机器学习方法在基因功能注释中的应用

目前,基于计算机数学方法对基因的功能注释已成为热点及挑战,其中以机器学习方法应用最为广泛。生物信息学家不断提出有效、快速、准确的机器学习方法用于基因功能的注释,极大促进了生物医学的发展。本文就关于机器学习方法在基因功能注释的应用与进展作一综述。主要介绍几种常用的方法,包括支持向量机、k近邻算法、决策树、随机森林、神经网络、马尔科夫随机场、logistic回归、聚类算法和贝叶斯分类器,并对目前机器学习方法应用于基因功能注释时如何选择数据源、如何改进算法以及如何提高预测性能上进行讨论。     

环境微生物研究中机器学习算法及应用

微生物在环境中无处不在，它们不仅是生物地球化学循环和环境演化的关键参与者，也在环境监测、生态治理和保护中发挥着重要作用。随着高通量技术的发展，大量微生物数据产生，运用机器学习对环境微生物大数据进行建模和分析，在微生物标志物识别、污染物预测和环境质量预测等领域的科学研究和社会应用方面均具有重要意义。机器学习可分为监督学习和无监督学习2大类。在微生物组学研究当中，无监督学习通过聚类、降维等方法高效地学习输入数据的特征，进而对微生物数据进行整合和归类。监督学习运用有特征和标记的微生物数据集训练模型，在面对只有特征没有标记的数据时可以判断出标记，从而实现对新数据的分类、识别和预测。然而，复杂的机器学习算法通常以牺牲可解释性为代价来重点关注模型预测的准确性。机器学习模型通常可以看作预测特定结果的“黑匣子”，即对模型如何得出预测所知甚少。为了将机器学习更多地运用于微生物组学研究、提高我们提取有价值的微生物信息的能力，深入了解机器学习算法、提高模型的可解释性尤为重要。本文主要介绍在环境微生物领域常用的机器学习算法和基于微生物组数据的机器学习模型的构建步骤，包括特征选择、算法选择、模型构建和评估等，并对各种机器学习模型在环境微生物领域的应用进行综述，深入探究微生物组与周围环境之间的关联，探讨提高模型可解释性的方法，并为未来环境监测、环境健康预测提供科学参考。     

Prediction Errors in Learning Drug Response from Gene Expression Data – Influence of Labeling,Sample Size,and Machine Learning Algorithm

Model-based prediction is dependent on many choices ranging from the sample collection and prediction endpoint to the choice of algorithm and its parameters. Here we studied the effects of such choices, exemplified by predicting sensitivity (as IC50) of cancer cell lines towards a variety of compounds. For this, we used three independent sample collections and applied several machine learning algorithms for predicting a variety of endpoints for drug response. We compared all possible models for combinations of sample collections, algorithm, drug, and labeling to an identically generated null model. The predictability of treatment effects varies among compounds, i.e. response could be predicted for some but not for all. The choice of sample collection plays a major role towards lowering the prediction error, as does sample size. However, we found that no algorithm was able to consistently outperform the other and there was no significant difference between regression and two- or three class predictors in this experimental setting. These results indicate that response-modeling projects should direct efforts mainly towards sample collection and data quality, rather than method adjustment.     

Transfer learning for cytochrome P450 isozyme selectivity prediction

In the drug discovery process, the metabolic fate of drugs is crucially important to prevent drug-drug interactions. Therefore, P450 isozyme selectivity prediction is an important task for screening drugs of appropriate metabolism profiles. Recently, large-scale activity data of five P450 isozymes (CYP1A2 CYP2C9, CYP3A4, CYP2D6, and CYP2C19) have been obtained using quantitative high-throughput screening with a bioluminescence assay. Although some isozymes share similar selectivities, conventional supervised learning algorithms independently learn a prediction model from each P450 isozyme. They are unable to exploit the other P450 isozyme activity data to improve the predictive performance of each P450 isozyme's selectivity. To address this issue, we apply transfer learning that uses activity data of the other isozymes to learn a prediction model from multiple P450 isozymes. After using the large-scale P450 isozyme selectivity dataset for five P450 isozymes, we evaluate the model's predictive performance. Experimental results show that, overall, our algorithm outperforms conventional supervised learning algorithms such as support vector machine (SVM), Weighted k-nearest neighbor classifier, Bagging, Adaboost, and latent semantic indexing (LSI). Moreover, our results show that the predictive performance of our algorithm is improved by exploiting the multiple P450 isozyme activity data in the learning process. Our algorithm can be an effective tool for P450 selectivity prediction for new chemical entities using multiple P450 isozyme activity data.     

