VPatho: a deep learning-based two-stage approach for accurate prediction of gain-of-function and loss-of-function variants.

Determining the pathogenicity and functional impact (i.e. gain-of-function; GOF or loss-of-function; LOF) of a variant is vital for unraveling the genetic level mechanisms of human diseases. To provide a 'one-stop' framework for the accurate identification of pathogenicity and functional impact of variants, we developed a two-stage deep-learning-based computational solution, termed VPatho, which was trained using a total of 9619 pathogenic GOF/LOF and 138 026 neutral variants curated from various databases. A total number of 138 variant-level, 262 protein-level and 103 genome-level features were extracted for constructing the models of VPatho. The development of VPatho consists of two stages: (i) a random under-sampling multi-scale residual neural network (ResNet) with a newly defined weighted-loss function (RUS-Wg-MSResNet) was proposed to predict variants' pathogenicity on the gnomAD_NV + GOF/LOF dataset; and (ii) an XGBOD model was constructed to predict the functional impact of the given variants. Benchmarking experiments demonstrated that RUS-Wg-MSResNet achieved the highest prediction performance with the weights calculated based on the ratios of neutral versus pathogenic variants. Independent tests showed that both RUS-Wg-MSResNet and XGBOD achieved outstanding performance. Moreover, assessed using variants from the CAGI6 competition, RUS-Wg-MSResNet achieved superior performance compared to state-of-the-art predictors. The fine-trained XGBOD models were further used to blind test the whole LOF data downloaded from gnomAD and accordingly, we identified 31 nonLOF variants that were previously labeled as LOF/uncertain variants. As an implementation of the developed approach, a webserver of VPatho is made publicly available at http://csbio.njust.edu.cn/bioinf/vpatho/ to facilitate community-wide efforts for profiling and prioritizing the query variants with respect to their pathogenicity and functional impact.

Feasibility of undersampled spiral trajectories in MREPT for fast conductivity imaging.

PURPOSE: To investigate spiral-based imaging including trajectories with undersampling as a fast and robust alternative for phase-based magnetic resonance electrical properties tomography (MREPT) techniques. METHODS: Spiral trajectories with various undersampling ratios were prescribed to acquire images from an experimental phantom and a healthy volunteer at 3T. The non-Cartesian acquisitions were reconstructed using SPIRiT, and conductivity maps were derived using phase-based cr-MREPT. The resulting maps were compared between different sampling trajectories. Additionally, a conductivity map was obtained using a Cartesian balanced SSFP acquisition from the volunteer to comparatively demonstrate the robustness of the proposed method. RESULTS: The phantom and volunteer results illustrate the benefits of the spiral acquisitions. Specifically, undersampled spiral acquisitions display improved robustness against field inhomogeneity artifacts and lowered SD values with shortened readout times. Furthermore, average of conductivity values measured for the cerebrospinal fluid with the spiral acquisitions were 1.703 S/m, indicating a close agreement with the theoretical values of 1.794 S/m. CONCLUSION: A spiral-based acquisition framework for conductivity imaging with and without undersampling is presented. Overall, spiral-based acquisitions improved robustness against field inhomogeneity artifacts, while achieving whole head coverage with multiple averages in less than a minute.

Efficient pulse sequence design framework for high-dimensional MR fingerprinting scans using systematic error index.

