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Privacy-hardened and hallucination-resistant synthetic data generation with logic-solvers.

MOTIVATION: Machine-generated or synthetic data is a valuable resource for training artificial intelligence algorithms, evaluating rare workflows, and sharing data under stricter data legislations. However, current statistical and deep learning methods struggle with large data volumes, are prone to hallucinating scenarios incompatible with reality, and seldom quantify privacy meaningfully. RESULTS: Here, we introduce Genomator, a logic solving approach (SAT solving), which efficiently produces private and realistic representations of the original data. We demonstrate the method on genomic data, which arguably is the most complex and private information. We benchmark Genomator against state-of-the-art methodologies (Markov generation, Wasserstein Generative Adversarial Network and Conditional Restricted Boltzmann Machines), demonstrating a 40%-530% accuracy improvement and 57%-172% higher privacy. Genomator is also 3-100 times more efficient, making it the only tested method that scales to whole genomes. We show the universal trade-off between privacy and accuracy, and use Genomator's tuning capability to cater to all applications along the spectrum, from provable private representations of sensitive cohorts, to datasets with indistinguishable pharmacogenomic profiles. Demonstrating the production-scale generation of tuneable synthetic genomes hold great potential for balancing underrepresented populations in medical research and advancing global data exchange. AVAILABILITY AND IMPLEMENTATION: Genomator is available at https://github.com/csiro/genomator.

Algorithms↗

Integrating Next-Generation Sequencing into von Willebrand Disease Diagnostics: Insights from the PCM-EVW-ES Multicenter Project.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, caused by quantitative or qualitative defects in von Willebrand factor (VWF). Diagnosis is challenging and requires integrating bleeding history, VWF antigen and activity measurements, FVIII assays, and specialized phenotyping. Genetic testing is increasingly recognized as a key component. Here, we review current concepts in VWD diagnostics and highlight the Spanish Clinical and Molecular Profile of von Willebrand Disease (PCM-EVW-ES) project as a model for genomics-enabled precision medicine. PCM-EVW-ES is a multicenter initiative involving 48 hospitals, centralized phenotypic testing, and next-generation sequencing of the VWF coding region, enabling definitive classification in 730 individuals with VWD to date. Harmonized recruitment criteria and standardized workflows improve subtype assignment, uncover complex genotypes, refine genotype-phenotype correlations, and facilitate the identification of asymptomatic carriers. The PCM-EVW-ES variant spectrum highlights recurrent disease-causing variants in Spain and underscores the value of coordinated national registries for variant curation. Building on these data, we propose a diagnostic algorithm in which bleeding assessment and first-line VWF/FVIII assays, combined with, early VWF molecular testing increases diagnostic accuracy and guides targeted second-line investigations to confirm and refine VWD subtype classification. We also outline persisting challenges, including the interpretation of variants of uncertain significance and patients without identifiable pathogenic VWF variants, and future directions integrating third-generation sequencing, expanded gene panels, functional studies, and artificial-intelligence-driven multiomic approaches. Together, these advances illustrate how robust multicenter studies can bridge the gap between complex diagnostics and clinical practice in VWD.

Humans↗

GENPRO: automatic generation of Prolog clause files for knowledge-based systems in the biomedical sciences.

With the increasing interest in using knowledge-based approaches for protein structure prediction and modelling, there is a requirement for general techniques to convert molecular biological data into structures that can be interpreted by artificial intelligence programming languages (e.g. Prolog). We describe here an interactive program that generates files in Prolog clausal form from the most commonly distributed protein structural data collections. The program is flexible and enables a variety of clause structures to be defined by the user through a general schema definition system. Our method can be extended to include other types of molecular biological database or those containing non-structural information, thus providing a uniform framework for handling the increasing volume of data available to knowledge-based systems in biomedicine.

Database Management Systems↗

A Sentiment-Based Comparison of AI- and Physician-Generated Empathic Statements in Palliative Care.

