Fuzzy kernel evidence Random Forest for identifying pseudouridine sites.

Pseudouridine is an RNA modification that is widely distributed in both prokaryotes and eukaryotes, and plays a critical role in numerous biological activities. Despite its importance, the precise identification of pseudouridine sites through experimental approaches poses significant challenges, requiring substantial time and resources.Therefore, there is a growing need for computational techniques that can reliably and quickly identify pseudouridine sites from vast amounts of RNA sequencing data. In this study, we propose fuzzy kernel evidence Random Forest (FKeERF) to identify pseudouridine sites. This method is called PseU-FKeERF, which demonstrates high accuracy in identifying pseudouridine sites from RNA sequencing data. The PseU-FKeERF model selected four RNA feature coding schemes with relatively good performance for feature combination, and then input them into the newly proposed FKeERF method for category prediction. FKeERF not only uses fuzzy logic to expand the original feature space, but also combines kernel methods that are easy to interpret in general for category prediction. Both cross-validation tests and independent tests on benchmark datasets have shown that PseU-FKeERF has better predictive performance than several state-of-the-art methods. This new method not only improves the accuracy of pseudouridine site identification, but also provides a certain reference for disease control and related drug development in the future.

Optimization-derived blood input function using a kernel method and its evaluation with total-body PET for brain parametric imaging.

Dynamic PET allows quantification of physiological parameters through tracer kinetic modeling. For dynamic imaging of brain or head and neck cancer on conventional PET scanners with a short axial field of view, the image-derived input function (ID-IF) from intracranial blood vessels such as the carotid artery (CA) suffers from severe partial volume effects. Alternatively, optimization-derived input function (OD-IF) by the simultaneous estimation (SIME) method does not rely on an ID-IF but derives the input function directly from the data. However, the optimization problem is often highly ill-posed. We proposed a new method that combines the ideas of OD-IF and ID-IF together through a kernel framework. While evaluation of such a method is challenging in human subjects, we used the uEXPLORER total-body PET system that covers major blood pools to provide a reference for validation. METHODS: The conventional SIME approach estimates an input function using a joint estimation together with kinetic parameters by fitting time activity curves from multiple regions of interests (ROIs). The input function is commonly parameterized with a highly nonlinear model which is difficult to estimate. The proposed kernel SIME method exploits the CA ID-IF as a priori information via a kernel representation to stabilize the SIME approach. The unknown parameters are linear and thus easier to estimate. The proposed method was evaluated using 18F-fluorodeoxyglucose studies with both computer simulations and 20 human-subject scans acquired on the uEXPLORER scanner. The effect of the number of ROIs on kernel SIME was also explored. RESULTS: The estimated OD-IF by kernel SIME showed a good match with the reference input function and provided more accurate estimation of kinetic parameters for both simulation and human-subject data. The kernel SIME led to the highest correlation coefficient (R = 0.97) and the lowest mean absolute error (MAE = 10.5 %) compared to using the CA ID-IF (R = 0.86, MAE = 108.2 %) and conventional SIME (R = 0.57, MAE = 78.7 %) in the human-subject evaluation. Adding more ROIs improved the overall performance of the kernel SIME method. CONCLUSION: The proposed kernel SIME method shows promise to provide an accurate estimation of the blood input function and kinetic parameters for brain PET parametric imaging.

An accelerated failure time regression model for illness-death data: A frailty approach.

This work presents a new model and estimation procedure for the illness-death survival data where the hazard functions follow accelerated failure time (AFT) models. A shared frailty variate induces positive dependence among failure times of a subject for handling the unobserved dependency between the nonterminal and the terminal failure times given the observed covariates. The motivation behind the proposed modeling approach is to leverage the well-known interpretability advantage of AFT models with respect to the observed covariates, while also benefiting from the simple and intuitive interpretation of the hazard functions. A semiparametric maximum likelihood estimation procedure is developed via a kernel smoothed-aided expectation-maximization algorithm, and variances are estimated by weighted bootstrap. We consider existing frailty-based illness-death models and place particular emphasis on highlighting the contribution of our current research. The breast cancer data of the Rotterdam tumor bank are analyzed using the proposed as well as existing illness-death models. The results are contrasted and evaluated based on a new graphical goodness-of-fit procedure. Simulation results and data analysis nicely demonstrate the practical utility of the shared frailty variate with the AFT regression model under the illness-death framework.

Propensity score analysis with local balance.