PURPOSE: For effective optimization of MR fingerprinting (MRF) pulse sequences, estimating and minimizing errors from actual scan conditions are crucial. Although virtual-scan simulations offer an approximation to these errors, their computational demands become expensive for high-dimensional MRF frameworks, where interactions between more than two tissue properties are considered. This complexity makes sequence optimization impractical. We introduce a new mathematical model, the systematic error index (SEI), to address the scalability challenges for high-dimensional MRF sequence design. METHODS: By eliminating the need to perform dictionary matching, the SEI model approximates quantification errors with low computational costs. The SEI model was validated in comparison with virtual-scan simulations. The SEI model was further applied to optimize three high-dimensional MRF sequences that quantify two to four tissue properties. The optimized scans were examined in simulations and healthy subjects. RESULTS: The proposed SEI model closely approximated the virtual-scan simulation outcomes while achieving hundred- to thousand-times acceleration in the computational speed. In both simulation and in vivo experiments, the optimized MRF sequences yield higher measurement accuracy with fewer undersampling artifacts at shorter scan times than the heuristically designed sequences. CONCLUSION: We developed an efficient method for estimating real-world errors in MRF scans with high computational efficiency. Our results illustrate that the SEI model could approximate errors both qualitatively and quantitatively. We also proved the practicality of the SEI model of optimizing sequences for high-dimensional MRF frameworks with manageable computational power. The optimized high-dimensional MRF scans exhibited enhanced robustness against undersampling and system imperfections with faster scan times.

Fast 3D fMRI acquisition with high spatial resolutions over a reduced FOV.

PURPOSE: To develop and demonstrate a fast 3D fMRI acquisition technique with high spatial resolution over a reduced FOV, named k-t 3D reduced FOV imaging (3D-rFOVI). METHODS: Based on 3D gradient-echo EPI, k-t 3D-rFOVI used a 2D RF pulse to reduce the FOV in the in-plane phase-encoding direction, boosting spatial resolution without increasing echo train length. For image acceleration, full sampling was applied in the central k-space region along the through-slab direction (kz) for all time frames, while randomized undersampling was used in outer kz regions at different time frames. Images were acquired at 3T and reconstructed using a method based on partial separability. fMRI detection sensitivity of k-t 3D-rFOVI was quantitively analyzed with simulation data. Human visual fMRI experiments were performed to evaluate k-t 3D-rFOVI and compare it with a commercial multiband EPI sequence. RESULTS: The simulation data showed that k-t 3D-rFOVI can detect 100% of fMRI activations with an acceleration factor (R) of 2 and ˜80% with R = 6. In the human fMRI data acquired with 1.5-mm spatial resolution and 800-ms volume TR (TRvol), k-t 3D-rFOVI with R = 4 detected 46% more activated voxels in the visual cortex than the multiband EPI. Additional fMRI experiments showed that k-t 3D-rFOVI can achieve TRvol of 480 ms with R = 6, while reliably detecting visual activation. CONCLUSIONS: k-t 3D-rFOVI can simultaneously achieve a high spatial resolution (1.5-mm isotropically) and short TRvol (480-ms) at 3T. It offers a robust acquisition technique for fast fMRI studies over a focused brain volume.

Accelerated model-based T1, T2* and proton density mapping using a Bayesian approach with automatic hyperparameter estimation.

PURPOSE: To achieve automatic hyperparameter estimation for the model-based recovery of quantitative MR maps from undersampled data, we propose a Bayesian formulation that incorporates the signal model and sparse priors among multiple image contrasts. THEORY: We introduce a novel approximate message passing framework "AMP-PE" that enables the automatic and simultaneous recovery of hyperparameters and quantitative maps. METHODS: We employed the variable-flip-angle method to acquire multi-echo measurements using gradient echo sequence. We explored undersampling schemes to incorporate complementary sampling patterns across different flip angles and echo times. We further compared AMP-PE with conventional compressed sensing approaches such as the l 1 $$ {l}_1 $$ -norm minimization, PICS and other model-based approaches such as GraSP, MOBA. RESULTS: Compared to conventional compressed sensing approaches such as the l 1 $$ {l}_1 $$ -norm minimization and PICS, AMP-PE achieved superior reconstruction performance with lower errors in T 2 ∗ $$ {\mathrm{T}}_2^{\ast } $$ mapping and comparable performance in T 1 $$ {\mathrm{T}}_1 $$ and proton density mappings. When compared to other model-based approaches including GraSP and MOBA, AMP-PE exhibited greater robustness and outperformed GraSP in reconstruction error. AMP-PE offers faster speed than MOBA. AMP-PE performed better than MOBA at higher sampling rates and worse than MOBA at a lower sampling rate. Notably, AMP-PE eliminates the need for hyperparameter tuning, which is a requisite for all the other approaches. CONCLUSION: AMP-PE offers the benefits of model-based recovery with the additional key advantage of automatic hyperparameter estimation. It works adeptly in situations where ground-truth is difficult to obtain and in clinical environments where it is desirable to automatically adapt hyperparameters to individual protocol, scanner and patient.

