BioMedInformatics, Volume 5, Issue 1 (March 2025) – 16 articles

Background: Critical studies have unwaveringly established the importance of peculiar single-nucleotide polymorphisms (SNPs) in apolipoproteins (Apos) genes as genetic risk factors for dyslipidemias and their related comorbidities. In this study, we employed in silico approaches to analyze mutations in Apos. Methods: A comprehensive set of computational tools was utilized. The tools for predictions derived from sequence analysis were: SIFT, PolyPhen-2, FATHMM and SNPs&GO; The tools for structure analysis were: mCSM, DynaMut2, MAESTROweb, and PremPS; for prediction of pathogenic potential were: MutPred2, and PhD-SNP; for profiling of aggregation propensity were: Camsol, and Aggrescan3D 2.0, and lastly, for residual frustration analysis, the Frustratometer was used. These approaches assess variant effects on protein structure, stability, and function. Results: We identified seventeen SNPs in total, twelve for ApoB, one for ApoC2, one for ApoC3, and three for ApoE, representing 70%, 6%, 6% and 18%, respectively. The pathogenity of ApoE, was highlighted in two SNPs the rs769452 with amino acid replacement L46P, and rs769455 with amino acid replacement R163C. The aggregation/solubility analysis revealed that the L46P leads to a decrease in ApoE aggregation. The R163C, showed a decrease in solubility in one of two tools used, resulting in destabilizing effects altering its solubility. Conclusions: The two mutations in ApoE studied with the in silico methodologies identified clinically significant genetic variants, highlighting the robustness of the integrated approach. The future direction of the research is to create a multiplex panel with the SNPs identified here in APOE and expanding to other proteins to have a panel genetic risk assessment and disease prediction in which ApoE correlates. Full article

Large language models (LLMs) have emerged as powerful tools for (semi-)automating the initial screening of abstracts in systematic reviews, offering the potential to significantly reduce the manual burden on research teams. This paper provides a broad overview of prompt engineering principles and highlights how traditional PICO (Population, Intervention, Comparison, Outcome) criteria can be converted into actionable instructions for LLMs. We analyze the trade-offs between “soft” prompts, which maximize recall by accepting articles unless they explicitly fail an inclusion requirement, and “strict” prompts, which demand explicit evidence for every criterion. Using a periodontics case study, we illustrate how prompt design affects recall, precision, and overall screening efficiency and discuss metrics (accuracy, precision, recall, F1 score) to evaluate performance. We also examine common pitfalls, such as overly lengthy prompts or ambiguous instructions, and underscore the continuing need for expert oversight to mitigate hallucinations and biases inherent in LLM outputs. Finally, we explore emerging trends, including multi-stage screening pipelines and fine-tuning, while noting ethical considerations related to data privacy and transparency. By applying systematic prompt engineering and rigorous evaluation, researchers can optimize LLM-based screening processes, allowing for faster and more comprehensive evidence synthesis across biomedical disciplines. Full article

Background: Epilepsy is one of the most common and devastating neurological disorders, manifesting with seizures and affecting approximately 1–2% of the world’s population. The criticality of seizure occurrence and associated risks, combined with the overwhelming need for more precise and innovative treatment methods, has led to the development of invasive neurostimulation devices programmed to detect and apply electrical stimulation therapy to suppress seizures and reduce the seizure burden. Tiny Machine Learning (TinyML) is a rapidly growing branch of machine learning. One of its key characteristics is the ability to run machine learning algorithms without the need for high computational complexity and powerful hardware resources. The featured work utilizes TinyML technology to implement an algorithm that can be integrated into the microprocessor of an implantable closed-loop brain neurostimulation system to accurately detect seizures in real-time by analyzing intracranial EEG (iEEG) signals. Methods: A dataset containing iEEG signal values from both non-epileptic and epileptic individuals was utilized for the implementation of the proposed algorithm. Appropriate data preprocessing was performed, and two training datasets with 1000 records of non-epileptic and epileptic iEEG signals were created. A test dataset with an independent dataset of 500 records was also created. The web-based platform Edge Impulse was used for model generation and visualization, and different model architectures were explored and tested. Finally, metrics of accuracy, confusion matrices, and ROC curves were used to evaluate the performance of the model. Results: Our model demonstrated high performance, achieving 98% and 99% accuracy on the validation and test EEG datasets, respectively. Our results support the use of TinyML technology in closed-loop neurostimulation devices for epilepsy, as it contributes significantly to the speed and accuracy of seizure detection. Conclusions: The proposed TinyML model demonstrated reliable seizure detection in real-time by analyzing EEG signals and distinguishing epileptic activity from normal brain electrical activity. These findings highlight the potential of TinyML in closed-loop neurostimulation systems for epilepsy, enhancing both speed and accuracy in seizure detection. Full article