Trait‐based risk assessment for invasive species: high performance across diverse taxonomic groups,geographic ranges and machine learning/statistical tools

Aim Trait‐based risk assessment for invasive species is becoming an important tool for identifying non‐indigenous species that are likely to cause harm. Despite this, concerns remain that the invasion process is too complex for accurate predictions to be made. Our goal was to test risk assessment performance across a range of taxonomic and geographical scales, at different points in the invasion process, with a range of statistical and machine learning algorithms. Location Regional to global data sets. Methods We selected six data sets differing in size, geography and taxonomic scope. For each data set, we created seven risk assessment tools using a range of statistical and machine learning algorithms. Performance of tools was compared to determine the effects of data set size and scale, the algorithm used, and to determine overall performance of the trait‐based risk assessment approach. Results Risk assessment tools with good performance were generated for all data sets. Random forests (RF) and logistic regression (LR) consistently produced tools with high performance. Other algorithms had varied performance. Despite their greater power and flexibility, machine learning algorithms did not systematically outperform statistical algorithms. Geographic scope of the data set, and size of the data set, did not systematically affect risk assessment performance. Main conclusions Across six representative data sets, we were able to create risk assessment tools with high performance. Additional data sets could be generated for other taxonomic groups and regions, and these could support efforts to prevent the arrival of new invaders. Random forests and LR approaches performed well for all data sets and could be used as a standard approach to risk assessment development.     

A Comparison of Supervised Machine Learning Algorithms and Feature Vectors for MS Lesion Segmentation Using Multimodal Structural MRI

Machine learning is a popular method for mining and analyzing large collections of medical data. We focus on a particular problem from medical research, supervised multiple sclerosis (MS) lesion segmentation in structural magnetic resonance imaging (MRI). We examine the extent to which the choice of machine learning or classification algorithm and feature extraction function impacts the performance of lesion segmentation methods. As quantitative measures derived from structural MRI are important clinical tools for research into the pathophysiology and natural history of MS, the development of automated lesion segmentation methods is an active research field. Yet, little is known about what drives performance of these methods. We evaluate the performance of automated MS lesion segmentation methods, which consist of a supervised classification algorithm composed with a feature extraction function. These feature extraction functions act on the observed T1-weighted (T1-w), T2-weighted (T2-w) and fluid-attenuated inversion recovery (FLAIR) MRI voxel intensities. Each MRI study has a manual lesion segmentation that we use to train and validate the supervised classification algorithms. Our main finding is that the differences in predictive performance are due more to differences in the feature vectors, rather than the machine learning or classification algorithms. Features that incorporate information from neighboring voxels in the brain were found to increase performance substantially. For lesion segmentation, we conclude that it is better to use simple, interpretable, and fast algorithms, such as logistic regression, linear discriminant analysis, and quadratic discriminant analysis, and to develop the features to improve performance.     

Feature Selection and the Class Imbalance Problem in Predicting Protein Function from Sequence

When the standard approach to predict protein function by sequence homology fails, other alternative methods can be used that require only the amino acid sequence for predicting function. One such approach uses machine learning to predict protein function directly from amino acid sequence features. However, there are two issues to consider before successful functional prediction can take place: identifying discriminatory features, and overcoming the challenge of a large imbalance in the training data. We show that by applying feature subset selection followed by undersampling of the majority class, significantly better support vector machine (SVM) classifiers are generated compared with standard machine learning approaches. As well as revealing that the features selected could have the potential to advance our understanding of the relationship between sequence and function, we also show that undersampling to produce fully balanced data significantly improves performance. The best discriminating ability is achieved using SVMs together with feature selection and full undersampling; this approach strongly outperforms other competitive learning algorithms. We conclude that this combined approach can generate powerful machine learning classifiers for predicting protein function directly from sequence.     

