylation data have been developed for tumor classification. These methods require large labeled training data sets to obtain clinically acceptable classification accuracy. While there is abundant unlabeled epigenetic data across multiple databases, labeling pathology data for machine learning models is time-consuming and resource-intensive, especially for rare tumor types. Semi-supervised learning (SSL) approaches have been used to maximize the utility of labeled and unlabeled data for classification tasks and are effectively applied in genomics. SSL methods have not yet been explored with epigenetic data nor demonstrated beneficial to central nervous system (CNS) tumor classification. Results: This paper explores the application of semi-supervised machine learning on methylation data to improve the accuracy of supervised learning models in classifying CNS tumors. We comprehensively evaluated 11 SSL methods and developed a novel combination approach that included a self-training with editing using support vector machine (SETRED-SVM) model and an L2-penalized, multinomial logistic regression model to obtain high confidence labels from a few labeled instances. Results across eight random forest and neural net models show that the pseudo-labels derived from our SSL method can significantly increase prediction accuracy for 82 CNS tumors and 9 normal controls. Conclusions: The proposed combination of semi-supervised technique and multinomial logistic regression holds the potential to leverage the abundant publicly available unlabeled methylation data effectively. Such an approach is highly beneficial in providing additional training examples, especially for scarce tumor types, to boost the prediction accuracy of supervised models. [ABSTRACT FROM AUTHOR]

Background: Transcription factors (TFs) bind regulatory DNA regions with sequence specificity, form complexes and regulate gene expression. In cooperative TF-TF binding, two transcription factors bind onto a shared DNA binding site as a pair. Previous work has demonstrated pairwise TF-TF-DNA interactions with position weight matrices (PWMs), which may however not sufficiently take into account the complexity and flexibility of pairwise binding. Results: We propose two random forest (RF) methods for joint TF-TF binding site prediction: ComBind and JointRF. We train models with previously published large-scale CAP-SELEX DNA libraries, which comprise DNA sequences enriched for binding of a selected TF pair. JointRF builds a random forest with sub-sequences selected from CAP-SELEX DNA reads with previously proposed pairwise PWM. JointRF outperforms (area under receiver operating characteristics curve, AUROC, 0.75) the current state-of-the-art method i.e. orientation and spacing specific pairwise PWMs (AUROC 0.59). Thus, JointRF may be utilized to improve prediction accuracy for pre-determined binding preferences. However, pairwise TF binding is currently considered flexible; a pair may bind DNA with different orientations and amounts of dinucleotide gaps or overlap between the two motifs. Thus, we developed ComBind, which utilizes random forests by considering simultaneously multiple orientations and spacings of the two factors. Our approach outperforms (AUROC 0.78) PWMs, as well as JointRF (p<0.00195). ComBind provides an approach for predicting TF-TF binding sites without prior knowledge on pairwise binding preferences. However, more research is needed to assess ComBind eligibility for practical applications. Conclusions: Random forest is well suited for modeling pairwise TF-TF-DNA binding specificities, and ComBind provides an improvement to pairwise binding site prediction accuracy. [ABSTRACT FROM AUTHOR]

The rapid global spread and dissemination of SARS-CoV-2 has provided the virus with numerous opportunities to develop several variants. Thus, it is critical to determine the degree of the variations and in which part of the virus those variations occurred. Therefore, in this study, methods that could be used to vectorize the sequence data, perform clustering analysis, and visualize the results were proposed using machine learning methods. To conduct this study, a total of 224,073 cases of SARS-CoV-2 sequence data were collected through NCBI and GISAID, and the data were visualized using dimensionality reduction and clustering analysis models such as T-SNE and DBSCAN. The SARS-CoV-2 virus, which was first detected, was distinguished from different variations, including Omicron and Delta, in the cluster results. Furthermore, it was possible to examine which codon changes in the spike protein caused the variants to be distinguished using feature importance extraction models such as Random Forest or Shapely Value. The proposed method has the advantage of being able to analyse and visualize a large amount of data at once compared to the existing tree-based sequence data analysis. The proposed method was able to identify and visualize significant changes between the SARS-CoV-2 virus, which was first detected in Wuhan, China, in December 2019, and the newly formed mutant virus group. As a result of clustering analysis using sequence data, it was possible to confirm the formation of clusters among various variants in a two-dimensional graph, and by extracting the importance of variables, it was possible to confirm which codon changes played a major role in distinguishing variants. Furthermore, since the proposed method can handle a variety of data sequences, it can be used for all kinds of diseases, including influenza and SARS-CoV-2. Therefore, the proposed method has the potential to become widely used for the effective analysis of disease variations. [ABSTRACT FROM AUTHOR]