CONTEXT: Empathic communication promotes trust in patient-provider relationships. As healthcare integrates artificial intelligence (AI) into patient communication, we have yet to understand how these models' communication compares to that of physicians. OBJECTIVES: Our primary objectives were to examine patient preferences for AI-generated vs. palliative care physician-generated empathic statements addressing fear and anxiety around cancer treatment, and to analyze associations between linguistic features and patient preferences. METHODS: We conducted a secondary analysis of the PALL-AI trial, a randomized controlled survey comparing cancer patients' preferences of AI- to physician-generated empathic statements. Physicians and AI were provided the same prompt with a maximum sentence length. Patient preferences for each statement were measured in blinded surveys. We analyzed sentiment of the statements using the Valence Aware Dictionary and Sentiment Reasoner (VADER) and the National Research Council Canada (NRC) Emotion Lexicon. We evaluated associations between sentiment scores and patient preferences using Spearman's correlation coefficients. RESULTS: A total of 105 patients completed blinded surveys, preferring the AI-generated statement 72.4% of the time. VADER sentiment analysis showed all three AI statements displayed positive sentiment, while all three physician statements displayed negative sentiment. Controlling for statement length, AI statements used twice as many positive words as human statements. However, they contained a similar number of negative words. Of the eight NRC emotions, "trust" and "joy" demonstrated the strongest correlations with patient preference. CONCLUSION: Patients preferred AI-generated statements around cancer care over those from palliative care physicians when standardized for prompt and statement length. Analysis shows AI-generated statements contain more positive language which may be the factor driving patient preference toward AI.

Humans↗

Computer modeling of adaptive depression.

Mild, delimited, and adaptive depression may be a specific example of a more general class of mechanism by which intelligent systems--individual, social, and artificial--adapt to dynamic, uncertain, and dangerous environments. Computer modeling, based on connectionist and artificial intelligence planning and learning programming techniques, supports this hypothesis by generating both adaptive behavior and analogs for 10 phenomena associated with depression: global, stable, and internal failure explantation, a cognitive loop of failure rumination, decreased motivation, self-esteem, and self-efficacy, and increased realism, negative generalization, and cognitive change. The idea of adaptive depression can be applied to more than one level of living systems. A better understanding of normal and adaptive depression may lead to a better understanding of clinical depression.

Adaptation, Psychological↗

A cognitive approach to game usability and design: mental model development in novice real-time strategy gamers.

We developed a technique to observe and characterize a novice real-time-strategy (RTS) player's mental model as it shifts with experience. We then tested this technique using an off-the-shelf RTS game, EA Games Generals. Norman defined mental models as, "an internal representation of a target system that provides predictive and explanatory power to the operator." In the case of RTS games, the operator is the player and the target system is expressed by the relationships within the game. We studied five novice participants in laboratory-controlled conditions playing a RTS game. They played Command and Conquer Generals for 2 h per day over the course of 5 days. A mental model analysis was generated using player dissimilarity-ratings of the game's artificial intelligence (AI) agents analyzed using multidimensional scaling (MDS) statistical methods. We hypothesized that novices would begin with an impoverished model based on the visible physical characteristics of the game system. As they gained experience and insight, their mental models would shift and accommodate the functional characteristics of the AI agents. We found that all five of the novice participants began with the predicted physical-based mental model. However, while their models did qualitatively shift with experience, they did not necessarily change to the predicted functional-based model. This research presents an opportunity for the design of games that are guided by shifts in a player's mental model as opposed to the typical progression through successive performance levels.

Cognition↗

Proteomics to diagnose human tumors and provide prognostic information.

Proteomics is a rapidly emerging scientific discipline that holds great promise in identifying novel diagnostic and prognostic biomarkers for human cancer. Technologic improvements have made it possible to profile and compare the protein composition within defined populations of cells. Laser capture microdissection is a tool for procuring pure populations of cells from human tissue sections to be used for downstream proteomic analysis. Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) has been used traditionally to separate complex mixtures of proteins. Improvements in this technology have greatly enhanced resolution and sensitivity providing a more reproducible and comprehensive survey. Image analysis software and robotic instrumentation have been developed to facilitate comparisons of complex protein expression patterns and isolation of differentially expressed proteins spots. Differential in-gel electrophoresis (DIGE) facilitates protein expression by labeling different populations of proteins with fluorescent dyes. Isotope-coded affinity tagging (ICAT) uses mass spectroscopy for protein separation and different isotope tags for distinguishing populations of proteins. Although in the past proteomics has been primarily used for discovery, significant efforts are being made to develop proteomic technologies into clinical tools. Reverse-phase protein arrays offer a robust new method of quantitatively assessing expression levels and the activation status of a panel of proteins. Surface-enhanced laser-desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopy rapidly assesses complex protein mixtures in tissue or serum. Combined with artificial intelligence-based pattern recognition algorithms, this emerging technology can generate highly accurate diagnostic information. It is likely that mass spectroscopy-based serum proteomics will evolve into useful clinical tools for the detection and treatment of human cancers.