基于机器学习的药物-靶标相互作用预测*

近年来,随着计算机硬件、软件工具和数据丰度的不断突破,以机器学习为代表的人工智能技术在生物、基础医学和药学等领域的应用不断拓展和融合,极大地推动了这些领域的发展,尤其是药物研发领域的变革。其中,药物-靶标相互作用(drug-target interactions, DTI)的识别是药物研发领域中的重要难题和人工智能技术交叉融合的热门方向,研究人员在DTI预测方面做了大量的工作,构建了许多重要的数据库,开发或拓展了各类机器学习算法和工具软件。对基于机器学习的DTI预测的基本流程进行了介绍,并对利用机器学习预测DTI的研究进行了回顾,同时对不同的机器学习方法运用于DTI预测的优缺点进行了简单总结,以期对开发更加有效的预测算法和DTI预测的发展提供帮助。     

Classification Performance-Based Feature Selection Algorithm for Machine Learning: P-Score

Feature selection algorithms are the cornerstone of machine learning. By increasing the properties of the samples and samples, the feature selection algorithm selects the significant features. The general name of the methods that perform this function is the feature selection algorithm. The general purpose of feature selection algorithms is to select the most relevant properties of data classes and to increase the classification performance. Thus, we can select features based on their classification performance. In this study, we have developed a feature selection algorithm based on decision support vectors classification performance. The method can work according to two different selection criteria. We tested the classification performances of the features selected with P-Score with three different classifiers. Besides, we assessed P-Score performance with 13 feature selection algorithms in the literature. According to the results of the study, the P-Score feature selection algorithm has been determined as a method which can be used in the field of machine learning.     

Consensus methods based on machine learning techniques for marine phytoplankton presence–absence prediction

We performed different consensus methods by combining binary classifiers, mostly machine learning classifiers, with the aim to test their capability as predictive tools for the presence–absence of marine phytoplankton species. The consensus methods were constructed by considering a combination of four methods (i.e., generalized linear models, random forests, boosting and support vector machines). Six different consensus methods were analyzed by taking into account six different ways of combining single-model predictions. Some of these methods are presented here for the first time. To evaluate the performance of the models, we considered eight phytoplankton species presence–absence data sets and data related to environmental variables. Some of the analyzed species are toxic, whereas others provoke water discoloration, which can cause alarm in the population. Besides the phytoplankton data sets, we tested the models on 10 well-known open access data sets. We evaluated the models' performances over a test sample. For most (72%) of the data sets, a consensus method was the method with the lowest classification error. In particular, a consensus method that weighted single-model predictions in accordance with single-model performances (weighted average prediction error — WA-PE model) was the one that presented the lowest classification error most of the time. For the phytoplankton species, the errors of the WA-PE model were between 10% for the species Akashiwo sanguinea and 38% for Dinophysis acuminata. This study provides novel approaches to improve the prediction accuracy in species distribution studies and, in particular, in those concerning marine phytoplankton species.     

Improving the Spatial Prediction of Soil Organic Carbon Stocks in a Complex Tropical Mountain Landscape by Methodological Specifications in Machine Learning Approaches

Tropical forests are significant carbon sinks and their soils’ carbon storage potential is immense. However, little is known about the soil organic carbon (SOC) stocks of tropical mountain areas whose complex soil-landscape and difficult accessibility pose a challenge to spatial analysis. The choice of methodology for spatial prediction is of high importance to improve the expected poor model results in case of low predictor-response correlations. Four aspects were considered to improve model performance in predicting SOC stocks of the organic layer of a tropical mountain forest landscape: Different spatial predictor settings, predictor selection strategies, various machine learning algorithms and model tuning. Five machine learning algorithms: random forests, artificial neural networks, multivariate adaptive regression splines, boosted regression trees and support vector machines were trained and tuned to predict SOC stocks from predictors derived from a digital elevation model and satellite image. Topographical predictors were calculated with a GIS search radius of 45 to 615 m. Finally, three predictor selection strategies were applied to the total set of 236 predictors. All machine learning algorithms—including the model tuning and predictor selection—were compared via five repetitions of a tenfold cross-validation. The boosted regression tree algorithm resulted in the overall best model. SOC stocks ranged between 0.2 to 17.7 kg m^-2, displaying a huge variability with diffuse insolation and curvatures of different scale guiding the spatial pattern. Predictor selection and model tuning improved the models’ predictive performance in all five machine learning algorithms. The rather low number of selected predictors favours forward compared to backward selection procedures. Choosing predictors due to their indiviual performance was vanquished by the two procedures which accounted for predictor interaction.     

