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AI-Supported, Integrative Prediction of Postoperative Delirium: Protocol for the CONFUSED Study.

BACKGROUND: Postoperative delirium (POD) is a frequent and serious complication in older surgical patients, characterized by acute cognitive dysfunction and fluctuating levels of consciousness. POD is associated with prolonged hospitalization, long-term cognitive decline, reduced quality of life, and increased mortality. Despite its clinical relevance, the underlying pathophysiological mechanisms remain poorly understood, and reliable biomarkers for early prediction and prevention are lacking. OBJECTIVE: The CONFUSED study aims to identify molecular and clinical predictors of POD by integrating clinical data with proteomic, transcriptomic, and epigenetic analyses. The primary objective is to develop predictive models for POD using multimodal data. Secondary objectives include the identification of delirium-associated genes, proteins, and epigenetic signatures, as well as the exploration of patient subgroups at increased risk for POD. METHODS: CONFUSED is a prospective observational cohort study conducted at a German university hospital. Adult patients undergoing major surgery under general anesthesia will be enrolled until 100 cases of POD have been observed, which is expected to require a total sample size of approximately 200 to 300 patients. Blood samples are collected at 4 predefined time points: before premedication, immediately after surgery, and on postoperative days 2 and 5. Samples undergo comprehensive proteomic profiling, transcriptomic analysis using RNA microarrays, DNA methylation analysis, and genotyping of selected polymorphisms. Clinical data, including demographics, comorbidities, perioperative variables, medications, and delirium assessments using the Confusion Assessment Method (CAM) and CAM for the intensive care unit, are systematically recorded. Statistical analyses include univariate and multivariate methods, as well as machine learning approaches such as random forests and support vector machines, to identify relevant biomarkers and develop predictive models. The study protocol follows STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) and TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) guidelines and was approved by the responsible ethics committees. RESULTS: The study was registered in the German Clinical Trials Register (DRKS00033854) on March 18, 2024. Recruitment started in January 2024 and is ongoing at the time of manuscript submission. As of now, 135 patients have been enrolled. Sample collection and laboratory analyses are ongoing. Data analysis began in January 2026, with first results anticipated in July 2026. Final data lock is anticipated after the completion of recruitment. CONCLUSIONS: By integrating multimodal molecular data with clinical parameters and applying advanced machine learning techniques, the CONFUSED study aims to improve the prediction and understanding of POD. The results are expected to support the development of personalized preventive strategies and contribute to improved perioperative care for patients at risk of POD.

Humans↗

Warmr: a data mining tool for chemical data.

Data mining techniques are becoming increasingly important in chemistry as databases become too large to examine manually. Data mining methods from the field of Inductive Logic Programming (ILP) have potential advantages for structural chemical data. In this paper we present Warmr, the first ILP data mining algorithm to be applied to chemoinformatic data. We illustrate the value of Warmr by applying it to a well studied database of chemical compounds tested for carcinogenicity in rodents. Data mining was used to find all frequent substructures in the database, and knowledge of these frequent substructures is shown to add value to the database. One use of the frequent substructures was to convert them into probabilistic prediction rules relating compound description to carcinogenesis. These rules were found to be accurate on test data, and to give some insight into the relationship between structure and activity in carcinogenesis. The substructures were also used to prove that there existed no accurate rule, based purely on atom-bond substructure with less than seven conditions, that could predict carcinogenicity. This results put a lower bound on the complexity of the relationship between chemical structure and carcinogenicity. Only by using a data mining algorithm, and by doing a complete search, is it possible to prove such a result. Finally the frequent substructures were shown to add value by increasing the accuracy of statistical and machine learning programs that were trained to predict chemical carcinogenicity. We conclude that Warmr, and ILP data mining methods generally, are an important new tool for analysing chemical databases.

Algorithms↗

Diagnostic performance of machine learning models versus established risk stratification for intracranial aneurysm rupture: a systematic review and bivariate meta-analysis.