Early Diagnosis↗

Animats: computer-simulated animals in behavioral research.

The term animat refers to a class of simulated animals. This article is intended as a nontechnical introduction to animat research. Animats can be robots interacting with the real world or computer simulations. In this article, the use of computer-generated animats is emphasized. The scientific use of animats has been pioneered by artificial intelligence and artificial life researchers. Behavior-based artificial intelligence uses animats capable of autonomous and adaptive activity as conceptual tools in the design of usefully intelligent systems. Artificial life proponents view some human artifacts, including informational structures that show adaptive behavior and self-replication, as animats may do, as analogous to biological organisms. Animat simulations may be used for rapid and inexpensive evaluation of new livestock environments or management techniques. The animat approach is a powerful heuristic for understanding the mechanisms that underlie behavior. The simple rules and capabilities of animat models generate emergent and sometimes unpredictable behavior. Adaptive variability in animat behavior may be exploited using artificial neural networks. These have computational properties similar to natural neurons and are capable of learning. Artificial neural networks can control behavior at all levels of an animat's functional organization. Improving the performance of animats often requires genetic programming. Genetic algorithms are computer programs that are capable of self-replication, simulating biological reproduction. Animats may thus evolve over generations. Selective forces may be provided by a human overseer or be part of the simulated environment. Animat techniques allow researchers to culture behavior outside the organism that usually produces it. This approach could contribute new insights in theoretical ethology on questions including the origins of social behavior and cooperation, adaptation, and the emergent nature of complex behavior. Animat studies applied to domestic animals have been few so far, and have involved simulations of space use by swine. I suggest other applications, including modeling animal movement during human handling and the effects of environmental enrichment on the satisfaction of behavioral needs. Appropriate use of animat models in a research program could result in savings of time and numbers of animals required. This approach may therefore come to be viewed as both ethically and economically advantageous.

Animal Welfare↗

Cancer-associated fusion transcripts: mechanisms, functional roles, and clinical implications.

Fusion transcripts are hybrid RNA molecules generated through genomic rearrangements or RNA-level fusion mechanisms. They represent important molecular features of many cancers and can function as oncogenic drivers, diagnostic biomarkers, prognostic indicators, and therapeutic targets. Since the discovery of the BCR::ABL1 fusion in chronic myeloid leukemia, numerous cancer-associated fusion transcripts have been identified across hematologic malignancies and solid tumors. These fusion events encompass diverse biological mechanisms, including constitutively active kinases, aberrant transcription factors, epigenetic regulators, and non-coding fusion RNAs. This review summarizes current knowledge of the mechanisms underlying fusion transcript formation, including genomic rearrangement-dependent and rearrangement-independent processes, as well as fusion circular RNAs. The functional roles of fusion transcripts in cancer biology and their clinical relevance as diagnostic, prognostic, and predictive biomarkers are discussed. In addition, recent advances in fusion transcript detection and characterization are reviewed, including next-generation sequencing, long-read sequencing, single-cell approaches, artificial intelligence-assisted computational methods, and CRISPR/Cas9-mediated strategies for functional modeling and functional validation of fusion transcripts. Despite the rapid expansion of fusion transcript catalogs, the biological and clinical significance of most identified fusion events remains incompletely understood. Future progress will depend on integrating advanced sequencing technologies, artificial intelligence-assisted computational prioritization, and systematic functional validation to distinguish clinically actionable fusion transcripts from biologically neutral events. Such multidisciplinary approaches will be essential for translating fusion transcript research into precision oncology and improving cancer diagnosis, patient stratification, and targeted therapy.