Background: SNARE proteins play an important role in different biological functions. This study aims to investigate the contribution of a new class of molecular descriptors (called SNARER) related to the chemical-physical properties of proteins in order to evaluate the performance of binary classifiers for SNARE proteins. Results: We constructed a SNARE proteins balanced dataset, D128, and an unbalanced one, DUNI, on which we tested and compared the performance of the new descriptors presented here in combination with the feature sets (GAAC, CTDT, CKSAAP and 188D) already present in the literature. The machine learning algorithms used were Random Forest, k-Nearest Neighbors and AdaBoost and oversampling and subsampling techniques were applied to the unbalanced dataset. The addition of the SNARER descriptors increases the precision for all considered ML algorithms. In particular, on the unbalanced DUNI dataset the accuracy increases in parallel with the increase in sensitivity while on the balanced dataset D128 the accuracy increases compared to the counterpart without the addition of SNARER descriptors, with a strong improvement in specificity. Our best result is the combination of our descriptors SNARER with CKSAAP feature on the dataset D128 with 92.3% of accuracy, 90.1% for sensitivity and 95% for specificity with the RF algorithm. Conclusions: The performed analysis has shown how the introduction of molecular descriptors linked to the chemical-physical and structural characteristics of the proteins can improve the classification performance. Additionally, it was pointed out that performance can change based on using a balanced or unbalanced dataset. The balanced nature of training can significantly improve forecast accuracy. [ABSTRACT FROM AUTHOR]

Background: Human protein kinases play important roles in cancers, are highly co-regulated by kinase families rather than a single kinase, and complementarily regulate signaling pathways. Even though there are > 100,000 protein kinase inhibitors, only 67 kinase drugs are currently approved by the Food and Drug Administration (FDA). Results: In this study, we used "merged moiety-based interpretable features (MMIFs)," which merged four moiety-based compound features, including Checkmol fingerprint, PubChem fingerprint, rings in drugs, and in-house moieties as the input features for building random forest (RF) models. By using > 200,000 bioactivity test data, we classified inhibitors as kinase family inhibitors or non-inhibitors in the machine learning. The results showed that our RF models achieved good accuracy (> 0.8) for the 10 kinase families. In addition, we found kinase common and specific moieties across families using the Shapley Additive exPlanations (SHAP) approach. We also verified our results using protein kinase complex structures containing important interactions of the hinges, DFGs, or P-loops in the ATP pocket of active sites. Conclusions: In summary, we not only constructed highly accurate prediction models for predicting inhibitors of kinase families but also discovered common and specific inhibitor moieties between different kinase families, providing new opportunities for designing protein kinase inhibitors. [ABSTRACT FROM AUTHOR]

Abstract Background Even when microbial communities vary wildly in their taxonomic composition, their functional composition is often surprisingly stable. This suggests that a functional perspective could provide much deeper insight into the principles governing microbiome assembly. Much work to date analyzing the functional composition of microbial communities, however, relies heavily on inference from genomic features. Unfortunately, output from these methods can be hard to interpret and often suffers from relatively high error rates. Results We built and analyzed a domain-specific microbial trait database from known microbe-trait pairs recorded in the literature to better understand the functional composition of the human microbiome. Using a combination of phylogentically conscious machine learning tools and a network science approach, we were able to link particular traits to areas of the human body, discover traits that determine the range of body areas a microbe can inhabit, and uncover drivers of metabolic breadth. Conclusions Domain-specific trait databases are an effective compromise between noisy methods to infer complex traits from genomic data and exhaustive, expensive attempts at database curation from the literature that do not focus on any one subset of taxa. They provide an accurate account of microbial traits and, by limiting the number of taxa considered, are feasible to build within a reasonable time-frame. We present a database specific for the human microbiome, in the hopes that this will prove useful for research into the functional composition of human-associated microbial communities.