Background: Variations in the states of Gene Regulatory Networks significantly influence disease outcomes and drug development. Boolean Networks serve as a tool to conceptualize and understand the complex relationships between genes. Threshold computation methods are used for the binarization of gene expression and the Boolean representation of its Gene Regulatory Network. This study aims to provide a platform that facilitates the exploration of the impact of different threshold computation methods on the binarization of gene expression and the subsequent Boolean representation of Gene Regulatory Networks. Methods: Threshold computation methods are implemented for binarizing gene expression, enabling the Boolean representation of the Gene Regulatory Networks. Variations in gene expression discretization and threshold computation methods often lead to differing Boolean representations, which may affect the subsequent analysis. Lluberes proposed a framework for analyzing gene expression when binarization varies based on these factors. This theoretical framework was implemented using the Python Dash framework. Results: A visualization tool has been developed to implement this framework. The tool allows users to upload gene expression datasets and interact with a dashboard to explore gene expression binarization and the inferred Boolean Networks. Conclusions: The developed visualization tool provides a platform that facilitates the exploration of how different binarization methods impact the interpretation of Gene Regulatory Networks, offering insights for disease research and drug development. Full article

Background: Large Language Models (LLMs) have demonstrated strong performances in clinical question-answering (QA) benchmarks, yet their effectiveness in addressing real-world consumer medical queries remains underexplored. This study evaluates the capabilities and limitations of LLMs in answering consumer health questions using the MedRedQA dataset, which consists of medical questions and answers by verified experts from the AskDocs subreddit. Methods: Five LLMs-GPT-4o mini, Llama 3.1-70B, Mistral-123B, Mistral-7B, and Gemini-Flash were assessed using a cross-evaluation framework. Each model generated responses to consumer queries and their outputs were evaluated by every model by comparing them with expert responses. Human evaluation was used to assess the reliability of models as evaluators. Results: GPT-4o mini achieved the highest alignment with expert responses according to four out of the five models’ judges, while Mistral-7B scored the lowest according to three out of five models’ judges. Overall, model responses show low alignment with expert responses. Conclusions: Current small or medium sized LLMs struggle to provide accurate answers to consumer health questions and must be significantly improved. Full article

Background: Understanding the dynamics of HIV transmission in heterogeneous populations is crucial for effective prevention strategies. This study introduces the Risk Modulation Point (RMP), a novel threshold identifying where HIV transmission transitions from unsustainable spread to self-sustaining epidemic dynamics. Methods: Using a deterministic, risk-stratified compartmental model, we examined HIV transmission across populations stratified into 100–200 risk groups, each characterized by behavioral heterogeneity modeled through a power-law distribution. The model captures key features of HIV progression, with simulations conducted across high- (~20%), moderate- (~5%), and low (~0.2%)-prevalence regimes. Results: Our findings reveal universal patterns in HIV dynamics. The RMP marks a consistent threshold across scenarios, separating low-risk groups where transmission is minimal from higher-risk groups sustaining the epidemic. Logistic growth in HIV prevalence across risk groups, with sharp transitions near the RMP, was observed universally. The force of infection follows power-law scaling, directly reflecting the level and nature of risk behavior within each group. Importantly, the location of the RMP remains largely invariant to the underlying sexual risk distribution, population resolution, and mixing patterns, making it applicable across both generalized and concentrated epidemics. Conclusion: The RMP framework offers actionable public health insights. It identifies key populations and transition regions for targeted interventions such as antiretroviral therapy and pre-exposure prophylaxis. By tracking shifts in the RMP, it also serves as an early warning indicator for epidemic transitions, guiding resource allocation and monitoring. The focus of the model on intrinsic epidemic dynamics, excluding external interventions, highlights its utility in uncovering fundamental transmission patterns. This study bridges theoretical modeling and practical application, providing a flexible framework for understanding HIV and other stratified epidemics. The findings advance HIV modeling by revealing generic patterns that transcend specific contexts, supporting data-driven public health strategies. Full article

Background: In clinical practice, identifying the location and extent of tumors and lesions is crucial for disease diagnosis and treatment. Artificial intelligence, particularly deep neural networks, offers precise and automated segmentation, yet limited data and high computational demands often hinder its application. Transfer learning helps mitigate these challenges by significantly reducing computational costs, although applying these models can still be resource intensive. This study aims to present flexible and computationally efficient architecture that leverages transfer learning and delivers highly accurate results across various medical imaging problems. Methods: We evaluated three datasets with varying similarities to ImageNet: ISIC 2018 (skin lesions), CBIS-DDSM (breast masses), and the Shenzhen and Montgomery CXR Set (lung segmentation). An ablation study on ISIC 2018 tested various pre-trained backbones, architectures, and loss functions. Results: The optimal configuration—DeepLabV3+ with a pre-trained ResNet50 backbone and Log-Cosh Dice loss—was validated on the remaining datasets, achieving state-of-the-art results. Conclusion: Computationally simpler architectures can deliver robust performance without extensive resources, establishing DeepLabV3+ with the ResNet50 as a baseline for future studies. In the medical domain, enhancing data quality is more critical for improving segmentation accuracy than increasing model complexity. Full article