Most propensity score (PS) analysis methods rely on a correctly specified parametric PS model, which may result in biased estimation of the average treatment effect (ATE) when the model is misspecified. More flexible nonparametric models for treatment assignment alleviate this issue, but they do not always guarantee covariate balance. Methods that force balance in the means of covariates and their transformations between the treatment groups, termed global balance in this article, do not always lead to unbiased estimation of ATE. Their estimated propensity scores only ensure global balance but not the balancing property, which is defined as the conditional independence between treatment assignment and covariates given the propensity score. The balancing property implies not only global balance but also local balance-the mean balance of covariates in propensity score stratified sub-populations. Local balance implies global balance, but the reverse is false. We propose the propensity score with local balance (PSLB) methodology, which incorporates nonparametric propensity score models and optimizes local balance. Extensive numerical studies showed that the proposed method can substantially outperform existing methods that estimate the propensity score by optimizing global balance, when the model is misspecified. The proposed method is implemented in the R package PSLB.

Two novel nonlinear multivariate grey models with kernel learning for small-sample time series prediction.

For many applications, small-sample time series prediction based on grey forecasting models has become indispensable. Many algorithms have been developed recently to make them effective. Each of these methods has a specialized application depending on the properties of the time series that need to be inferred. In order to develop a generalized nonlinear multivariable grey model with higher compatibility and generalization performance, we realize the nonlinearization of traditional GM(1,N), and we call it NGM(1,N). The unidentified nonlinear function that maps the data into a better representational space is present in both the NGM(1,N) and its response function. The original optimization problem with linear equality constraints is established in terms of parameter estimation for the NGM(1,N), and two different approaches are taken to solve it. The former is the Lagrange multiplier method, which converts the optimization problem into a linear system to be solved; and the latter is the standard dualization method utilizing Lagrange multipliers, that uses a flexible estimation equation for the development coefficient. As the size of the training data increases, the estimation results of the potential development coefficient get richer and the final estimation results using the average value are more reliable. The kernel function expresses the dot product of two unidentified nonlinear functions during the solving process, greatly lowering the computational complexity of nonlinear functions. Three numerical examples show that the LDNGM(1,N) outperforms the other multivariate grey models compared in terms of generalization performance. The duality theory and framework with kernel learning are instructive for further research around multivariate grey models to follow. Supplementary Information: The online version contains supplementary material available at 10.1007/s11071-023-08296-y.

MCKAT: a multi-dimensional copy number variant kernel association test.

BACKGROUND: Copy number variants (CNVs) are the gain or loss of DNA segments in the genome. Studies have shown that CNVs are linked to various disorders, including autism, intellectual disability, and schizophrenia. Consequently, the interest in studying a possible association of CNVs to specific disease traits is growing. However, due to the specific multi-dimensional characteristics of the CNVs, methods for testing the association between CNVs and the disease-related traits are still underdeveloped. We propose a novel multi-dimensional CNV kernel association test (MCKAT) in this paper. We aim to find significant associations between CNVs and disease-related traits using kernel-based methods. RESULTS: We address the multi-dimensionality in CNV characteristics. We first design a single pair CNV kernel, which contains three sub-kernels to summarize the similarity between two CNVs considering all CNV characteristics. Then, aggregate single pair CNV kernel to the whole chromosome CNV kernel, which summarizes the similarity between CNVs in two or more chromosomes. Finally, the association between the CNVs and disease-related traits is evaluated by comparing the similarity in the trait with kernel-based similarity using a score test in a random effect model. We apply MCKAT on genome-wide CNV datasets to examine the association between CNVs and disease-related traits, which demonstrates the potential usefulness the proposed method has for the CNV association tests. We compare the performance of MCKAT with CKAT, a uni-dimensional kernel method. Based on the results, MCKAT indicates stronger evidence, smaller p-value, in detecting significant associations between CNVs and disease-related traits in both rare and common CNV datasets. CONCLUSION: A multi-dimensional copy number variant kernel association test can detect statistically significant associated CNV regions with any disease-related trait. MCKAT can provide biologists with CNV hot spots at the cytogenetic band level that CNVs on them may have a significant association with disease-related traits. Using MCKAT, biologists can narrow their investigation from the whole genome, including many genes and CNVs, to more specific cytogenetic bands that MCKAT identifies. Furthermore, MCKAT can help biologists detect significantly associated CNVs with disease-related traits across a patient group instead of examining each subject's CNVs case by case.

Predictive generalized varying-coefficient longitudinal model.