BACKGROUND: Machine learning (ML) models have been proposed to improve the discrimination of intracranial aneurysm rupture status beyond established clinical risk stratification tools. However, reported performance is heterogeneous and the relative contribution of model architecture and feature dominance remains unclear. METHODS: We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-diagnostic test accuracy systematic review and diagnostic meta-analysis of studies evaluating ML models for intracranial aneurysm rupture discrimination. PubMed, Embase and CENTRAL were searched to February 2026. Sensitivity and specificity were pooled using a bivariate random-effects model, with summary receiver operating characteristic curves generated across training, internal testing and external validation datasets. Models were compared with regression-based approaches and Population, Hypertension, Age, Size of aneurysm, Earlier subarachnoid haemorrhage, Site of aneurysm (PHASES) scores. Subgroup and meta-regression analyses explored associations between algorithm family and feature domain. RESULTS: Sixty-two retrospective cohorts (29 709 patients 209 models) met the inclusion criteria. In training datasets, pooled sensitivity and specificity for ML were 0.81 (95% CI 0.75 to 0.85) and 0.83 (0.80-0.86), with an area under the curve (AUC) of 0.878, exceeding PHASES (AUC 0.667). In testing datasets, ML retained higher discrimination (AUC 0.837) than regression models (0.806) and PHASES (0.646). In external validation, sensitivity was preserved (0.82), but specificity declined (0.66). Deep learning demonstrated the highest AUCs (training and testing). Incorporation of haemodynamic or radiomic features improved pooled discrimination relative to morphology alone. Evidence of small-study effects and mostly unclear Prediction Model Risk Of Bias Assessment Tool ratings were observed. CONCLUSIONS: ML approaches demonstrate higher pooled discrimination for aneurysm rupture status than conventional risk scores in retrospective datasets, but reduced external validation specificity and heterogeneity limit confidence for clinical translation. Prospective, externally validated, calibrated models are required before integration into routine cerebrovascular risk stratification.

Humans↗

ProMeta: a meta-learning framework for robust disease diagnosis and prediction from plasma proteomics.

MOTIVATION: The plasma proteome offers a dynamic window of human health, capturing the real-time intersections between genetics and physiology. However, the application of deep learning to proteomics is currently hindered by a reliance on large-scale labeled datasets, rendering standard models ineffective for rare or novel diseases where patient samples are inherently scarce. RESULTS: Here, we present ProMeta, a meta-learning framework designed to enable robust disease modeling under extreme data restrictions. By integrating knowledge-guided pathway encoding with bi-level meta-optimization, ProMeta projects unstructured proteomic profiles into biologically interpretable functional tokens. This architecture allows the model to learn a global initialization containing transferable biological priors from biobank-scale data, facilitating rapid adaptation to novel tasks. Through comprehensive benchmark experiments, ProMeta consistently outperformed transfer learning and traditional machine learning baselines in both disease diagnosis and prediction tasks. In the most challenging 4-shot scenarios (utilizing only 2 cases and 2 controls), the model achieved robust generalization with an average AUROC of ∼0.69, representing a 24.6% relative improvement over the best-performing baseline methods. Mechanistic investigation revealed that ProMeta disentangles cases from controls in the latent space prior to task-specific adaptation, confirming the acquisition of universal biological rules rather than rote memorization. Furthermore, gradient-based interpretation identified disease-specific protein biomarkers and functional pathways consistent with known pathophysiology. Collectively, ProMeta overcomes the data-scarcity bottleneck in precision medicine, providing a scalable, interpretable framework for characterizing the full spectrum of human diseases, particularly for rare conditions lacking extensive clinical cohorts. AVAILABILITY AND IMPLEMENTATION: The source code of ProMeta is available at GitHub (https://github.com/lihan97/ProMeta).

Proteomics↗

Properties Governing Native State Entanglements and Relationships to Protein Function.