Abstract Background Cis-regulatory elements (CREs) are DNA sequence segments that regulate gene expression. Among CREs are promoters, enhancers, Boundary Elements (BEs) and Polycomb Response Elements (PREs), all of which are enriched in specific sequence motifs that form particular occurrence landscapes. We have recently introduced a hierarchical machine learning approach (SVM-MOCCA) in which Support Vector Machines (SVMs) are applied on the level of individual motif occurrences, modelling local sequence composition, and then combined for the prediction of whole regulatory elements. We used SVM-MOCCA to predict PREs in Drosophila and found that it was superior to other methods. However, we did not publish a polished implementation of SVM-MOCCA, which can be useful for other researchers, and we only tested SVM-MOCCA with IUPAC motifs and PREs. Results We here present an expanded suite for modelling CRE sequences in terms of motif occurrence combinatorics—Motif Occurrence Combinatorics Classification Algorithms (MOCCA). MOCCA contains efficient implementations of several modelling methods, including SVM-MOCCA, and a new method, RF-MOCCA, a Random Forest–derivative of SVM-MOCCA. We used SVM-MOCCA and RF-MOCCA to model Drosophila PREs and BEs in cross-validation experiments, making this the first study to model PREs with Random Forests and the first study that applies the hierarchical MOCCA approach to the prediction of BEs. Both models significantly improve generalization to PREs and boundary elements beyond that of previous methods—including 4-spectrum and motif occurrence frequency Support Vector Machines and Random Forests—, with RF-MOCCA yielding the best results. Conclusion MOCCA is a flexible and powerful suite of tools for the motif-based modelling of CRE sequences in terms of motif composition. MOCCA can be applied to any new CRE modelling problems where motifs have been identified. MOCCA supports IUPAC and Position Weight Matrix (PWM) motifs. For ease of use, MOCCA implements generation of negative training data, and additionally a mode that requires only that the user specifies positives, motifs and a genome. MOCCA is licensed under the MIT license and is available on Github at https://github.com/bjornbredesen/MOCCA .

Abstract Background Moonlighting proteins (MPs) are a subclass of multifunctional proteins in which more than one independent or usually distinct function occurs in a single polypeptide chain. Identification of unknown cellular processes, understanding novel protein mechanisms, improving the prediction of protein functions, and gaining information about protein evolution are the main reasons to study MPs. They also play an important role in disease pathways and drug-target discovery. Since detecting MPs experimentally is quite a challenge, most of them are detected randomly. Therefore, introducing an appropriate computational approach to predict MPs seems reasonable. Results In this study, we introduced a competent model for detecting moonlighting and non-MPs through extracted features from protein sequences. We attempted to set up a well-judged scheme for detecting outlier proteins. Consequently, 37 distinct feature vectors were utilized to study each protein’s impact on detecting MPs. Furthermore, 8 different classification methods were assessed to find the best performance. To detect outliers, each one of the classifications was executed 100 times by tenfold cross-validation on feature vectors; proteins which misclassified 90 times or more were grouped. This process was applied to every single feature vector and eventually the intersection of these groups was determined as the outlier proteins. The results of tenfold cross-validation on a dataset of 351 samples (containing 215 moonlighting and 136 non-moonlighting proteins) reveal that the SVM method on all feature vectors has the highest performance among all methods in this study and other available methods. Besides, the study of outliers showed that 57 of 351 proteins in the dataset could be an appropriate candidate for the outlier. Among the outlier proteins, there were non-MPs (such as P69797) that have been misclassified in 8 different classification methods with 16 different feature vectors. Because these proteins have been obtained by computational methods, the results of this study could reduce the likelihood of hypothesizing whether these proteins are non-moonlighting at all. Conclusions MPs are difficult to be identified through experimentation. Using distinct feature vectors, our method enabled identification of novel moonlighting proteins. The study also pinpointed that a number of non-MPs are likely to be moonlighting.

BackgroundThe Random Forest (RF) algorithm for supervised machine learning is an ensemble learning method widely used in science and many other fields. Its popularity has been increasing, but relatively few studies address the parameter selection process: a critical step in model fitting. Due to numerous assertions regarding the performance reliability of the default parameters, many RF models are fit using these values. However there has not yet been a thorough examination of the parameter-sensitivity of RFs in computational genomic studies. We address this gap here.ResultsWe examined the effects of parameter selection on classification performance using the RF machine learning algorithm on two biological datasets with distinct p/n ratios: sequencing summary statistics (low p/n) and microarray-derived data (high p/n). Here, p, refers to the number of variables and, n, the number of samples. Our findings demonstrate that parameterization is highly correlated with prediction accuracy and variable importance measures (VIMs). Further, we demonstrate that different parameters are critical in tuning different datasets, and that parameter-optimization significantly enhances upon the default parameters.ConclusionsParameter performance demonstrated wide variability on both low and high p/n data. Therefore, there is significant benefit to be gained by model tuning RFs away from their default parameter settings.

