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1. Advanced graph and sequence neural networks for molecular property prediction and drug discovery

   https://doi.org/10.1093/bioinformatics/btac112  

   Wang, Zhengyang ; Liu, Meng ; Luo, Youzhi ; Xu, Zhao ; Xie, Yaochen ; Wang, Limei ; Cai, Lei ; Qi, Qi ; Yuan, Zhuoning ; Yang, Tianbao ; et al ( February 2022 , Bioinformatics)

   Properties of molecules are indicative of their functions and thus are useful in many applications. With the advances of deep-learning methods, computational approaches for predicting molecular properties are gaining increasing momentum. However, there lacks customized and advanced methods and comprehensive tools for this task currently.

   Here, we develop a suite of comprehensive machine-learning methods and tools spanning different computational models, molecular representations and loss functions for molecular property prediction and drug discovery. Specifically, we represent molecules as both graphs and sequences. Built on these representations, we develop novel deep models for learning from molecular graphs and sequences. In order to learn effectively from highly imbalanced datasets, we develop advanced loss functions that optimize areas under precision–recall curves (PRCs) and receiver operating characteristic (ROC) curves. Altogether, our work not only serves as a comprehensive tool, but also contributes toward developing novel and advanced graph and sequence-learning methodologies. Results on both online and offline antibiotics discovery and molecular property prediction tasks show that our methods achieve consistent improvements over prior methods. In particular, our methods achieve #1 ranking in terms of both ROC-AUC (area under curve) and PRC-AUC on the AI Cures open challenge for drug discovery related to COVID-19.

   Our source code is released as part of the MoleculeX library (https://github.com/divelab/MoleculeX) under AdvProp.

   Supplementary data are available at Bioinformatics online.

    

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2. Receiver operating characteristic curves and confidence bands for support vector machines

   https://doi.org/10.1111/biom.13365  

   Luckett, Daniel J. ; Laber, Eric B. ; El‐Kamary, Samer S. ; Fan, Cheng ; Jhaveri, Ravi ; Perou, Charles M. ; Shebl, Fatma M. ; Kosorok, Michael R. ( September 2020 , Biometrics)

   Many problems that appear in biomedical decision‐making, such as diagnosing disease and predicting response to treatment, can be expressed as binary classification problems. The support vector machine (SVM) is a popular classification technique that is robust to model misspecification and effectively handles high‐dimensional data. The relative costs of false positives and false negatives can vary across application domains. The receiving operating characteristic (ROC) curve provides a visual representation of the trade‐off between these two types of errors. Because the SVM does not produce a predicted probability, an ROC curve cannot be constructed in the traditional way of thresholding a predicted probability. However, a sequence of weighted SVMs can be used to construct an ROC curve. Although ROC curves constructed using weighted SVMs have great potential for allowing ROC curves analyses that cannot be done by thresholding predicted probabilities, their theoretical properties have heretofore been underdeveloped. We propose a method for constructing confidence bands for the SVM ROC curve and provide the theoretical justification for the SVM ROC curve by showing that the risk function of the estimated decision rule is uniformly consistent across the weight parameter. We demonstrate the proposed confidence band method using simulation studies. We present a predictive model for treatment response in breast cancer as an illustrative example.

    

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3. AUCpreD: proteome-level protein disorder prediction by AUC-maximized deep convolutional neural fields

   https://doi.org/10.1093/bioinformatics/btw446  

   Wang, Sheng ; Ma, Jianzhu ; Xu, Jinbo ( August 2016 , Bioinformatics)

   Protein intrinsically disordered regions (IDRs) play an important role in many biological processes. Two key properties of IDRs are (i) the occurrence is proteome-wide and (ii) the ratio of disordered residues is about 6%, which makes it challenging to accurately predict IDRs. Most IDR prediction methods use sequence profile to improve accuracy, which prevents its application to proteome-wide prediction since it is time-consuming to generate sequence profiles. On the other hand, the methods without using sequence profile fare much worse than using sequence profile.

   This article formulates IDR prediction as a sequence labeling problem and employs a new machine learning method called Deep Convolutional Neural Fields (DeepCNF) to solve it. DeepCNF is an integration of deep convolutional neural networks (DCNN) and conditional random fields (CRF); it can model not only complex sequence–structure relationship in a hierarchical manner, but also correlation among adjacent residues. To deal with highly imbalanced order/disorder ratio, instead of training DeepCNF by widely used maximum-likelihood, we develop a novel approach to train it by maximizing area under the ROC curve (AUC), which is an unbiased measure for class-imbalanced data.

