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The prediction of interactions between novel drugs and biological targets is a vital step in the early stage of the drug discovery pipeline. Many deep learning approaches have been proposed over the last decade, with a substantial fraction of them sharing the same underlying two-branch architecture. Their distinction is limited to the use of different types of feature representations and branches (multi-layer perceptrons, convolutional neural networks, graph neural networks and transformers). In contrast, the strategy used to combine the outputs (embeddings) of the branches has remained mostly the same. The same general architecture has also been used extensively in the area of recommender systems, where the choice of an aggregation strategy is still an open question. In this work, we investigate the effectiveness of three different embedding aggregation strategies in the area of drug–target interaction (DTI) prediction. We formally define these strategies and prove their universal approximator capabilities. We then present experiments that compare the different strategies on benchmark datasets from the area of DTI prediction, showcasing conditions under which specific strategies could be the obvious choice.

  [...]we discuss some key future advances, open questions and challenges in this developing field, when moving toward low-frequency variants and cross-phenotype interactions. Multivariate modeling approaches have already been shown to provide improved insights into genetic mechanisms and the interaction networks behind many complex traits, including atherosclerosis, coronary heart disease, and lipid levels, which would have gone undetected using the standard univariate modeling [2], [19]-[22].

Due to relatively high costs and labor required for experimental profiling of the full target space of chemical compounds, various machine learning models have been proposed as cost-effective means to advance this process in terms of predicting the most potent compound-target interactions for subsequent verification. However, most of the model predictions lack direct experimental validation in the laboratory, making their practical benefits for drug discovery or repurposing applications largely unknown. Here, we therefore introduce and carefully test a systematic computational-experimental framework for the prediction and pre-clinical verification of drug-target interactions using a well-established kernel-based regression algorithm as the prediction model. To evaluate its performance, we first predicted unmeasured binding affinities in a large-scale kinase inhibitor profiling study, and then experimentally tested 100 compound-kinase pairs. The relatively high correlation of 0.77 (p < 0.0001) between the predicted and measured bioactivities supports the potential of the model for filling the experimental gaps in existing compound-target interaction maps. Further, we subjected the model to a more challenging task of predicting target interactions for such a new candidate drug compound that lacks prior binding profile information. As a specific case study, we used tivozanib, an investigational VEGF receptor inhibitor with currently unknown off-target profile. Among 7 kinases with high predicted affinity, we experimentally validated 4 new off-targets of tivozanib, namely the Src-family kinases FRK and FYN A, the non-receptor tyrosine kinase ABL1, and the serine/threonine kinase SLK. Our sub-sequent experimental validation protocol effectively avoids any possible information leakage between the training and validation data, and therefore enables rigorous model validation for practical applications. These results demonstrate that the kernel-based modeling approach offers practical benefits for probing novel insights into the mode of action of investigational compounds, and for the identification of new target selectivities for drug repurposing applications.

To develop and validate a classifier system for prediction of prostate cancer (PCa) Gleason score (GS) using radiomics and texture features of T2-weighted imaging (T2w), diffusion weighted imaging (DWI) acquired using high b values, and T2-mapping (T2). T2w, DWI (12 b values, 0-2000 s/mm2), and T2 data sets of 62 patients with histologically confirmed PCa were acquired at 3T using surface array coils. The DWI data sets were post-processed using monoexponential and kurtosis models, while T2w was standardized to a common scale. Local statistics and 8 different radiomics/texture descriptors were utilized at different configurations to extract a total of 7105 unique per-tumor features. Regularized logistic regression with implicit feature selection and leave pair out cross validation was used to discriminate tumors with 3+3 vs >3+3 GS. In total, 100 PCa lesions were analysed, of those 20 and 80 had GS of 3+3 and >3+3, respectively. The best model performance was obtained by selecting the top 1% features of T2w, ADCm and K with ROC AUC of 0.88 (95% CI of 0.82-0.95). Features from T2 mapping provided little added value. The most useful texture features were based on the gray-level co-occurrence matrix, Gabor transform, and Zernike moments. Texture feature analysis of DWI, post-processed using monoexponential and kurtosis models, and T2w demonstrated good classification performance for GS of PCa. In multisequence setting, the optimal radiomics based texture extraction methods and parameters differed between different image types.