Non-covalent lasso entanglements are structural motifs found in a majority of globular proteins, and their misfolding has been linked to a range of biological consequences. Here, we characterize these motifs' structural and physicochemical properties, sequence biases, functional site correlations, and universal features across E. coli, S. cerevisiae, and H. sapiens. We find that the crossing residues, which pierce the plane of the entanglement loop, are 11-times more likely to be a β-strand than an α-helix or random coil, and that around this position the protein sequence is 2.5-times more likely to be composed of a stretch of all hydrophobic residues (most often Val, Ile, or Phe) compared to other sequence motifs. Functionally, crossing residues are enriched at enzyme active sites in S. cerevisiae and small molecule binding residues across all species to degrees greater than expected by random chance. Metal binding residues are enriched in these entanglements in H. sapiens. Increasing statistical power by pooling together these species data, we find RNA-binding residues are enriched in these entanglement components. On the other hand, there is a spatial depletion of crossing residues at sites involved in protein binding. Using machine learning, we identified eight robust features predictive of these entanglements, achieving AUROC scores of 0.8 across species. These results are significant because they suggest a direct role for components of native entanglements in particular protein functions, as well as identifying strong secondary structure and sequence preferences in native entanglements.

Humans↗

Disease candidate genes prediction using positive labeled and unlabeled instances.

Identifying disease genes and understanding their performance is critical in producing drugs for genetic diseases. Nowadays, laboratory approaches are not only used for disease gene identification but also using computational approaches like machine learning are becoming considerable for this purpose. In machine learning methods, researchers can only use two data types (disease genes and unknown genes) to predict disease candidate genes. Notably, there is no source for the negative data set. The proposed method is a two-step process: The first step is the extraction of reliable negative genes from a set of unlabeled genes by one-class learning and a filter based on distance indicators from known disease genes; this step is performed separately for each disease. The second step is the learning of a binary model using causing genes of each disease as a positive learning set and the reliable negative genes extracted from that disease. Each gene in the unlabeled gene's production and ranking step is assigned a normalized score using two filters and a learned model. Consequently, disease genes are predicted and ranked. The proposed method evaluation of various six diseases and Cancer class indicates better results than other studies.

Humans↗

Predicting functional family of novel enzymes irrespective of sequence similarity: a statistical learning approach.

The function of a protein that has no sequence homolog of known function is difficult to assign on the basis of sequence similarity. The same problem may arise for homologous proteins of different functions if one is newly discovered and the other is the only known protein of similar sequence. It is desirable to explore methods that are not based on sequence similarity. One approach is to assign functional family of a protein to provide useful hint about its function. Several groups have employed a statistical learning method, support vector machines (SVMs), for predicting protein functional family directly from sequence irrespective of sequence similarity. These studies showed that SVM prediction accuracy is at a level useful for functional family assignment. But its capability for assignment of distantly related proteins and homologous proteins of different functions has not been critically and adequately assessed. Here SVM is tested for functional family assignment of two groups of enzymes. One consists of 50 enzymes that have no homolog of known function from PSI-BLAST search of protein databases. The other contains eight pairs of homologous enzymes of different families. SVM correctly assigns 72% of the enzymes in the first group and 62% of the enzyme pairs in the second group, suggesting that it is potentially useful for facilitating functional study of novel proteins. A web version of our software, SVMProt, is accessible at http://jing.cz3.nus.edu.sg/cgi-bin/svmprot.cgi.

Artificial Intelligence↗

Consistency and reproducibility of attribute extraction by different machine learning systems.

Machine learning systems as tools for intelligent data analysis are used for extracting attributes relevant for prediction of defined outcomes. The aim of the paper was to compare two machine learning (ML) systems and propose method for intra- and inter-testing of consistency and reproducibility in attributes extracted from real dataset. See5 and FMLS extracted relevant attributes from real medical dataset. Comparison of results of both systems shows that: accuracy and sensitivity are nearly the same for both FMLS and See5 when FMLS was forced by attributes extracted by See5, and little bit lower when FMLS used its own extracted attributes; specificity is nearly the same for both FMLS and See5 when FMLS was forced by attributes extracted by See5, and much more higher when FMLS used its own extracted attributes; both of ML systems show intra-testing consistency and does not show any inter-testing consistency.

Artificial Intelligence↗

Support vector machines for predicting apoptosis proteins types.

Apoptosis proteins have a central role in the development and homeostasis of an organism. These proteins are very important for understanding the mechanism of programmed cell death, and their function is related to their types. According to the classification scheme by Zhou and Doctor (2003), the apoptosis proteins are categorized into the following four types: (1) cytoplasmic protein; (2) plasma membrane-bound protein; (3) mitochondrial inner and outer proteins; (4) other proteins. A powerful learning machine, the Support Vector Machine, is applied for predicting the type of a given apoptosis protein by incorporating the sqrt-amino acid composition effect. High success rates were obtained by the re-substitute test (98/98 = 100 %) and the jackknife test (89/98 = 90.8%).

