Feasibility Evaluation of Online Classification-based Control for Gross Movement in a 2-DoF Prosthetic Arm.

Regression and classification models have been extensively studied to exploit the myoelectric and kinematic input information from the residual limb for the control of multiple degree-of-freedom (DoF) powered prostheses. The gross movement control of above-elbow prostheses is mainly based on regression models which map the available inputs to continuous prosthetic poses. However, the regression output is sensitive to the variation in the input signal. The myoelectric signal variation is usually large due to unintentional muscle contractions, which can deteriorate the user-in-the-loop performance with respect to the offline analysis. Alternatively, the classification models offer the advantage of being more robust to the input signal variation, but they were predominantly used for fine motor functions such as grasping. For gross motor functions, the discrete output may cause issues. Therefore, this work attempts to investigate the feasibility of utilising the classification model to control a 2-DoF transhumeral prosthesis for gross movement. The performance of 6 able-bodied subjects was evaluated in performing reaching and orientation matching tasks with a prosthetic arm in a virtual reality environment. The results were compared with the case of using their intact arms and existing results using the regression model. Our findings indicate that the classification-based method provides comparable performance to the regression model, making it a potential alternative for gross arm movement in multi-DoF prosthetic arms.

Machine learning approaches to study the structure-activity relationships of LpxC inhibitors.

Antimicrobial resistance (AMR) has emerged as one of the global threats to human health in the 21st century. Drug discovery of inhibitors against novel targets rather than conventional bacterial targets has been considered an inevitable strategy for the growing threat of AMR infections. In this study, we applied quantitative structure-activity relationship (QSAR) modeling to the LpxC inhibitors to predict the inhibitory activity. In addition, we performed various cheminformatics analysis consisting of the exploration of the chemical space, identification of chemotypes, performing structure-activity landscape and activity cliffs as well as construction of the Structure-Activity Similarity (SAS) map. We built a total of 24 QSAR classification models using PubChem and MACCS fingerprint with 12 various machine learning algorithms. The best model with PubChem fingerprint is the Extremely Gradient Boost model (accuracy on the training set: 0.937; accuracy on the 10-fold cross-validation set: 0.795; accuracy on the test set: 0.799). Furthermore, it was found that the best model using the MACCS fingerprint was the Random Forest model (accuracy on the training set: 0.955; accuracy on the 10-fold cross-validation set: 0.803; accuracy on the test set: 0.785). In addition, we have identified eight consensus activity cliff generators that are highly informative for further SAR investigations. It is hoped that findings presented herein can provide guidance for further lead optimization of LpxC inhibitors.

Machine Learning Approaches to Investigate the Structure-Activity Relationship of Angiotensin-Converting Enzyme Inhibitors.

Angiotensin-converting enzyme inhibitors (ACEIs) play a crucial role in treating conditions such as hypertension, heart failure, and kidney diseases. Nevertheless, the ACEIs currently available on the market are linked to a variety of adverse effects including renal insufficiency, which restricts their usage. There is thus an urgent need to optimize the currently available ACEIs. This study represents a structure-activity relationship investigation of ACEIs, employing machine learning to analyze data sets sourced from the ChEMBL database. Exploratory data analysis was performed to visualize the physicochemical properties of compounds by investigating the distributions, patterns, and statistical significance among the different bioactivity groups. Further scaffold analysis has identified 9 representative Murcko scaffolds with frequencies ≥10. Scaffold diversity has revealed that active ACEIs had more scaffold diversity than their intermediate and inactive counterparts, thereby indicating the significance of performing lead optimization on scaffolds of active ACEIs. Scaffolds 1, 3, 6, and 8 are unfavorable in comparison with scaffolds 2, 3, 5, 7, and 9. QSAR investigation of compiled data sets consisting of 549 compounds led to the selection of Mordred descriptor and Random Forest algorithm as the best model, which afforded robust model performance (accuracy: 0.981, 0.77, and 0.745; MCC: 0.972, 0.658, and 0.617 for the training set, 10-fold cross-validation set, and testing set, respectively). To enhance the model's robustness and predictability, we reduced the chemical diversity of the input compounds by using the 9 most prevalent Murcko scaffold-matched compounds (comprising a total of 168) followed by a subsequent QSAR model investigation using Mordred descriptor and extremely gradient boost algorithm (accuracy: 0.973, 0.849, and 0.823; MCC: 0.959, 0.786, and 0.742 for the training set, 10-fold cross-validation set, and testing set, respectively). Further illustration of the structure-activity relationship using SALI plots has enabled the identification of clusters of compounds that create activity cliffs. These findings, as presented in this study, contribute to the advancement of drug discovery and the optimization of ACEIs.