PSoL: a positive sample only learning algorithm for finding non-coding RNA genes

MOTIVATION: Small non-coding RNA (ncRNA) genes play important regulatory roles in a variety of cellular processes. However, detection of ncRNA genes is a great challenge to both experimental and computational approaches. In this study, we describe a new approach called positive sample only learning (PSoL) to predict ncRNA genes in the Escherichia coli genome. Although PSoL is a machine learning method for classification, it requires no negative training data, which, in general, is hard to define properly and affects the performance of machine learning dramatically. In addition, using the support vector machine (SVM) as the core learning algorithm, PSoL can integrate many different kinds of information to improve the accuracy of prediction. Besides the application of PSoL for predicting ncRNAs, PSoL is applicable to many other bioinformatics problems as well. RESULTS: The PSoL method is assessed by 5-fold cross-validation experiments which show that PSoL can achieve about 80% accuracy in recovery of known ncRNAs. We compared PSoL predictions with five previously published results. The PSoL method has the highest percentage of predictions overlapping with those from other methods.     

Inference from clustering with application to gene-expression microarrays.

There are many algorithms to cluster sample data points based on nearness or a similarity measure. Often the implication is that points in different clusters come from different underlying classes, whereas those in the same cluster come from the same class. Stochastically, the underlying classes represent different random processes. The inference is that clusters represent a partition of the sample points according to which process they belong. This paper discusses a model-based clustering toolbox that evaluates cluster accuracy. Each random process is modeled as its mean plus independent noise, sample points are generated, the points are clustered, and the clustering error is the number of points clustered incorrectly according to the generating random processes. Various clustering algorithms are evaluated based on process variance and the key issue of the rate at which algorithmic performance improves with increasing numbers of experimental replications. The model means can be selected by hand to test the separability of expected types of biological expression patterns. Alternatively, the model can be seeded by real data to test the expected precision of that output or the extent of improvement in precision that replication could provide. In the latter case, a clustering algorithm is used to form clusters, and the model is seeded with the means and variances of these clusters. Other algorithms are then tested relative to the seeding algorithm. Results are averaged over various seeds. Output includes error tables and graphs, confusion matrices, principal-component plots, and validation measures. Five algorithms are studied in detail: K-means, fuzzy C-means, self-organizing maps, hierarchical Euclidean-distance-based and correlation-based clustering. The toolbox is applied to gene-expression clustering based on cDNA microarrays using real data. Expression profile graphics are generated and error analysis is displayed within the context of these profile graphics. A large amount of generated output is available over the web.     

Identifying Cognitive States Using Regularity Partitions

Functional Magnetic Resonance (fMRI) data can be used to depict functional connectivity of the brain. Standard techniques have been developed to construct brain networks from this data; typically nodes are considered as voxels or sets of voxels with weighted edges between them representing measures of correlation. Identifying cognitive states based on fMRI data is connected with recording voxel activity over a certain time interval. Using this information, network and machine learning techniques can be applied to discriminate the cognitive states of the subjects by exploring different features of data. In this work we wish to describe and understand the organization of brain connectivity networks under cognitive tasks. In particular, we use a regularity partitioning algorithm that finds clusters of vertices such that they all behave with each other almost like random bipartite graphs. Based on the random approximation of the graph, we calculate a lower bound on the number of triangles as well as the expectation of the distribution of the edges in each subject and state. We investigate the results by comparing them to the state of the art algorithms for exploring connectivity and we argue that during epochs that the subject is exposed to stimulus, the inspected part of the brain is organized in an efficient way that enables enhanced functionality.     