A novel fusion technology utilizing complex network and sequence information for FAD-binding site identification.

Flavin adenine dinucleotide (FAD) binding sites play an increasingly important role as useful targets for inhibiting bacterial infections. To reveal protein topological structural information as a reasonable complement for the identification FAD-binding sites, we designed a novel fusion technology according to sequence and complex network. The specially designed feature vectors were combined and fed into CatBoost for model construction. Moreover, due to the minority class (positive samples) is more significant for biological researches, a random under-sampling technique was applied to solve the imbalance. Compared with the previous methods, our methods achieved the best results for two independent test datasets. Especially, the MCC obtained by FADsite and FADsite_seq were 14.37 %-53.37 % and 21.81 %-60.81 % higher than the results of existing methods on Test6; and they showed improvements ranging from 6.03 % to 21.96 % and 19.77 %-35.70 % on Test4. Meanwhile, statistical tests show that our methods significantly differ from the state-of-the-art methods and the cross-entropy loss shows that our methods have high certainty. The excellent results demonstrated the effectiveness of using sequence and complex network information in identifying FAD-binding sites. It may be complementary to other biological studies. The data and resource codes are available at https://github.com/Kangxiaoneuq/FADsite.

Understanding random resampling techniques for class imbalance correction and their consequences on calibration and discrimination of clinical risk prediction models.

OBJECTIVE: Class imbalance is sometimes considered a problem when developing clinical prediction models and assessing their performance. To address it, correction strategies involving manipulations of the training dataset, such as random undersampling or oversampling, are frequently used. The aim of this article is to illustrate the consequences of these class imbalance correction strategies on clinical prediction models' internal validity in terms of calibration and discrimination performances. METHODS: We used both heuristic intuition and formal mathematical reasoning to characterize the relations between conditional probabilities of interest and probabilities targeted when using random undersampling or oversampling. We propose a plug-in estimator that represents a natural correction for predictions obtained from models that have been trained on artificially balanced datasets ("naïve" models). We conducted a Monte Carlo simulation with two different data generation processes and present a real-world example using data from the International Stroke Trial database to empirically demonstrate the consequences of applying random resampling techniques for class imbalance correction on calibration and discrimination (in terms of Area Under the ROC, AUC) for logistic regression and tree-based prediction models. RESULTS: Across our simulations and in the real-world example, calibration of the naïve models was very poor. The models using the plug-in estimator generally outperformed the models relying on class imbalance correction in terms of calibration while achieving the same discrimination performance. CONCLUSION: Random resampling techniques for class imbalance correction do not generally improve discrimination performance (i.e., AUC), and their use is hard to justify when aiming at providing calibrated predictions. Improper use of such class imbalance correction techniques can lead to suboptimal data usage and less valid risk prediction models.

Prediction of hypertension risk based on multiple feature fusion.