Sensor Selection with Composite Features in Identifying User-Intended Poses for Human-Prosthetic Interfaces.

A Human-Prosthetic Interface (HPI) serves to estimate and realise the limb pose intended by the human user, using the information obtained from sensors worn by the user. In recent studies, the HPI maps multi-joint limb poses (i.e. coordinated movement of the body and limbs) to the inputs of multiple sensors. This is in contrast to the conventional methods where each degree of freedom of the powered prosthesis is mapped to the input of one/a pair of sensors. In this approach, it is necessary to systematically select sensors that carry the most information for the intended set of poses, to improve system accuracy and/or minimise the number of sensors, thus the complexity, in the prosthetic system. In this paper, sensor selection process is systematically formulated to maximise the information contained in the input features for a given number of sensors. Most importantly, it accounts for composite features, which are features requiring information from multiple sensors. Such composite features exist and are important in HPIs as we seek to capture coordinated motion involving movements of multiple limb and body segments. A non-convex optimisation problem is formulated which accounts for the constraint introduced by the composite features. A projection matrix is utilised as the optimisation variable to select intended features for evaluation. The problem is solved by the proposed Sensor Selection with Composite Features (SS-CF) algorithm which adapts convex-relaxation techniques. The SS-CF is benchmarked against HPI with expert-selected sensors in the literature and against a greedy heuristic method. The outcome demonstrated the efficacy of the SS-CF algorithm.

Exploring the Chemical Space of CYP17A1 Inhibitors Using Cheminformatics and Machine Learning.

Cytochrome P450 17A1 (CYP17A1) is one of the key enzymes in steroidogenesis that produces dehydroepiandrosterone (DHEA) from cholesterol. Abnormal DHEA production may lead to the progression of severe diseases, such as prostatic and breast cancers. Thus, CYP17A1 is a druggable target for anti-cancer molecule development. In this study, cheminformatic analyses and quantitative structure-activity relationship (QSAR) modeling were applied on a set of 962 CYP17A1 inhibitors (i.e., consisting of 279 steroidal and 683 nonsteroidal inhibitors) compiled from the ChEMBL database. For steroidal inhibitors, a QSAR classification model built using the PubChem fingerprint along with the extra trees algorithm achieved the best performance, reflected by the accuracy values of 0.933, 0.818, and 0.833 for the training, cross-validation, and test sets, respectively. For nonsteroidal inhibitors, a systematic cheminformatic analysis was applied for exploring the chemical space, Murcko scaffolds, and structure-activity relationships (SARs) for visualizing distributions, patterns, and representative scaffolds for drug discoveries. Furthermore, seven total QSAR classification models were established based on the nonsteroidal scaffolds, and two activity cliff (AC) generators were identified. The best performing model out of these seven was model VIII, which is built upon the PubChem fingerprint along with the random forest algorithm. It achieved a robust accuracy across the training set, the cross-validation set, and the test set, i.e., 0.96, 0.92, and 0.913, respectively. It is anticipated that the results presented herein would be instrumental for further CYP17A1 inhibitor drug discovery efforts.

Cheminformatic Analysis and Machine Learning Modeling to Investigate Androgen Receptor Antagonists to Combat Prostate Cancer.

