Hierarchical Support Vector Regression Research Articles

In Silico Prediction of Skin Permeability Using a Two-QSAR Approach.

Topical and transdermal drug delivery is an effective, safe, and preferred route of drug administration. As such, skin permeability is one of the critical parameters that should be taken into consideration in the process of drug discovery and development. The ex vivo human skin model is considered as the best surrogate to evaluate in vivo skin permeability. This investigation adopted a novel two-QSAR scheme by collectively incorporating machine learning-based hierarchical support vector regression (HSVR) and classical partial least square (PLS) to predict the skin permeability coefficient and to uncover the intrinsic permeation mechanism, respectively, based on ex vivo excised human skin permeability data compiled from the literature. The derived HSVR model functioned better than PLS as represented by the predictive performance in the training set, test set, and outlier set in addition to various statistical estimations. HSVR also delivered consistent performance upon the application of a mock test, which purposely mimicked the real challenges. PLS, contrarily, uncovered the interpretable relevance between selected descriptors and skin permeability. Thus, the synergy between interpretable PLS and predictive HSVR models can be of great use for facilitating drug discovery and development by predicting skin permeability.

Development of a Hierarchical Support Vector Regression-Based In Silico Model for Caco-2 Permeability.

Drug absorption is one of the critical factors that should be taken into account in the process of drug discovery and development. The human colon carcinoma cell layer (Caco-2) model has been frequently used as a surrogate to preliminarily investigate the intestinal absorption. In this study, a quantitative structure–activity relationship (QSAR) model was generated using the innovative machine learning-based hierarchical support vector regression (HSVR) scheme to depict the exceedingly confounding passive diffusion and transporter-mediated active transport. The HSVR model displayed good agreement with the experimental values of the training samples, test samples, and outlier samples. The predictivity of HSVR was further validated by a mock test and verified by various stringent statistical criteria. Consequently, this HSVR model can be employed to forecast the Caco-2 permeability to assist drug discovery and development.

Predicting the Critical Number of Layers for Hierarchical Support Vector Regression.

Hierarchical support vector regression (HSVR) models a function from data as a linear combination of SVR models at a range of scales, starting at a coarse scale and moving to finer scales as the hierarchy continues. In the original formulation of HSVR, there were no rules for choosing the depth of the model. In this paper, we observe in a number of models a phase transition in the training error—the error remains relatively constant as layers are added, until a critical scale is passed, at which point the training error drops close to zero and remains nearly constant for added layers. We introduce a method to predict this critical scale a priori with the prediction based on the support of either a Fourier transform of the data or the Dynamic Mode Decomposition (DMD) spectrum. This allows us to determine the required number of layers prior to training any models.

In Silico Prediction of Intestinal Permeability by Hierarchical Support Vector Regression.

The vast majority of marketed drugs are orally administrated. As such, drug absorption is one of the important drug metabolism and pharmacokinetics parameters that should be assessed in the process of drug discovery and development. A nonlinear quantitative structure–activity relationship (QSAR) model was constructed in this investigation using the novel machine learning-based hierarchical support vector regression (HSVR) scheme to render the extremely complicated relationships between descriptors and intestinal permeability that can take place through various passive diffusion and carrier-mediated active transport routes. The predictions by HSVR were found to be in good agreement with the observed values for the molecules in the training set (n = 53, r2 = 0.93, = 0.84, RMSE = 0.17, s = 0.08), test set (n = 13, q2 = 0.75–0.89, RMSE = 0.26, s = 0.14), and even outlier set (n = 8, q2 = 0.78–0.92, RMSE = 0.19, s = 0.09). The built HSVR model consistently met the most stringent criteria when subjected to various statistical assessments. A mock test also assured the predictivity of HSVR. Consequently, this HSVR model can be adopted to facilitate drug discovery and development.

In Silico Prediction of Intestinal Permeability by Hierarchical Support Vector Regression

In Silico Prediction of Intestinal Permeability by Hierarchical Support Vector Regression

In Silico Prediction of PAMPA Effective Permeability Using a Two-QSAR Approach.