We propose a nonparametric bivariate varying coefficient generalized linear model to predict a mean response trajectory in the future given an individual's characteristics at present or an earlier time point in a longitudinal study. Given the measurement time of the predictors, the coefficients vary as functions of the future time over which the prediction of the mean response is concerned and illustrate the dynamic association between the future response and the earlier measured predictors. We use a nonparametric approach that takes advantage of features of both the kernel and the spline methods for estimation. The resulting coefficient estimator is asymptotically consistent under mild regularity conditions. We also develop a new bootstrap approach to construct simultaneous confidence bands for statistical inference about the coefficients and the predicted response trajectory based on the coverage rate of bootstrap estimates. We use the Framingham Heart Study to illustrate the methodology. The proposed procedure is applied to predict the probability trajectory of hypertension risk given individuals' health condition in early adulthood and to examine the impact of risk factors in early adulthood on a long-term risk of hypertension over several decades.

Improved identification of abdominal aortic aneurysm using the Kernelized Expectation Maximization algorithm.

Abdominal aortic aneurysm (AAA) monitoring and risk of rupture is currently assumed to be correlated with the aneurysm diameter. Aneurysm growth, however, has been demonstrated to be unpredictable. Using PET to measure uptake of [18F]-NaF in calcified lesions of the abdominal aorta has been shown to be useful for identifying AAA and to predict its growth. The PET low spatial resolution, however, can affect the accuracy of the diagnosis. Advanced edge-preserving reconstruction algorithms can overcome this issue. The kernel method has been demonstrated to provide noise suppression while retaining emission and edge information. Nevertheless, these findings were obtained using simulations, phantoms and a limited amount of patient data. In this study, the authors aim to investigate the usefulness of the anatomically guided kernelized expectation maximization (KEM) and the hybrid KEM (HKEM) methods and to judge the statistical significance of the related improvements. Sixty-one datasets of patients with AAA and 11 from control patients were reconstructed with ordered subsets expectation maximization (OSEM), HKEM and KEM and the analysis was carried out using the target-to-blood-pool ratio, and a series of statistical tests. The results show that all algorithms have similar diagnostic power, but HKEM and KEM can significantly recover uptake of lesions and improve the accuracy of the diagnosis by up to 22% compared to OSEM. The same improvements are likely to be obtained in clinical applications based on the quantification of small lesions, like for example cancer. This article is part of the theme issue 'Synergistic tomographic image reconstruction: part 1'.

Predicting viral exposure response from modeling the changes of co-expression networks using time series gene expression data.

BACKGROUND: Deciphering the relationship between clinical responses and gene expression profiles may shed light on the mechanisms underlying diseases. Most existing literature has focused on exploring such relationship from cross-sectional gene expression data. It is likely that the dynamic nature of time-series gene expression data is more informative in predicting clinical response and revealing the physiological process of disease development. However, it remains challenging to extract useful dynamic information from time-series gene expression data. RESULTS: We propose a statistical framework built on considering co-expression network changes across time from time series gene expression data. It first detects change point for co-expression networks and then employs a Bayesian multiple kernel learning method to predict exposure response. There are two main novelties in our method: the use of change point detection to characterize the co-expression network dynamics, and the use of kernel function to measure the similarity between subjects. Our algorithm allows exposure response prediction using dynamic network information across a collection of informative gene sets. Through parameter estimations, our model has clear biological interpretations. The performance of our method on the simulated data under different scenarios demonstrates that the proposed algorithm has better explanatory power and classification accuracy than commonly used machine learning algorithms. The application of our method to time series gene expression profiles measured in peripheral blood from a group of subjects with respiratory viral exposure shows that our method can predict exposure response at early stage (within 24 h) and the informative gene sets are enriched for pathways related to respiratory and influenza virus infection. CONCLUSIONS: The biological hypothesis in this paper is that the dynamic changes of the biological system are related to the clinical response. Our results suggest that when the relationship between the clinical response and a single gene or a gene set is not significant, we may benefit from studying the relationships among genes in gene sets that may lead to novel biological insights.

Rolling Element Bearing Fault Diagnosis under Impulsive Noise Environment Based on Cyclic Correntropy Spectrum.