Prostate cancer (PCa) is a major leading cause of mortality of cancer among males. There have been numerous studies to develop antagonists against androgen receptor (AR), a crucial therapeutic target for PCa. This study is a systematic cheminformatic analysis and machine learning modeling to study the chemical space, scaffolds, structure-activity relationship, and landscape of human AR antagonists. There are 1678 molecules as final data sets. Chemical space visualization by physicochemical property visualization has demonstrated that molecules from the potent/active class generally have a mildly smaller molecular weight (MW), octanol-water partition coefficient (log P), number of hydrogen-bond acceptors (nHA), number of rotatable bonds (nRot), and topological polar surface area (TPSA) than molecules from intermediate/inactive class. The chemical space visualization in the principal component analysis (PCA) plot shows significant overlapping distributions between potent/active class molecules and intermediate/inactive class molecules; potent/active class molecules are intensively distributed, while intermediate/inactive class molecules are widely and sparsely distributed. Murcko scaffold analysis has shown low scaffold diversity in general, and scaffold diversity of potent/active class molecules is even lower than intermediate/inactive class molecules, indicating the necessity for developing molecules with novel scaffolds. Furthermore, scaffold visualization has identified 16 representative Murcko scaffolds. Among them, scaffolds 1, 2, 3, 4, 7, 8, 10, 11, 15, and 16 are highly favorable scaffolds due to their high scaffold enrichment factor values. Based on scaffold analysis, their local structure-activity relationships (SARs) were investigated and summarized. In addition, the global SAR landscape was explored by quantitative structure-activity relationship (QSAR) modelings and structure-activity landscape visualization. A QSAR classification model incorporating all of the 1678 molecules stands out as the best model from a total of 12 candidate models for AR antagonists (built on PubChem fingerprint, extra trees algorithm, accuracy for training set: 0.935, 10-fold cross-validation set: 0.735 and test set: 0.756). Deeper insights into the structure-activity landscape highlighted a total of seven significant activity cliff (AC) generators (ChEMBL molecule IDs: 160257, 418198, 4082265, 348918, 390728, 4080698, and 6530), which provide valuable SAR information for medicinal chemistry. The findings in this study provide new insights and guidelines for hit identification and lead optimization for the development of novel AR antagonists.

Towards combating antibiotic resistance by exploring the quantitative structure-activity relationship of NDM-1 inhibitors.

The emergence of New Delhi metallo-beta-lactamase-1 (NDM-1) has conferred enteric bacteria resistance to almost all beta-lactam antibiotics. Its capability of horizontal transfer through plasmids, amongst humans, animal reservoirs and the environment, has added up to the totality of antimicrobial resistance control, animal husbandry and food safety. Thus far, there have been no effective drugs for neutralizing NDM-1. This study explores the structure-activity relationship of NDM-1 inhibitors. IC50 values of NDM-1 inhibitors were compiled from both the ChEMBL database and literature. After curation, a final set of 686 inhibitors were used for machine learning model building using the random forest algorithm against 12 sets of molecular fingerprints. Benchmark results indicated that the KlekotaRothCount fingerprint provided the best overall performance with an accuracy of 0.978 and 0.778 for the training and testing set, respectively. Model interpretation revealed that nitrogen-containing features (KRFPC 4080, KRFPC 3882, KRFPC 677, KRFPC 3608, KRFPC 3750, KRFPC 4287 and KRFPC 3943), sulfur-containing substructures (KRFPC 2855 and KRFPC 4843), aromatic features (KRFPC 1566, KRFPC 1564, KRFPC 1642, KRFPC 3608, KRFPC 4287 and KRFPC 3943), carbonyl features (KRFPC 1193 and KRFPC 3025), aliphatic features (KRFPC 2975, KRFPC 297, KRFPC 3224 and KRFPC 669) are features contributing to NDM-1 inhibitory activity. It is anticipated that findings from this study would help facilitate the drug discovery of NDM-1 inhibitors by providing guidelines for further lead optimization.

Separability of Input Features and the Resulting Accuracy in Classifying Target Poses for Active Transhumeral Prosthetic Interfaces.

In active prostheses, it is desired to achieve target poses for a given family of tasks, for example, in the task of forward reaching using a transhumeral prosthesis with coordinated joint movements. To do so, it is necessary to distinguish these target poses accurately using the input features (e.g. kinematic and sEMG) obtained from the human users. However, the input features have conventionally been selected through human observations and influenced heavily by the availability of sensors in this context, which may not always yield the most relevant information to differentiate the target poses in the given task. In order to better select from a pool of available input features, those most appropriate for a given set of target poses, a measure that correlates well with the resulting classification accuracy is required so that it can inform the interface design process. In this paper, a scatter-matrix based class separability measure is adopted to quantitatively evaluate the separability of the target poses from their corresponding input features. A human experiment was performed on ten able-bodied subjects. Subjects were asked to perform forward-reaching movements with their arms on nine target poses in a virtual reality (VR) platform and the corresponding kinematic information of their arm movement and muscle activities were recorded. The accuracy of the prosthetic interface in determining the intended target poses of the human user during forward reaching is evaluated for different combinations of input features, selected from the kinematic and sEMG sensors worn by the users. The results demonstrate that employing input features that yield a high separability measure between target poses results in a high accuracy in identifying the intended target poses in the execution of the task.