   Our experimental results show that our IDR prediction method AUCpreD outperforms existing popular disorder predictors. More importantly, AUCpreD works very well even without sequence profile, comparing favorably to or even outperforming many methods using sequence profile. Therefore, our method works for proteome-wide disorder prediction while yielding similar or better accuracy than the others.

   http://raptorx2.uchicago.edu/StructurePropertyPred/predict/

   wangsheng@uchicago.edu, jinboxu@gmail.com

   Supplementary data are available at Bioinformatics online.

    

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4. Stochastic AUC Optimization Algorithms With Linear Convergence

   Natole, Michael ; Ying, Yiming ; Lyu, Siwei ( June 2019 , Frontiers in applied mathematics and statistics)

   Area under the ROC curve (AUC) is a standard metric that is used to measure classification performance for imbalanced class data. Developing stochastic learning algorithms that maximize AUC over accuracy is of practical interest. However, AUC maximization presents a challenge since the learning objective function is defined over a pair of instances of opposite classes. Existing methods circumvent this issue but with high space and time complexity. From our previous work of redefining AUC optimization as a convex-concave saddle point problem, we propose a new stochastic batch learning algorithm for AUC maximization. The key difference from our previous work is that we assume that the underlying distribution of the data is uniform, and we develop a batch learning algorithm that is a stochastic primal-dual algorithm (SPDAM) that achieves a linear convergence rate. We establish the theoretical convergence of SPDAM with high probability and demonstrate its effectiveness on standard benchmark datasets. 

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5. Meta-Analysis of Altered Gut Microbiota Reveals Microbial and Metabolic Biomarkers for Colorectal Cancer

   https://doi.org/10.1128/spectrum.00013-22  

   Avuthu, Nagavardhini ; Guda, Chittibabu ( June 2022 , Microbiology Spectrum)

   Claesen, Jan (Ed.)

   ABSTRACT Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. The dysbiotic gut microbiota and its metabolite secretions play a significant role in CRC development and progression. In this study, we identified microbial and metabolic biomarkers applicable to CRC using a meta-analysis of metagenomic datasets from diverse geographical regions. We used LEfSe, random forest (RF), and co-occurrence network methods to identify microbial biomarkers. Geographic dataset-specific markers were identified and evaluated using area under the ROC curve (AUC) scores and random effect size. Co-occurrence networks analysis showed a reduction in the overall microbial associations and the presence of oral pathogenic microbial clusters in CRC networks. Analysis of predicted metabolites from CRC datasets showed the enrichment of amino acids, cadaverine, and creatine in CRC, which were positively correlated with CRC-associated microbes ( Peptostreptococcus stomatis , Gemella morbillorum , Bacteroides fragilis , Parvimonas spp., Fusobacterium nucleatum , Solobacterium moorei , and Clostridium symbiosum ), and negatively correlated with control-associated microbes. Conversely, butyrate, nicotinamide, choline, tryptophan, and 2-hydroxybutanoic acid showed positive correlations with control-associated microbes ( P < 0.05). Overall, our study identified a set of global CRC biomarkers that are reproducible across geographic regions. We also reported significant differential metabolites and microbe-metabolite interactions associated with CRC. This study provided significant insights for further investigations leading to the development of noninvasive CRC diagnostic tools and therapeutic interventions. IMPORTANCE Several studies showed associations between gut dysbiosis and CRC. Yet, the results are not conclusive due to cohort-specific associations that are influenced by genomic, dietary, and environmental stimuli and associated reproducibility issues with various analysis approaches. Emerging evidence suggests the role of microbial metabolites in modulating host inflammation and DNA damage in CRC. However, the experimental validations have been hindered by cost, resources, and cumbersome technical expertise required for metabolomic investigations. In this study, we performed a meta-analysis of CRC microbiota data from diverse geographical regions using multiple methods to achieve reproducible results. We used a computational approach to predict the metabolomic profiles using existing CRC metagenomic datasets. We identified a reliable set of CRC-specific biomarkers from this analysis, including microbial and metabolite markers. In addition, we revealed significant microbe-metabolite associations through correlation analysis and microbial gene families associated with dysregulated metabolic pathways in CRC, which are essential in understanding the vastly sporadic nature of CRC development and progression. 

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