Abstract Background Protein post-translational modification (PTM) is a key issue to investigate the mechanism of protein’s function. With the rapid development of proteomics technology, a large amount of protein sequence data has been generated, which highlights the importance of the in-depth study and analysis of PTMs in proteins. Method We proposed a new multi-classification machine learning pipeline MultiLyGAN to identity seven types of lysine modified sites. Using eight different sequential and five structural construction methods, 1497 valid features were remained after the filtering by Pearson correlation coefficient. To solve the data imbalance problem, Conditional Generative Adversarial Network (CGAN) and Conditional Wasserstein Generative Adversarial Network (CWGAN), two influential deep generative methods were leveraged and compared to generate new samples for the types with fewer samples. Finally, random forest algorithm was utilized to predict seven categories. Results In the tenfold cross-validation, accuracy (Acc) and Matthews correlation coefficient (MCC) were 0.8589 and 0.8376, respectively. In the independent test, Acc and MCC were 0.8549 and 0.8330, respectively. The results indicated that CWGAN better solved the existing data imbalance and stabilized the training error. Alternatively, an accumulated feature importance analysis reported that CKSAAP, PWM and structural features were the three most important feature-encoding schemes. MultiLyGAN can be found at https://github.com/Lab-Xu/MultiLyGAN . Conclusions The CWGAN greatly improved the predictive performance in all experiments. Features derived from CKSAAP, PWM and structure schemes are the most informative and had the greatest contribution to the prediction of PTM.

Abstract Background Circular RNA (circRNA) is a novel type of RNA with a closed-loop structure. Increasing numbers of circRNAs are being identified in plants and animals, and recent studies have shown that circRNAs play an important role in gene regulation. Therefore, identifying circRNAs from increasing amounts of RNA-seq data is very important. However, traditional circRNA recognition methods have limitations. In recent years, emerging machine learning techniques have provided a good approach for the identification of circRNAs in animals. However, using these features to identify plant circRNAs is infeasible because the characteristics of plant circRNA sequences are different from those of animal circRNAs. For example, plants are extremely rich in splicing signals and transposable elements, and their sequence conservation in rice, for example is far less than that in mammals. To solve these problems and better identify circRNAs in plants, it is urgent to develop circRNA recognition software using machine learning based on the characteristics of plant circRNAs. Results In this study, we built a software program named PCirc using a machine learning method to predict plant circRNAs from RNA-seq data. First, we extracted different features, including open reading frames, numbers of k-mers, and splicing junction sequence coding, from rice circRNA and lncRNA data. Second, we trained a machine learning model by the random forest algorithm with tenfold cross-validation in the training set. Third, we evaluated our classification according to accuracy, precision, and F1 score, and all scores on the model test data were above 0.99. Fourth, we tested our model by other plant tests, and obtained good results, with accuracy scores above 0.8. Finally, we packaged the machine learning model built and the programming script used into a locally run circular RNA prediction software, Pcirc ( https://github.com/Lilab-SNNU/Pcirc ). Conclusion Based on rice circRNA and lncRNA data, a machine learning model for plant circRNA recognition was constructed in this study using random forest algorithm, and the model can also be applied to plant circRNA recognition such as Arabidopsis thaliana and maize. At the same time, after the completion of model construction, the machine learning model constructed and the programming scripts used in this study are packaged into a localized circRNA prediction software Pcirc, which is convenient for plant circRNA researchers to use.

Background: Long non-coding RNAs (lncRNAs) play a crucial role in diverse biological processes and have been confirmed to be concerned with various diseases. Largely uncharacterized of the physiological role and functions of lncRNA remains. MicroRNAs (miRNAs), which are usually 20–24 nucleotides, have several critical regulatory parts in cells. LncRNA can be regarded as a sponge to adsorb miRNA and indirectly regulate transcription and translation. Thus, the identification of lncRNA-miRNA associations is essential and valuable. Results: In our work, we present DWLMI to infer the potential associations between lncRNAs and miRNAs by representing them as vectors via a lncRNA-miRNA-disease-protein-drug graph. Specifically, DeepWalk can be used to learn the behavior representation of vertices. The methods of fingerprint, k-mer and MeSH descriptors were mainly used to learn the attribute representation of vertices. By combining the above two kinds of information, unknown lncRNA-miRNA associations can be predicted by the random forest classifier. Under the five-fold cross-validation, the proposed DWLMI model obtained an average prediction accuracy of 95.22% with a sensitivity of 94.35% at the AUC of 98.56%. Conclusions: The experimental results demonstrated that DWLMI can effectively predict the potential lncRNA-miRNA associated pairs, and the results can provide a new insight for related non-coding RNA researchers in the field of combing biology big data with deep learning. [ABSTRACT FROM AUTHOR]