Oral administration is the preferred and predominant route of choice for medication. As such, drug absorption is one of critical drug metabolism and pharmacokinetics (DM/PK) parameters that should be taken into consideration in the process of drug discovery and development. The cell-free in vitro parallel artificial membrane permeability assay (PAMPA) has been adopted as the primary screening to assess the passive diffusion of compounds in the practical applications. A classical quantitative structure–activity relationship (QSAR) model and a machine learning (ML)-based QSAR model were derived using the partial least square (PLS) scheme and hierarchical support vector regression (HSVR) scheme to elucidate the underlying passive diffusion mechanism and to predict the PAMPA effective permeability, respectively, in this study. It was observed that HSVR executed better than PLS as manifested by the predictions of the samples in the training set, test set, and outlier set as well as various statistical assessments. When applied to the mock test, which was designated to mimic real challenges, HSVR also showed better predictive performance. PLS, conversely, cannot cover some mechanistically interpretable relationships between descriptors and permeability. Accordingly, the synergy of predictive HSVR and interpretable PLS models can be greatly useful in facilitating drug discovery and development by predicting passive diffusion.

Theoretical Prediction of the Complex P-Glycoprotein Substrate Efflux Based on the Novel Hierarchical Support Vector Regression Scheme.

P-glycoprotein (P-gp), a membrane-bound transporter, can eliminate xenobiotics by transporting them out of the cells or blood–brain barrier (BBB) at the expense of ATP hydrolysis. Thus, P-gp mediated efflux plays a pivotal role in altering the absorption and disposition of a wide range of substrates. Nevertheless, the mechanism of P-gp substrate efflux is rather complex since it can take place through active transport and passive permeability in addition to multiple P-gp substrate binding sites. A nonlinear quantitative structure–activity relationship (QSAR) model was developed in this study using the novel machine learning-based hierarchical support vector regression (HSVR) scheme to explore the perplexing relationships between descriptors and efflux ratio. The predictions by HSVR were found to be in good agreement with the observed values for the molecules in the training set (n = 50, r2 = 0.96, = 0.94, RMSE = 0.10, s = 0.10) and test set (n = 13, q2 = 0.80–0.87, RMSE = 0.21, s = 0.22). When subjected to a variety of statistical validations, the developed HSVR model consistently met the most stringent criteria. A mock test also asserted the predictivity of HSVR. Consequently, this HSVR model can be adopted to facilitate drug discovery and development.

In silico prediction of the mutagenicity of nitroaromatic compounds using a novel two-QSAR approach

Certain drugs are nitroaromatic compounds, which are potentially toxic. As such, it is of practical importance to assess and predict their mutagenic potency in the process of drug discovery. A classical quantitative structure-activity relationship (QSAR) model was developed using the linear partial least square (PLS) scheme to understand the underline mutagenic mechanism and a non-classical QSAR model was derived using the machine learning-based hierarchical support vector regression (HSVR) to predict the mutagenicity of nitroaromatic compounds based on a series of mutagenicity data (TA98−S9). It was observed that HSVR performed better than PLS as manifested by the predictions of the samples in the training set, test set, and outlier set as well as various statistical validations. A mock test designated to mimic real challenges also confirmed the better performance of HSVR. Furthermore, HSVR exhibited superiority in predictivity, generalization capabilities, consistent performance, and robustness when compared with various published predictive models. PLS, conversely, revealed some mechanistically interpretable relationships between descriptors and mutagenicity. Thus, this two-QSAR approach using the predictive HSVR and interpretable PLS models in a synergistic fashion can be adopted to facilitate drug discovery and development by designing safer drug candidates with nitroaromatic moiety.

Intelligent Optimization of the Film-to-Fiber Ratio of a Degradable Braided Bicomponent Ureteral Stent.

A hierarchical support vector regression (SVR) model (HSVRM) was employed to correlate the compositions and mechanical properties of bicomponent stents composed of poly(lactic-co-glycolic acid) (PGLA) film and poly(glycolic acid) (PGA) fibers for urethral repair for the first time. PGLA film and PGA fibers could provide ureteral stents with good compressive and tensile properties, respectively. In bicomponent stents, high film content led to high stiffness, while high fiber content resulted in poor compressional properties. To simplify the procedures to optimize the ratio of PGLA film and PGA fiber in the stents, a hierarchical support vector regression model (HSVRM) and particle swarm optimization (PSO) algorithm were used to construct relationships between the film-to-fiber weight ratio and the measured compressional/tensile properties of the stents. The experimental data and simulated data fit well, proving that the HSVRM could closely reflect the relationship between the component ratio and performance properties of the ureteral stents.

Hierarchical approach for multiscale support vector regression.