Rolling element bearings are widely used in various industrial machines. Fault diagnosis of rolling element bearings is a necessary tool to prevent any unexpected accidents and improve industrial efficiency. Although proved to be a powerful method in detecting the resonance band excited by faults, the spectral kurtosis (SK) exposes an obvious weakness in the case of impulsive background noise. To well process the bearing fault signal in the presence of impulsive noise, this paper proposes a fault diagnosis method based on the cyclic correntropy (CCE) function and its spectrum. Furthermore, an important parameter of CCE function, namely kernel size, is analyzed to emphasize its critical influence on the fault diagnosis performance. Finally, comparisons with the SK-based Fast Kurtogram are conducted to highlight the superiority of the proposed method. The experimental results show that the proposed method not only largely suppresses the impulsive noise, but also has a robust self-adaptation ability. The application of the proposed method is validated on a simulated signal and real data, including rolling element bearing data of a train axle.

Dynamic characteristics of oxygen consumption.

BACKGROUND: Previous studies have indicated that oxygen uptake ([Formula: see text]) is one of the most accurate indices for assessing the cardiorespiratory response to exercise. In most existing studies, the response of [Formula: see text] is often roughly modelled as a first-order system due to the inadequate stimulation and low signal to noise ratio. To overcome this difficulty, this paper proposes a novel nonparametric kernel-based method for the dynamic modelling of [Formula: see text] response to provide a more robust estimation. METHODS: Twenty healthy non-athlete participants conducted treadmill exercises with monotonous stimulation (e.g., single step function as input). During the exercise, [Formula: see text] was measured and recorded by a popular portable gas analyser ([Formula: see text], COSMED). Based on the recorded data, a kernel-based estimation method was proposed to perform the nonparametric modelling of [Formula: see text]. For the proposed method, a properly selected kernel can represent the prior modelling information to reduce the dependence of comprehensive stimulations. Furthermore, due to the special elastic net formed by [Formula: see text] norm and kernelised [Formula: see text] norm, the estimations are smooth and concise. Additionally, the finite impulse response based nonparametric model which estimated by the proposed method can optimally select the order and fit better in terms of goodness-of-fit comparing to classical methods. RESULTS: Several kernels were introduced for the kernel-based [Formula: see text] modelling method. The results clearly indicated that the stable spline (SS) kernel has the best performance for [Formula: see text] modelling. Particularly, based on the experimental data from 20 participants, the estimated response from the proposed method with SS kernel was significantly better than the results from the benchmark method [i.e., prediction error method (PEM)] ([Formula: see text] vs [Formula: see text]). CONCLUSIONS: The proposed nonparametric modelling method is an effective method for the estimation of the impulse response of VO2-Speed system. Furthermore, the identified average nonparametric model method can dynamically predict [Formula: see text] response with acceptable accuracy during treadmill exercise.

Kernel Sparse Representation with Hybrid Regularization for On-Road Traffic Sensor Data Imputation.

The problem of missing values (MVs) in traffic sensor data analysis is universal in current intelligent transportation systems because of various reasons, such as sensor malfunction, transmission failure, etc. Accurate imputation of MVs is the foundation of subsequent data analysis tasks since most analysis algorithms need complete data as input. In this work, a novel MVs imputation approach termed as kernel sparse representation with elastic net regularization (KSR-EN) is developed for reconstructing MVs to facilitate analysis with traffic sensor data. The idea is to represent each sample as a linear combination of other samples due to inherent spatiotemporal correlation, as well as periodicity of daily traffic flow. To discover few yet correlated samples and make full use of the valuable information, a combination of l1-norm and l2-norm is employed to penalize the combination coefficients. Moreover, the linear representation among samples is extended to nonlinear representation by mapping input data space into high-dimensional feature space, which further enhances the recovery performance of our proposed approach. An efficient iterative algorithm is developed for solving KSR-EN model. The proposed method is verified on both an artificially simulated dataset and a public road network traffic sensor data. The results demonstrate the effectiveness of the proposed approach in terms of MVs imputation.

Robust Pedestrian Classification Based on Hierarchical Kernel Sparse Representation.

Vision-based pedestrian detection has become an active topic in computer vision and autonomous vehicles. It aims at detecting pedestrians appearing ahead of the vehicle using a camera so that autonomous vehicles can assess the danger and take action. Due to varied illumination and appearance, complex background and occlusion pedestrian detection in outdoor environments is a difficult problem. In this paper, we propose a novel hierarchical feature extraction and weighted kernel sparse representation model for pedestrian classification. Initially, hierarchical feature extraction based on a CENTRIST descriptor is used to capture discriminative structures. A max pooling operation is used to enhance the invariance of varying appearance. Then, a kernel sparse representation model is proposed to fully exploit the discrimination information embedded in the hierarchical local features, and a Gaussian weight function as the measure to effectively handle the occlusion in pedestrian images. Extensive experiments are conducted on benchmark databases, including INRIA, Daimler, an artificially generated dataset and a real occluded dataset, demonstrating the more robust performance of the proposed method compared to state-of-the-art pedestrian classification methods.