Humans↗

Targeted Nanoparticle Delivery CRISPR/Cas9: overcoming biological barriers, enhancing stability, and improving therapeutic precision.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has emerged as a promising gene-editing platform for genetic disorders; however, its in vivo application remains limited by low delivery efficiency and biological barriers. Many CRISPR payloads fail to reach target sites due to extracellular degradation, immune clearance, and intracellular trafficking limitations. This review examines the interplay between biological barriers and nanoparticle engineering strategies for CRISPR/Cas9 delivery. A barrier-oriented engineering approach is proposed as a central framework, encompassing ligand-based surface modification for enhanced targeting and uptake, improved circulation stability via PEGylation and biomimetic coatings, and optimized payload release through endosomal escape strategies. Stimulus-responsive nanoparticle systems further enable spatiotemporal control over payload release. Nuclear targeting strategies, including optimization of nuclear localization signals (NLS) and exploitation of endogenous trafficking pathways, are highlighted as key factors for improving genome-level editing efficiency. Despite these advances, major challenges-including limited intracellular delivery efficiency, insufficient targeting precision, and safety concerns-continue to hinder clinical translation. Future directions highlight artificial intelligence-driven nanoparticle design, personalized delivery systems, and next-generation CRISPR platforms. Overall, an integrated, barrier-oriented engineering strategy is essential for advancing CRISPR/Cas9 delivery toward clinical applications, ultimately advancing global good health and well-being.

CRISPR/Cas9↗

Sequential state generation by model neural networks.

Sequential patterns of neural output activity form the basis of many biological processes, such as the cyclic pattern of outputs that control locomotion. I show how such sequences can be generated by a class of model neural networks that make defined sets of transitions between selected memory states. Sequence-generating networks depend upon the interplay between two sets of synaptic connections. One set acts to stabilize the network in its current memory state, while the second set, whose action is delayed in time, causes the network to make specified transitions between the memories. The dynamic properties of these networks are described in terms of motion along an energy surface. The performance of the networks, both with intact connections and with noisy or missing connections, is illustrated by numerical examples. In addition, I present a scheme for the recognition of externally generated sequences by these networks.

Artificial Intelligence↗

Conceptual graphs as an operational model for descriptive findings.

Clinical findings are often based on impression and expressed by verbal descriptions. For their structured documentation a coherent and consistent representation model is demanding. The proposed approach is an attempt to take conceptual graphs as a formal notation for findings. Conceptual graphs are finite, connected, and bipartite graphs consisting of concept nodes that are linked by conceptual relation nodes. Concepts are organized in a type hierarchy. A subclass of conceptual graphs, called conceptual finding graphs, will be introduced that capture descriptive findings with well-defined characteristics. It will be shown, how conceptual finding graphs can serve as a coherent and consistent basis for data acquisition, database storage, and verbalization of descriptive findings. The data entry of findings can be supported by the definition of selectional constraints for conceptual relations. Database storage can be achieved by mapping conceptual finding graphs into a relational database schema. Findings can be verbalized by a text generator which takes conceptual finding graphs as input and produces morpho-syntactic surface structures. The model has been applied to an interactive report generator for bone scan studies. It provides the user with a controlled reporting vocabulary on an adaptive graphical interface, and allows the assembling of complex findings by term selection and combination based on selectional constraints. The entered findings can be stored without loss of structure. A text generation produces acceptable German reports.

Artificial Intelligence↗

A hybrid system for diagnosing multiple disorders.

This paper investigates the advantages of introducing feedback between the processes of automated medical diagnosis and automated diagnostic-knowledge acquisition. Experimental results show that a diagnostic system with such feedback is capable of an efficiency/accuracy trade-off when applied to the problem of diagnosing multiple disorders. A primary feature of this work is a new mechanism, called the "diagnostic-unit" representation, for remembering results of previous diagnoses. The diagnostic-unit representation is explicitly tailored to capture the most likely relationships between disorders and clusters of findings. Unlike typical bipartite "If-Then" representations, the diagnostic-unit representation uses a general graph representation to efficiently represent complex causal relationships between disorders and clusters of findings. In addition to the basic diagnostic-unit concept, this paper presents experience-based strategies for incrementally deriving and updating diagnostic units and the various relationships between them. Techniques for selecting diagnostic units relevant to a given problem and then combining them to generate solutions are also described.

Artificial Intelligence↗

Trends in computer hardware and software.