Abstract Background Millions of people are suffering from cancers, but accurate early diagnosis and effective treatment are still tough for all doctors. Common ways against cancer include surgical operation, radiotherapy and chemotherapy. However, they are all very harmful for patients. Recently, the anticancer peptides (ACPs) have been discovered to be a potential way to treat cancer. Since ACPs are natural biologics, they are safer than other methods. However, the experimental technology is an expensive way to find ACPs so we purpose a new machine learning method to identify the ACPs. Results Firstly, we extracted the feature of ACPs in two aspects: sequence and chemical characteristics of amino acids. For sequence, average 20 amino acids composition was extracted. For chemical characteristics, we classified amino acids into six groups based on the patterns of hydrophobic and hydrophilic residues. Then, deep belief network has been used to encode the features of ACPs. Finally, we purposed Random Relevance Vector Machines to identify the true ACPs. We call this method ‘DRACP’ and tested the performance of it on two independent datasets. Its AUC and AUPR are higher than 0.9 in both datasets. Conclusion We developed a novel method named ‘DRACP’ and compared it with some traditional methods. The cross-validation results showed its effectiveness in identifying ACPs.

Abstract Background The aim of a recent research project was the investigation of the mechanisms involved in the onset of type 2 diabetes in the absence of familiarity. This has led to the development of a computational model that recapitulates the aetiology of the disease and simulates the immunological and metabolic alterations linked to type-2 diabetes subjected to clinical, physiological, and behavioural features of prototypical human individuals. Results We analysed the time course of 46,170 virtual subjects, experiencing different lifestyle conditions. We then set up a statistical model able to recapitulate the simulated outcomes. Conclusions The resulting machine learning model adequately predicts the synthetic dataset and can, therefore, be used as a computationally-cheaper version of the detailed mathematical model, ready to be implemented on mobile devices to allow self-assessment by informed and aware individuals. The computational model used to generate the dataset of this work is available as a web-service at the following address: http://kraken.iac.rm.cnr.it/T2DM .

Abstract Background Cytokines act by binding to specific receptors in the plasma membrane of target cells. Knowledge of cytokine–receptor interaction (CRI) is very important for understanding the pathogenesis of various human diseases—notably autoimmune, inflammatory and infectious diseases—and identifying potential therapeutic targets. Recently, machine learning algorithms have been used to predict CRIs. “Gold Standard” negative datasets are still lacking and strong biases in negative datasets can significantly affect the training of learning algorithms and their evaluation. To mitigate the unrepresentativeness and bias inherent in the negative sample selection (non-interacting proteins), we propose a clustering-based approach for representative negative sample selection. Results We used deep autoencoders to investigate the effect of different sampling approaches for non-interacting pairs on the training and the performance of machine learning classifiers. By using the anomaly detection capabilities of deep autoencoders we deduced the effects of different categories of negative samples on the training of learning algorithms. Random sampling for selecting non-interacting pairs results in either over- or under-representation of hard or easy to classify instances. When K-means based sampling of negative datasets is applied to mitigate the inadequacies of random sampling, random forest (RF) together with the combined feature set of atomic composition, physicochemical-2grams and two different representations of evolutionary information performs best. Average model performances based on leave-one-out cross validation (loocv) over ten different negative sample sets that each model was trained with, show that RF models significantly outperform the previous best CRI predictor in terms of accuracy (+ 5.1%), specificity (+ 13%), mcc (+ 0.1) and g-means value (+ 5.1). Evaluations using tenfold cv and training/testing splits confirm the competitive performance. Conclusions A comparative analysis was performed to assess the effect of three different sampling methods (random, K-means and uniform sampling) on the training of learning algorithms using different evaluation methods. Models trained on K-means sampled datasets generally show a significantly improved performance compared to those trained on random selections—with RF seemingly benefiting most in our particular setting. Our findings on the sampling are highly relevant and apply to many applications of supervised learning approaches in bioinformatics.