OBJECTIVE: In the application of machine learning to the prediction of hypertension, many factors have seriously affected the classification accuracy and generalization performance. We propose a pulse wave classification model based on multi-feature fusion for accuracy prediction of hypertension. METHODS AND MATERIALS: We propose an ensemble under-sampling model with dynamic weights to decrease the influence of class imbalance on classification, further to automatically classify of hypertension on inquiry diagnosis. We also build a deep learning model based on hybrid attention mechanism, which transforms pulse waves to feature maps for extraction of in-depth features, so as to automatically classify hypertension on pulse diagnosis. We build the multi-feature fusion model based on dynamic Dempster/Shafer (DS) theory combining inquiry diagnosis and pulse diagnosis to enhance fault tolerance of prediction for multiple classifiers. In addition, this study calculates feature importance ranking of scale features on inquiry diagnosis and temporal and frequency-domain features on pulse diagnosis. RESULTS: The accuracy, sensitivity, specificity, F1-score and G-mean after 5-fold cross-validation were 94.08%, 93.43%, 96.86%, 93.45% and 95.12%, respectively, based on the hypertensive samples of 409 cases from Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine and Hospital of Integrated Traditional Chinese and Western Medicine. We find the key factors influencing hypertensive classification accuracy, so as to assist in the prevention and clinical diagnosis of hypertension. CONCLUSION: Compared with the state-of-the-art models, the multi-feature fusion model effectively utilizes the patients' correlated multimodal features, and has higher classification accuracy and generalization performance.

usDSM: a novel method for deleterious synonymous mutation prediction using undersampling scheme.

Although synonymous mutations do not alter the encoded amino acids, they may impact protein function by interfering with the regulation of RNA splicing or altering transcript splicing. New progress on next-generation sequencing technologies has put the exploration of synonymous mutations at the forefront of precision medicine. Several approaches have been proposed for predicting the deleterious synonymous mutations specifically, but their performance is limited by imbalance of the positive and negative samples. In this study, we firstly expanded the number of samples greatly from various data sources and compared six undersampling strategies to solve the problem of the imbalanced datasets. The results suggested that cluster centroid is the most effective scheme. Secondly, we presented a computational model, undersampling scheme based method for deleterious synonymous mutation (usDSM) prediction, using 14-dimensional biology features and random forest classifier to detect the deleterious synonymous mutation. The results on the test datasets indicated that the proposed usDSM model can attain superior performance in comparison with other state-of-the-art machine learning methods. Lastly, we found that the deep learning model did not play a substantial role in deleterious synonymous mutation prediction through a lot of experiments, although it achieves superior results in other fields. In conclusion, we hope our work will contribute to the future development of computational methods for a more accurate prediction of the deleterious effect of human synonymous mutation. The web server of usDSM is freely accessible at http://usdsm.xialab.info/.

Mitigating undersampling errors in MR fingerprinting by sequence optimization.

PURPOSE: To develop a method for MR Fingerprinting (MRF) sequence optimization that takes both the applied undersampling pattern and a realistic reference map into account. METHODS: A predictive model for the undersampling error leveraging on perturbation theory was exploited to optimize the MRF flip angle sequence for improved robustness against undersampling artifacts. In this framework parameter maps from a previously acquired MRF scan were used as reference. Sequences were optimized for different sequence lengths, smoothness constraints and undersampling factors. Numerical simulations and in vivo measurements in eight healthy subjects were performed to assess the effect of the performed optimization. The optimized MRF sequences were compared to a conventionally shaped flip angle pattern and an optimized pattern based on the Cramér-Rao lower bound (CRB). RESULTS: Numerical simulations and in vivo results demonstrate that the undersampling errors can be suppressed by flip angle optimization. Analysis of the in vivo results show that a sequence optimized for improved robustness against undersampling with a flip angle train of length 400 yielded significantly lower median absolute errors in T 1 : 5 . 6 % ± 2 . 9 % and T 2 : 7 . 9 % ± 2 . 3 % compared to the conventional ( T 1 : 8 . 0 % ± 1 . 9 % , T 2 : 14 . 5 % ± 2 . 6 % ) and CRB-based ( T 1 : 21 . 6 % ± 4 . 1 % , T 2 : 31 . 4 % ± 4 . 4 % ) sequences. CONCLUSION: The proposed method is able to optimize the MRF flip angle pattern such that significant mitigation of the artifacts from strong k-space undersampling in MRF is achieved.