Previously identified and current trends in the development of computer systems and in the use of computers for health care applications are reviewed. Trends identified in a 1982 article were increasing miniaturization and archival ability, increasing software costs, increasing software independence, user empowerment through new software technologies, shorter computer-system life cycles, and more rapid development and support of pharmaceutical services. Most of these trends continue today. Current trends in hardware and software include the increasing use of reduced instruction-set computing, migration to the UNIX operating system, the development of large software libraries, microprocessor-based smart terminals that allow remote validation of data, speech synthesis and recognition, application generators, fourth-generation languages, computer-aided software engineering, object-oriented technologies, and artificial intelligence. Current trends specific to pharmacy and hospitals are the withdrawal of vendors of hospital information systems from the pharmacy market, improved linkage of information systems within hospitals, and increased regulation by government. The computer industry and its products continue to undergo dynamic change. Software development continues to lag behind hardware, and its high cost is offsetting the savings provided by hardware.

Clinical Pharmacy Information Systems↗

Proteomics in environmental pollution research: Advances, challenges, and future directions.

Environmental proteomics has emerged as a powerful approach for elucidating the molecular mechanisms underlying pollutant-induced biological effects. Although this field has developed rapidly, the systematic review of recent proteomics applications in environmental pollution research remains limited. This review explored the emerging roles of toxicoproteomics in biomarker discovery and mechanistic elucidation, as well as ecotoxicoproteomics in ecological risk assessment and bioremediation strategies. Here, we review the field, highlighting recent trends such as the integration of proteomics with genomics, transcriptomics, and metabolomics to provide a comprehensive view of biological responses to environmental stressors. We further discuss the growing application of artificial intelligence in improving proteomics data interpretation and accelerating biomarker discovery. In addition, recent technological advances in environmental proteomics are highlighted, including next-generation tissue microarray proteomics, nanoscale proteomics, single-cell proteomics, and spatial proteomics. Despite its potential, proteomics faces challenges, such as high operational costs, computational complexity in analysis, and technical limitations in low-abundance protein detection. We propose that the convergence of proteomics with artificial intelligence and multi-omics approaches offers promising solutions to these challenges, enhancing the practical application of proteomics in environmental monitoring and risk assessment.

Proteomics↗

Determination of near-optimum use of hospital diagnostic resources using the "GENES" genetic algorithm shell.

"GENES", a genetic algorithm shell developed by the authors, was used to optimize allocation of hospital resources for a small set of hypothetical patients. GENES creates a random population of rule sets of the IF..THEN type, which are variable in both the number of rules in each set and in the size of each rule. GENES applies each rule set to a patient data base, ranks the goodness of each set as applied, and uses the mechanisms of population genetics, i.e. mutation, crossover, inversion and survival of the fittest, to create a new, and often improved generation of rule sets. It also allows for the time dependent nature of medical tests, the possibility of injury associated with those tests, and the fact that results may not always be conclusive. Using 10-11 artificially created patients admitted under the diagnosis of possible gall bladder disease, a rule set was obtained which selected a testing strategy from a list of available hospital resources and correctly diagnosed all patients at minimum cost in no more than 3807 generations.

Algorithms↗

Computational Methods for analysis of foci: validation for radiation-induced gamma-H2AX foci in human cells.

Observation and counting of gamma-H2AX foci in untreated cells as well as in cells exposed to cytotoxic agents is a widely used method for documenting the presence of double-strand breaks (DSBs) in the DNA and for analysis of their repair. Similar methods are employed to analyze formation of foci by a variety of proteins implicated in the cellular responses to DNA damage. Despite the wide application of the approach, the manual counting that is frequently used is prone to inaccuracies and investigator-related biases and artifacts. To alleviate this limitation, we developed and describe here personal computer-based algorithms, operating as utilities on available software, that allow an objective and quantitative analysis of foci from confocal images. The algorithms allow focus counting as well as size definition and correct for focus coincidence due to the overlap normally occurring with an increasing number of foci per nucleus. Furthermore, the software allows measurement of the integrated optical density (IOD) of each individual focus, which enables analysis of properties of foci as a function of time. Finally, the information generated by the above analysis algorithms can be employed to evaluate colocalization between foci formed by different proteins. A validation of the software is presented for radiation-induced gamma-H2AX foci in three widely used human cell lines and colocalization tested with RAD51 and gamma-H2AX foci. The computational methods presented extend to images generated by digital cameras.

Artificial Intelligence↗