BackgroundRecent techniques for tagging and visualizing single molecules in fixed or living organisms and cell lines have been revolutionizing our understanding of the spatial and temporal dynamics of fundamental biological processes. However, fluorescence microscopy images are often noisy, and it can be difficult to distinguish a fluorescently labeled single molecule from background speckle.ResultsWe present a computational pipeline to distinguish the true signal of fluorescently labeled molecules from background fluorescence and noise. We test our technique using the challenging case of wide-field, epifluorescence microscope image stacks from single molecule fluorescence in situ experiments on nematode embryos where there can be substantial out-of-focus light and structured noise. The software recognizes and classifies individual mRNA spots by measuring several features of local intensity maxima and classifying them with a supervised random forest classifier. A key innovation of this software is that, by estimating the probability that each local maximum is a true spot in a statistically principled way, it makes it possible to estimate the error introduced by image classification. This can be used to assess the quality of the data and to estimate a confidence interval for the molecule count estimate, all of which are important for quantitative interpretations of the results of single-molecule experiments.ConclusionsThe software classifies spots in these images well, with >95% AUROC on realistic artificial data and outperforms other commonly used techniques on challenging real data. Its interval estimates provide a unique measure of the quality of an image and confidence in the classification.

Background: A thermal face recognition under different conditions is proposed in this article. The novelty of the proposed method is applying temperature information in the recognition of thermal face. The physiological information is obtained from the face using a thermal camera, and a machine learning classifier is utilized for thermal face recognition. The steps of preprocessing, feature extraction and classification are incorporated in training phase. First of all, by using Bayesian framework, the human face can be extracted from thermal face image. Several thermal points are selected as a feature vector. These points are utilized to train Random Forest (RF). Random Forest is a supervised learning algorithm. It is an ensemble of decision trees. Namely, RF merges multiple decision trees together to obtain a more accurate classification. Feature vectors from the testing image are fed into the classifier for face recognition. Results: Experiments were conducted under different conditions, including normal, adding noise, wearing glasses, face mask, and glasses with mask. To compare the performance with the convolutional neural network-based technique, experimental results of the proposed method demonstrate its robustness against different challenges. Conclusions: Comparisons with other techniques demonstrate that the proposed method is robust under less feature points, which is around one twenty-eighth to one sixtieth of those by other classic methods. [ABSTRACT FROM AUTHOR]

Background: Amyloids are insoluble fibrillar aggregates that are highly associated with complex human diseases, such as Alzheimer's disease, Parkinson's disease, and type II diabetes. Recently, many studies reported that some specific regions of amino acid sequences may be responsible for the amyloidosis of proteins. It has become very important for elucidating the mechanism of amyloids that identifying the amyloidogenic regions. Accordingly, several computational methods have been put forward to discover amyloidogenic regions. The majority of these methods predicted amyloidogenic regions based on the physicochemical properties of amino acids. In fact, position, order, and correlation of amino acids may also influence the amyloidosis of proteins, which should be also considered in detecting amyloidogenic regions. Results: To address this problem, we proposed a novel machine-learning approach for predicting amyloidogenic regions, called ReRF-Pred. Firstly, the pseudo amino acid composition (PseAAC) was exploited to characterize physicochemical properties and correlation of amino acids. Secondly, tripeptides composition (TPC) was employed to represent the order and position of amino acids. To improve the distinguishability of TPC, all possible tripeptides were analyzed by the binomial distribution method, and only those which have significantly different distribution between positive and negative samples remained. Finally, all samples were characterized by PseAAC and TPC of their amino acid sequence, and a random forest-based amyloidogenic regions predictor was trained on these samples. It was proved by validation experiments that the feature set consisted of PseAAC and TPC is the most distinguishable one for detecting amyloidosis. Meanwhile, random forest is superior to other concerned classifiers on almost all metrics. To validate the effectiveness of our model, ReRF-Pred is compared with a series of gold-standard methods on two datasets: Pep-251 and Reg33. The results suggested our method has the best overall performance and makes significant improvements in discovering amyloidogenic regions. Conclusions: The advantages of our method are mainly attributed to that PseAAC and TPC can describe the differences between amyloids and other proteins successfully. The ReRF-Pred server can be accessed at http://106.12.83.135:8080/ReRF-Pred/. [ABSTRACT FROM AUTHOR]