Photon source term after single collision in targets of silicon, copper and lead for 50-500 keV X-ray beams.

Single-scattered X-ray doses at 1 m from silicon, copper and lead targets were calculated using an analytical point-kernel method considering the self-absorption, and the calculated values were compared with detailed results of a Monte Carlo calculation with respect to the emission angle. In the calculations, a slab slanted at 3° to the beam axis was used for silicon in addition to the cylindrical targets for the three materials, and the slab geometry showed the largest doses. The analytical calculations were underestimated compared with the Monte Carlo calculations by less than 24% for silicon and 40% for copper, particularly at large-angle scattering, which was attributable to the buildup effect of the single-scattered X-rays in the targets. By considering the buildup effect, the difference from Monte Carlo results decreased to less than 20%. For lead, the influence of fluorescent X-rays produced by the source beam was dominant in the backward direction, which was also calculated analytically. The simple analytical program can be applied to any target size and shape by considering self-absorption and the buildup effect, both of which inform the simple dose estimation method.

Identifying optimal biomarker combinations for treatment selection via a robust kernel method.

Treatment-selection markers predict an individual's response to different therapies, thus allowing for the selection of a therapy with the best predicted outcome. A good marker-based treatment-selection rule can significantly impact public health through the reduction of the disease burden in a cost-effective manner. Our goal in this article is to use data from randomized trials to identify optimal linear and nonlinear biomarker combinations for treatment selection that minimize the total burden to the population caused by either the targeted disease or its treatment. We frame this objective into a general problem of minimizing a weighted sum of 0-1 loss and propose a novel penalized minimization method that is based on the difference of convex functions algorithm (DCA). The corresponding estimator of marker combinations has a kernel property that allows flexible modeling of linear and nonlinear marker combinations. We compare the proposed methods with existing methods for optimizing treatment regimens such as the logistic regression model and the weighted support vector machine. Performances of different weight functions are also investigated. The application of the proposed method is illustrated using a real example from an HIV vaccine trial: we search for a combination of Fc receptor genes for recommending vaccination in preventing HIV infection.

Multidimensional Alternating Kernel Method for cortical layer segmentation in 3D reconstructed histology.

The neocortex of the brain can be divided into six layers each with a distinct cell composition and connectivity pattern. Recently, sensory deprivation, including congenital deafness, has been shown to alter cortical structure (e.g. the cortical thickness) of the feline auditory cortex with variable and inconsistent results. Thus, understanding these complex changes will require further study of the constituent cortical layers in three-dimensional space. Further progress crucially depends on the use of objective computational techniques that can reliably characterize spatial properties of the complex cortical structure. Here a method for cortical laminar segmentation is derived and applied to the three-dimensional cortical areas reconstructed from a series of histological sections from four feline brains. In this approach, the Alternating Kernel Method was extended to fit a multi-variate Gaussian mixture model to a feature space consisting of both staining intensity and a biologically plausible equivolumetric depth map. This research method•Extends the Alternating Kernel Method to multi-dimensional feature spaces.•Uses it to segment the cortical layers in reconstructed histology volume. Segmentation features include staining intensity and a biologically plausible equivolumetric depth map.•Validates results in auditory cortical areas of feline brains, two with normal hearing and two with congenital deafness.

In defense of local descriptor-based few-shot object detection.

State-of-the-art image object detection computational models require an intensive parameter fine-tuning stage (using deep convolution network, etc). with tens or hundreds of training examples. In contrast, human intelligence can robustly learn a new concept from just a few instances (i.e., few-shot detection). The distinctive perception mechanisms between these two families of systems enlighten us to revisit classical handcraft local descriptors (e.g., SIFT, HOG, etc.) as well as non-parametric visual models, which innately require no learning/training phase. Herein, we claim that the inferior performance of these local descriptors mainly results from a lack of global structure sense. To address this issue, we refine local descriptors with spatial contextual attention of neighbor affinities and then embed the local descriptors into discriminative subspace guided by Kernel-InfoNCE loss. Differing from conventional quantization of local descriptors in high-dimensional feature space or isometric dimension reduction, we actually seek a brain-inspired few-shot feature representation for the object manifold, which combines data-independent primitive representation and semantic context learning and thus helps with generalization. The obtained embeddings as pattern vectors/tensors permit us an accelerated but non-parametric visual similarity computation as the decision rule for final detection. Our approach to few-shot object detection is nearly learning-free, and experiments on remote sensing imageries (approximate 2-D affine space) confirm the efficacy of our model.