Apoptosis↗

Improving the accuracy of protein secondary structure prediction using structural alignment.

BACKGROUND: The accuracy of protein secondary structure prediction has steadily improved over the past 30 years. Now many secondary structure prediction methods routinely achieve an accuracy (Q3) of about 75%. We believe this accuracy could be further improved by including structure (as opposed to sequence) database comparisons as part of the prediction process. Indeed, given the large size of the Protein Data Bank (>35,000 sequences), the probability of a newly identified sequence having a structural homologue is actually quite high. RESULTS: We have developed a method that performs structure-based sequence alignments as part of the secondary structure prediction process. By mapping the structure of a known homologue (sequence ID >25%) onto the query protein's sequence, it is possible to predict at least a portion of that query protein's secondary structure. By integrating this structural alignment approach with conventional (sequence-based) secondary structure methods and then combining it with a "jury-of-experts" system to generate a consensus result, it is possible to attain very high prediction accuracy. Using a sequence-unique test set of 1644 proteins from EVA, this new method achieves an average Q3 score of 81.3%. Extensive testing indicates this is approximately 4-5% better than any other method currently available. Assessments using non sequence-unique test sets (typical of those used in proteome annotation or structural genomics) indicate that this new method can achieve a Q3 score approaching 88%. CONCLUSION: By using both sequence and structure databases and by exploiting the latest techniques in machine learning it is possible to routinely predict protein secondary structure with an accuracy well above 80%. A program and web server, called PROTEUS, that performs these secondary structure predictions is accessible at http://wishart.biology.ualberta.ca/proteus. For high throughput or batch sequence analyses, the PROTEUS programs, databases (and server) can be downloaded and run locally.

Algorithms↗

Prediction of RNA-binding proteins from primary sequence by a support vector machine approach.

Elucidation of the interaction of proteins with different molecules is of significance in the understanding of cellular processes. Computational methods have been developed for the prediction of protein-protein interactions. But insufficient attention has been paid to the prediction of protein-RNA interactions, which play central roles in regulating gene expression and certain RNA-mediated enzymatic processes. This work explored the use of a machine learning method, support vector machines (SVM), for the prediction of RNA-binding proteins directly from their primary sequence. Based on the knowledge of known RNA-binding and non-RNA-binding proteins, an SVM system was trained to recognize RNA-binding proteins. A total of 4011 RNA-binding and 9781 non-RNA-binding proteins was used to train and test the SVM classification system, and an independent set of 447 RNA-binding and 4881 non-RNA-binding proteins was used to evaluate the classification accuracy. Testing results using this independent evaluation set show a prediction accuracy of 94.1%, 79.3%, and 94.1% for rRNA-, mRNA-, and tRNA-binding proteins, and 98.7%, 96.5%, and 99.9% for non-rRNA-, non-mRNA-, and non-tRNA-binding proteins, respectively. The SVM classification system was further tested on a small class of snRNA-binding proteins with only 60 available sequences. The prediction accuracy is 40.0% and 99.9% for snRNA-binding and non-snRNA-binding proteins, indicating a need for a sufficient number of proteins to train SVM. The SVM classification systems trained in this work were added to our Web-based protein functional classification software SVMProt, at http://jing.cz3.nus.edu.sg/cgi-bin/svmprot.cgi. Our study suggests the potential of SVM as a useful tool for facilitating the prediction of protein-RNA interactions.

Algorithms↗

Prediction of P-glycoprotein substrates by a support vector machine approach.