Support vector regression (SVR) is based on a linear combination of displaced replicas of the same function, called a kernel. When the function to be approximated is nonstationary, the single kernel approach may be ineffective, as it is not able to follow the variations in the frequency content in the different regions of the input space. The hierarchical support vector regression (HSVR) model presented here aims to provide a good solution also in these cases. HSVR consists of a set of hierarchical layers, each containing a standard SVR with Gaussian kernel at a given scale. Decreasing the scale layer by layer, details are incorporated inside the regression function. HSVR has been widely applied to noisy synthetic and real datasets and it has shown the ability in denoising the original data, obtaining an effective multiscale reconstruction of better quality than that obtained by standard SVR. Results also compare favorably with multikernel approaches. Furthermore, tuning the SVR configuration parameters is strongly simplified in the HSVR model.

Predicting Mutagenicity of Aromatic Amines by Various Machine Learning Approaches

Aromatic amines are prevalently used in a wide variety of industries and are ubiquitous in foods and environment. Many of this class of compounds are potentially mutagenic or even carcinogenic, and the assessment and prediction of their mutagenicity are of practical importance because mutagenicity and carcinogenicity are toxicological end points that play major roles in the genesis of cancer and tumor. Quantitative structure-activity relationship of a homogeneous set of mutagenicity data (TA98 + S9), which was comprehensively compiled from literature, was developed by four machine learning methods, namely hierarchical support vector regression (HSVR), support vector machine, radial basis function neural networks, and genetic function algorithm. The predictions by these models are in good agreement with the experimental observations for those molecules in the training set (n = 97, r(2) = 0.78-0.93, q(2) = 0.64-0.93, root mean square error [RMSE] = 0.51-0.90, SD = 0.34-0.56) and the test set (n = 25, r(2) = 0.73-0.85, RMSE = 0.65-0.85, SD = 0.33-0.51). In addition, several validation criteria were adopted to verify those generated models, and a set of outliers was deliberately selected to examine the robustness of these four predictive models (n = 14, r(2) = 0.35-0.84, RMSE = 0.55-1.21, SD = 0.25-0.72). Finally, various cross-comparison schemes, namely forward comparisons, backward comparisons, and most common molecule comparisons, with assorted published predictive models were carried out. Our results indicate that the HSVR model is the most accurate, robust, and consistent and can be employed as a tool for predicting mutagenicity of aromatic amines.

A step in the realization of a speech recognition system based on gestural phonology and landmarks.

Current state-of-the-art speech recognition systems poorly perform in casual speech as they are not robust against acoustic variations. Variability is an intrinsic problem of phone-based recognition systems as phone-units may be distinctive in the cognitive domain, but their physical characteristics can vary considerably due to coarticulation. Articulatory phonology proposes that articulatory constriction gesture is an invariant action unit and speech can be decomposed into a constellation of gestures. Speech recognition studies have recently employed this framework in the sense that speech acoustic variations can be accounted for by gestural coarticulation and reduction. The VT time-functions are time-varying physical realizations of gestural constellations at distinct vocal tract sites for a given utterance. This study aims to predict VT time-functions from acoustic signals as a component model in a complete gesture-based speech recognition system. We will compare artificial neural-network (ANN) based nonlinear regression models against hierarchical support vector regression (SVR) to obtain VT time-functions from the speech signal. A single ANN can generate all 8 VT time functions, whereas SVRs generate one output at a time, necessitating use of 8 SVRs. We also explore usage of spectral parameters such as MFCC and PLPs against knowledge-based acoustic parameters (APs).

Prediction of human cytochrome P450 2B6‐substrate interactions using hierarchical support vector regression approach

The human cytochrome P450 2B6 can metabolize a number of clinical drugs. Inhibition of CYP2B6 by coadministered multiple drugs may lead to drug-drug interactions and undesired drug toxicity. The aim of this investigation is to develop an in silico model to predict the interactions between P450 2B6 and novel inhibitors using a novel hierarchical support vector regression (HSVR) approach, which simultaneously takes into account the coverage of applicability domain (AD) and the level of predictivity. Thirty-seven molecules were deliberately selected and rigorously scrutinized from the literature data, of which 26 and 11 molecules were treated as the training set and the test set to generate the models and to validate the generated models, respectively. The generated HSVR model gave rise to an r2 value of 0.97 for observed versus predicted pK(m) values for the training set, a q2 value of 0.93 by the 10-fold cross-validation, and an r2 value of 0.82 for the test set. Additionally, the predicted results show that the HSVR model outperformed the individual local models, the global model, and the consensus model. Thus, this HSVR model provides an accurate tool for the prediction of human cytochrome P450 2B6-substrate interactions and can be utilized as a primary filter to eliminate the potential selective inhibitor of CYP2B6.