The automatic detection of facial expressions of pain is needed to ensure accurate pain assessment of patients who are unable to self-report pain. To overcome the challenges of automatic systems for determining pain levels based on facial expressions in clinical patient monitoring, a surface electromyography method was tested for feasibility in healthy volunteers. In the current study, two types of experimental gradually increasing pain stimuli were induced in thirty-one healthy volunteers who attended the study. We used a surface electromyography method to measure the activity of five facial muscles to detect facial expressions during pain induction. Statistical tests were used to analyze the continuous electromyography data, and a supervised machine learning was applied for pain intensity prediction model. Muscle activation of corrugator supercilii was most strongly associated with self-reported pain, and the levator labii superioris and orbicularis oculi showed a statistically significant increase in muscle activation when the pain stimulus reached subjects' self -reported pain thresholds. The two strongest features associated with pain, the waveform length of the corrugator supercilii and levator labii superioris, were selected for a prediction model. The performance of the pain prediction model resulted in a c-index of 0.64. In the study results, the most detectable difference in muscle activity during the pain experience was connected to eyebrow lowering, nose wrinkling and upper lip raising. As the performance of the prediction model remains modest, yet with a statistically significant ordinal classification, we suggest testing with a larger sample size to further explore the variables that affect variation in expressiveness and subjective pain experience.

Three methods to estimate the presence of ground surface stones from publicly available Airborne Laser Scanning (ALS) point clouds are presented. The first method approximates the local curvature by local linear multi-scale fitting, and the second method uses Discrete-Differential Gaussian curvature based on the ground surface triangulation. The third baseline method applies Laplace filtering to Digital Elevation Model (DEM) in a 2 m regular grid data. All methods produce an approximate Gaussian curvature distribution which is then vectorized and classified by logistic regression. Two training data sets consisted of 88 and 674 polygons of mass-flow deposits, respectively. The locality of the polygon samples is a sparse canopy boreal forest, where the density of ALS ground returns is sufficiently high to reveal information about terrain micro-topography. The surface stoniness of each polygon sample was categorized for supervised learning by expert observation on the site. The leave-pair-out (L2O) cross-validation of the local linear fit method results in the area under curve A U C = 0 . 74 and A U C = 0 . 85 on two data sets, respectively. This performance can be expected to suit real world applications such as detecting coarse-grained sediments for infrastructure construction. A wall-to-wall predictor based on the study was demonstrated.

The aim of this prospective single-institution clinical trial (NCT02002455) was to evaluate the potential of advanced post-processing methods for 18 F-Fluciclovine PET and multisequence multiparametric MRI in the prediction of prostate cancer (PCa) aggressiveness, defined by Gleason Grade Group (GGG). 21 patients with PCa underwent PET/CT, PET/MRI and MRI before prostatectomy. DWI was post-processed using kurtosis (ADC k , K), mono- (ADC m ), and biexponential functions (f, D p , D f ) while Logan plots were used to calculate volume of distribution (V T ). In total, 16 unique PET (V T , SUV) and MRI derived quantitative parameters were evaluated. Univariate and multivariate analysis were carried out to estimate the potential of the quantitative parameters and their combinations to predict GGG 1 vs >1, using logistic regression with a nested leave-pair out cross validation (LPOCV) scheme and recursive feature elimination technique applied for feature selection. The second order rotating frame imaging (RAFF), monoexponential and kurtosis derived parameters had LPOCV AUC in the range of 0.72 to 0.92 while the corresponding value for V T was 0.85. T he best performance for GGG prediction was achieved by K parameter of kurtosis function followed by quantitative parameters based on DWI, RAFF and 18 F-FACBC PET. No major improvement was achieved using parameter combinations with or without feature selection. Addition of 18 F-FACBC PET derived parameters (V T , SUV) to DWI and RAFF derived parameters did not improve LPOCV AUC.

The rut formation during forest operations is an undesirable phenomenon. A methodology is being proposed to measure the rut depth distribution of a logging site by photogrammetric point clouds produced by unmanned aerial vehicles (UAV). The methodology includes five processing steps that aim at reducing the noise from the surrounding trees and undergrowth for identifying the trails. A canopy height model is produced to focus the point cloud on the open pathway around the forest machine trail. A triangularized ground model is formed by a point cloud filtering method. The ground model is vectorized using the histogram of directed curvatures (HOC) method to produce an overall ground visualization. Finally, a manual selection of the trails leads to an automated rut depth profile analysis. The bivariate correlation (Pearson’s r) between rut depths measured manually and by UAV photogrammetry is r = 0.67 . The two-class accuracy a of detecting the rut depth exceeding 20 cm is a = 0.65 . There is potential for enabling automated large-scale evaluation of the forestry areas by using autonomous drones and the process described.