P-glycoproteins (P-gp) actively transport a wide variety of chemicals out of cells and function as drug efflux pumps that mediate multidrug resistance and limit the efficacy of many drugs. Methods for facilitating early elimination of potential P-gp substrates are useful for facilitating new drug discovery. A computational ensemble pharmacophore model has recently been used for the prediction of P-gp substrates with a promising accuracy of 63%. It is desirable to extend the prediction range beyond compounds covered by the known pharmacophore models. For such a purpose, a machine learning method, support vector machine (SVM), was explored for the prediction of P-gp substrates. A set of 201 chemical compounds, including 116 substrates and 85 nonsubstrates of P-gp, was used to train and test a SVM classification system. This SVM system gave a prediction accuracy of at least 81.2% for P-gp substrates based on two different evaluation methods, which is substantially improved against that obtained from the multiple-pharmacophore model. The prediction accuracy for nonsubstrates of P-gp is 79.2% using 5-fold cross-validation. These accuracies are slightly better than those obtained from other statistical classification methods, including k-nearest neighbor (k-NN), probabilistic neural networks (PNN), and C4.5 decision tree, that use the same sets of data and molecular descriptors. Our study indicates the potential of SVM in facilitating the prediction of P-gp substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Linear regression models for solvent accessibility prediction in proteins.

The relative solvent accessibility (RSA) of an amino acid residue in a protein structure is a real number that represents the solvent exposed surface area of this residue in relative terms. The problem of predicting the RSA from the primary amino acid sequence can therefore be cast as a regression problem. Nevertheless, RSA prediction has so far typically been cast as a classification problem. Consequently, various machine learning techniques have been used within the classification framework to predict whether a given amino acid exceeds some (arbitrary) RSA threshold and would thus be predicted to be "exposed," as opposed to "buried." We have recently developed novel methods for RSA prediction using nonlinear regression techniques which provide accurate estimates of the real-valued RSA and outperform classification-based approaches with respect to commonly used two-class projections. However, while their performance seems to provide a significant improvement over previously published approaches, these Neural Network (NN) based methods are computationally expensive to train and involve several thousand parameters. In this work, we develop alternative regression models for RSA prediction which are computationally much less expensive, involve orders-of-magnitude fewer parameters, and are still competitive in terms of prediction quality. In particular, we investigate several regression models for RSA prediction using linear L1-support vector regression (SVR) approaches as well as standard linear least squares (LS) regression. Using rigorously derived validation sets of protein structures and extensive cross-validation analysis, we compare the performance of the SVR with that of LS regression and NN-based methods. In particular, we show that the flexibility of the SVR (as encoded by metaparameters such as the error insensitivity and the error penalization terms) can be very beneficial to optimize the prediction accuracy for buried residues. We conclude that the simple and computationally much more efficient linear SVR performs comparably to nonlinear models and thus can be used in order to facilitate further attempts to design more accurate RSA prediction methods, with applications to fold recognition and de novo protein structure prediction methods.

Amino Acids↗

Transfer Learning across Material Properties Using Center-Environment Features: From Energetics to Mechanical Properties in Multicomponent Mo Alloys.

Transfer learning (TL) provides a viable approach to mitigate data scarcity in materials informatics. While conventional TL focuses on predicting identical properties across different systems, this work demonstrates a cross-property extension of TL from energy to mechanical properties via end-to-end model weight pre-training and fine-tuning: knowledge learned from predicting substitution energies is transferred to predict distinctly different mechanical properties, substantially improving computational efficiency given the typically higher cost of acquiring target-domain data. To accelerate computational alloy design, machine learning models using center-environment (CE) features were first developed to predict substitution energies of alloying elements in molybdenum (Mo)-based alloys. The Random Forest models achieved the optimal performance and transferability-R2 = 0.97, 〈MAE〉 = 0.11 eV, and 〈RMSE〉 = 0.16 eV-against the density functional theory (DFT) benchmark. The model dependency of feature selection and importance analysis was discussed. The transferability of the energy models was validated on unknown systems with new elements. Subsequently, the energy models were fine-tuned using limited mechanical property data to construct energy-to-property (E2P) TL models capable of predicting elastic properties, including bulk modulus, Young's modulus, shear modulus, and elastic constants, achieving an improved accuracy over the non-transferred ML by ∼10-30%, with its transferability verified by additional DFT calculations. This cross-property E2P transfer learning framework opens a new avenue for accelerating computational materials discovery and may be extended to other multiproperty predictions governed by similar physical principles.

center-environment feature↗

Predicting protein--protein interactions from primary structure.