Combining multi-species genomic data for microRNA identification using a Naive Bayes classifier

MOTIVATION: Most computational methodologies for microRNA gene prediction utilize techniques based on sequence conservation and/or structural similarity. In this study we describe a new technique, which is applicable across several species, for predicting miRNA genes. This technique is based on machine learning, using the Naive Bayes classifier. It automatically generates a model from the training data, which consists of sequence and structure information of known miRNAs from a variety of species. RESULTS: Our study shows that the application of machine learning techniques, along with the integration of data from multiple species is a useful and general approach for miRNA gene prediction. Based on our experiments, we believe that this new technique is applicable to an extensive range of eukaryotes' genomes. Specific structure and sequence features are first used to identify miRNAs followed by a comparative analysis to decrease the number of false positives (FPs). The resulting algorithm exhibits higher specificity and similar sensitivity compared to currently used algorithms that rely on conserved genomic regions to decrease the rate of FPs.     

An improvement of extreme learning machine for compact single-hidden-layer feedforward neural networks

Recently, a novel learning algorithm called extreme learning machine (ELM) was proposed for efficiently training single-hidden-layer feedforward neural networks (SLFNs). It was much faster than the traditional gradient-descent-based learning algorithms due to the analytical determination of output weights with the random choice of input weights and hidden layer biases. However, this algorithm often requires a large number of hidden units and thus slowly responds to new observations. Evolutionary extreme learning machine (E-ELM) was proposed to overcome this problem; it used the differential evolution algorithm to select the input weights and hidden layer biases. However, this algorithm required much time for searching optimal parameters with iterative processes and was not suitable for data sets with a large number of input features. In this paper, a new approach for training SLFNs is proposed, in which the input weights and biases of hidden units are determined based on a fast regularized least-squares scheme. Experimental results for many real applications with both small and large number of input features show that our proposed approach can achieve good generalization performance with much more compact networks and extremely high speed for both learning and testing.     

Determination of causes of death via spectrochemical analysis of forensic autopsies‐based pulmonary edema fluid samples with deep learning algorithm

This study investigated whether infrared spectroscopy combined with a deep learning algorithm could be a useful tool for determining causes of death by analyzing pulmonary edema fluid from forensic autopsies. A newly designed convolutional neural network‐based deep learning framework, named DeepIR and eight popular machine learning algorithms, were used to construct classifiers. The prediction performances of these classifiers demonstrated that DeepIR outperformed the machine learning algorithms in establishing classifiers to determine the causes of death. Moreover, DeepIR was generally less dependent on preprocessing procedures than were the machine learning algorithms; it provided the validation accuracy with a narrow range from 0.9661 to 0.9856 and the test accuracy ranging from 0.8774 to 0.9167 on the raw pulmonary edema fluid spectral dataset and the nine preprocessing protocol‐based datasets in our study. In conclusion, this study demonstrates that the deep learning‐equipped Fourier transform infrared spectroscopy technique has the potential to be an effective aid for determining causes of death.     

Fuzzy ARTMAP prediction of biological activities for potential HIV-1 protease inhibitors using a small molecular data set

Obtaining satisfactory results with neural networks depends on the availability of large data samples. The use of small training sets generally reduces performance. Most classical Quantitative Structure-Activity Relationship (QSAR) studies for a specific enzyme system have been performed on small data sets. We focus on the neuro-fuzzy prediction of biological activities of HIV-1 protease inhibitory compounds when inferring from small training sets. We propose two computational intelligence prediction techniques which are suitable for small training sets, at the expense of some computational overhead. Both techniques are based on the FAMR model. The FAMR is a Fuzzy ARTMAP (FAM) incremental learning system used for classification and probability estimation. During the learning phase, each sample pair is assigned a relevance factor proportional to the importance of that pair. The two proposed algorithms in this paper are: 1) The GA-FAMR algorithm, which is new, consists of two stages: a) During the first stage, we use a genetic algorithm (GA) to optimize the relevances assigned to the training data. This improves the generalization capability of the FAMR. b) In the second stage, we use the optimized relevances to train the FAMR. 2) The Ordered FAMR is derived from a known algorithm. Instead of optimizing relevances, it optimizes the order of data presentation using the algorithm of Dagher et al. In our experiments, we compare these two algorithms with an algorithm not based on the FAM, the FS-GA-FNN introduced in [4], [5]. We conclude that when inferring from small training sets, both techniques are efficient, in terms of generalization capability and execution time. The computational overhead introduced is compensated by better accuracy. Finally, the proposed techniques are used to predict the biological activities of newly designed potential HIV-1 protease inhibitors.