A distance-based kernel for classification via Support Vector Machines.

Support Vector Machines (SVMs) are a type of supervised machine learning algorithm widely used for classification tasks. In contrast to traditional methods that split the data into separate training and testing sets, here we propose an innovative approach where subsets of the original data are randomly selected to train the model multiple times. This iterative training process aims to identify a representative data subset, leading to improved inferences about the population. Additionally, we introduce a novel distance-based kernel specifically designed for binary-type features based on a similarity matrix that efficiently handles both binary and multi-class classification problems. Computational experiments on publicly available datasets of varying sizes demonstrate that our proposed method significantly outperforms existing approaches in terms of classification accuracy. Furthermore, the distance-based kernel achieves superior performance compared to other well-known kernels from the literature and those used in previous studies on the same datasets. These findings validate the effectiveness of our proposed classification method and distance-based kernel for SVMs. By leveraging random subset selection and a unique kernel design, we achieve notable improvements in classification accuracy. These results have significant implications for diverse classification problems in Machine Learning and data analysis.

Triple modality image reconstruction of PET data using SPECT, PET, CT information increases lesion uptake in images of patients treated with radioembolization with [Formula: see text] micro-spheres.

PURPOSE: Nuclear medicine imaging modalities like computed tomography (CT), single photon emission CT (SPECT) and positron emission tomography (PET) are employed in the field of theranostics to estimate and plan the dose delivered to tumors and the surrounding tissues and to monitor the effect of the therapy. However, therapeutic radionuclides often provide poor images, which translate to inaccurate treatment planning and inadequate monitoring images. Multimodality information can be exploited in the reconstruction to enhance image quality. Triple modality PET/SPECT/CT scanners are particularly useful in this context due to the easier registration process between images. In this study, we propose to include PET, SPECT and CT information in the reconstruction of PET data. The method is applied to Yttrium-90 ([Formula: see text]Y) data. METHODS: Data from a NEMA phantom filled with [Formula: see text]Y were used for validation. PET, SPECT and CT data from 10 patients treated with Selective Internal Radiation Therapy (SIRT) were used. Different combinations of prior images using the Hybrid kernelized expectation maximization were investigated in terms of VOI activity and noise suppression. RESULTS: Our results show that triple modality PET reconstruction provides significantly higher uptake when compared to the method used as standard in the hospital and OSEM. In particular, using CT-guided SPECT images, as guiding information in the PET reconstruction significantly increases uptake quantification on tumoral lesions. CONCLUSION: This work proposes the first triple modality reconstruction method and demonstrates up to 69% lesion uptake increase over standard methods with SIRT [Formula: see text]Y patient data. Promising results are expected for other radionuclide combination used in theranostic applications using PET and SPECT.

Benzodiazepine-related dementia risks and protopathic biases revealed by multiple-kernel learning with electronic medical records.

Objectives: To simultaneously estimate how the risk of incident dementia nonlinearly varies with the administration period and cumulative dose of benzodiazepines, the duration of disorders with an indication for benzodiazepines, and other potential confounders, with the goal of settling the controversy over the role of benzodiazepines in the development of dementia. Methods: The classical hazard model was extended using the techniques of multiple-kernel learning. Regularised maximum-likelihood estimation, including determination of hyperparameter values with 10-fold cross-validation, bootstrap goodness-of-fit test, and bootstrap estimation of confidence intervals, was applied to cohorts retrospectively extracted from electronic medical records of our university hospitals between 1 November 2004 and 31 July 2020. The analysis was mainly focused on 8160 patients aged 40 or older with new onset of insomnia, affective disorders, or anxiety disorders, who were followed up for 4.10±3.47 years. Results: Besides previously reported risk associations, we detected significant nonlinear risk variations over 2-4 years attributable to the duration of insomnia and anxiety disorders, and to the administration period of short-acting benzodiazepines. After nonlinear adjustment for potential confounders, we observed no significant risk associations with long-term use of benzodiazepines. Conclusions: The pattern of the detected nonlinear risk variations suggested reverse causation and confounding. Their putative bias effects over 2-4 years suggested similar biases in previously reported results. These results, together with the lack of significant risk associations with long-term use of benzodiazepines, suggested the need to reconsider previous results and methods for future analysis.