MOTIVATION: An ambitious goal of proteomics is to elucidate the structure, interactions and functions of all proteins within cells and organisms. The expectation is that this will provide a fuller appreciation of cellular processes and networks at the protein level, ultimately leading to a better understanding of disease mechanisms and suggesting new means for intervention. This paper addresses the question: can protein-protein interactions be predicted directly from primary structure and associated data? Using a diverse database of known protein interactions, a Support Vector Machine (SVM) learning system was trained to recognize and predict interactions based solely on primary structure and associated physicochemical properties. RESULTS: Inductive accuracy of the trained system, defined here as the percentage of correct protein interaction predictions for previously unseen test sets, averaged 80% for the ensemble of statistical experiments. Future proteomics studies may benefit from this research by proceeding directly from the automated identification of a cell's gene products to prediction of protein interaction pairs.

Artificial Intelligence↗

Combining multi-species genomic data for microRNA identification using a Naive Bayes classifier.

MOTIVATION: Most computational methodologies for microRNA gene prediction utilize techniques based on sequence conservation and/or structural similarity. In this study we describe a new technique, which is applicable across several species, for predicting miRNA genes. This technique is based on machine learning, using the Naive Bayes classifier. It automatically generates a model from the training data, which consists of sequence and structure information of known miRNAs from a variety of species. RESULTS: Our study shows that the application of machine learning techniques, along with the integration of data from multiple species is a useful and general approach for miRNA gene prediction. Based on our experiments, we believe that this new technique is applicable to an extensive range of eukaryotes' genomes. Specific structure and sequence features are first used to identify miRNAs followed by a comparative analysis to decrease the number of false positives (FPs). The resulting algorithm exhibits higher specificity and similar sensitivity compared to currently used algorithms that rely on conserved genomic regions to decrease the rate of FPs.

Algorithms↗

miRNAMap: genomic maps of microRNA genes and their target genes in mammalian genomes.

Recent work has demonstrated that microRNAs (miRNAs) are involved in critical biological processes by suppressing the translation of coding genes. This work develops an integrated database, miRNAMap, to store the known miRNA genes, the putative miRNA genes, the known miRNA targets and the putative miRNA targets. The known miRNA genes in four mammalian genomes such as human, mouse, rat and dog are obtained from miRBase, and experimentally validated miRNA targets are identified in a survey of the literature. Putative miRNA precursors were identified by RNAz, which is a non-coding RNA prediction tool based on comparative sequence analysis. The mature miRNA of the putative miRNA genes is accurately determined using a machine learning approach, mmiRNA. Then, miRanda was applied to predict the miRNA targets within the conserved regions in 3'-UTR of the genes in the four mammalian genomes. The miRNAMap also provides the expression profiles of the known miRNAs, cross-species comparisons, gene annotations and cross-links to other biological databases. Both textual and graphical web interface are provided to facilitate the retrieval of data from the miRNAMap. The database is freely available at http://mirnamap.mbc.nctu.edu.tw/.

Animals↗

Will my protein crystallize? A sequence-based predictor.

We propose a machine-learning approach to sequence-based prediction of protein crystallizability in which we exploit subtle differences between proteins whose structures were solved by X-ray analysis [or by both X-ray and nuclear magnetic resonance (NMR) spectroscopy] and those proteins whose structures were solved by NMR spectroscopy alone. Because the NMR technique is usually applied on relatively small proteins, sequence length distributions of the X-ray and NMR datasets were adjusted to avoid predictions biased by protein size. As feature space for classification, we used frequencies of mono-, di-, and tripeptides represented by the original 20-letter amino acid alphabet as well as by several reduced alphabets in which amino acids were grouped by their physicochemical and structural properties. The classification algorithm was constructed as a two-layered structure in which the output of primary support vector machine classifiers operating on peptide frequencies was combined by a second-level Naive Bayes classifier. Due to the application of metamethods for cost sensitivity, our method is able to handle real datasets with unbalanced class representation. An overall prediction accuracy of 67% [65% on the positive (crystallizable) and 69% on the negative (noncrystallizable) class] was achieved in a 10-fold cross-validation experiment, indicating that the proposed algorithm may be a valuable tool for more efficient target selection in structural genomics. A Web server for protein crystallizability prediction called SECRET is available at http://webclu.bio.wzw.tum.de:8080/secret.

Amino Acid Sequence↗