Background: Tumor mutation burden (TMB), a genomic biomarker, has proven to be a strong predictor of immunotherapy response but is not widely adopted. This study investigates the association between TMB and immune checkpoint inhibitors (ICIs) response in TNBC patients. Methods: From the TCGA database, patients were stratified into two levels based on TMB and validated using survival analysis. Then, four machine learning models were trained to classify TNBC patients based on histological features into high and low TMB. To further validate our approach, we compared the genomic landscapes of both groups, identified differentially expressed genes (DEGs), and performed pathway enrichment analysis. Results: Our findings revealed a significant association between TMB and ICI response in TNBC. Random forest model effectively classified TNBC patients based on the representative histological features and clinical data with an accuracy of 0.82 on the validation set. The genomic analysis revealed that FAT3, TTN, and DYNC2H1 had a significantly high mutation rate in the TMB groups. Genes impacting cancer progression and immunogenicity were identified in the DEG analysis as IGF2, CLEC3A, and CASC9. Conclusions: This study constructs a model to identify suitable TNBC patients for immunotherapy and highlights the potential role of TMB associated with genomic alterations in predicting immune response in TNBC. Full article

EEG microstates are brief, stable topographical configurations of brain activity that provide insights into alterations in brain function and connectivity. Anomalies in microstates are associated with different neuropsychiatric conditions, especially schizophrenia. Recent advances in both EEG techniques and machine learning point to the potential role of microstates as diagnostic markers for psychotic disorders. This systematic review aims to gather current knowledge on machine learning applied to EEG microstate analysis in psychotic disorders. Following PRISMA guidelines, we searched Scopus, PubMed, and Scholar databases, including 10 studies. Overall results show that EEG microstates can be used to accurately classify diagnoses within the psychosis spectrum, across all stages, outperforming models based on conventional EEG measures, with a prominent role of microstate D. One study also suggests that microstate anomalies may be directly linked to symptom severity. Integrating EEG microstates with machine learning shows promise in improving our understanding of psychotic disorders and developing more precise diagnostic tools. Full article

Background: Transforming one-dimensional (1D) biomedical signals into two-dimensional (2D) images enables the application of convolutional neural networks (CNNs) for classification tasks. In this study, we investigated the effectiveness of different 1D-to-2D transformation methods to classify electrocardiogram (ECG) and electroencephalogram (EEG) signals. Methods: We select five transformation methods: Continuous Wavelet Transform (CWT), Fast Fourier Transform (FFT), Short-Time Fourier Transform (STFT), Signal Reshaping (SR), and Recurrence Plots (RPs). We used the MIT-BIH Arrhythmia Database for ECG signals and the Epilepsy EEG Dataset from the University of Bonn for EEG signals. After converting the signals from 1D to 2D, using the aforementioned methods, we employed two types of 2D CNNs: a minimal CNN and the LeNet-5 model. Our results indicate that RPs, CWT, and STFT are the methods to achieve the highest accuracy across both CNN architectures. Results: These top-performing methods achieved accuracies of 99%, 98%, and 95%, respectively, on the minimal 2D CNN and accuracies of 99%, 99%, and 99%, respectively, on the LeNet-5 model for the ECG signals. For the EEG signals, all three methods achieved accuracies of 100% on the minimal 2D CNN and accuracies of 100%, 99%, and 99% on the LeNet-5 2D CNN model, respectively. Conclusions: This superior performance is most likely related to the methods’ capacity to capture time–frequency information and nonlinear dynamics inherent in time-dependent signals such as ECGs and EEGs. These findings underline the significance of using appropriate transformation methods, suggesting that the incorporation of time–frequency analysis and nonlinear feature extraction in the transformation process improves the effectiveness of CNN-based classification for biological data. Full article

Introduction: Remote health monitoring plays a crucial role in telehealth services and the effective management of patients, which can be enhanced by vital sign prediction from facial videos. Facial videos are easily captured through various imaging devices like phone cameras, webcams, or surveillance systems. Methods: This study introduces a hybrid deep learning model aimed at estimating heart rate (HR), blood oxygen saturation level (SpO2), and blood pressure (BP) from facial videos. The hybrid model integrates convolutional neural network (CNN), convolutional long short-term memory (convLSTM), and video vision transformer (ViViT) architectures to ensure comprehensive analysis. Given the temporal variability of HR and BP, emphasis is placed on temporal resolution during feature extraction. The CNN processes video frames one by one while convLSTM and ViViT handle sequences of frames. These high-resolution temporal features are fused to predict HR, BP, and SpO2, capturing their dynamic variations effectively. Results: The dataset encompasses 891 subjects of diverse races and ages, and preprocessing includes facial detection and data normalization. Experimental results demonstrate high accuracies in predicting HR, SpO2, and BP using the proposed hybrid models. Discussion: Facial images can be easily captured using smartphones, which offers an economical and convenient solution for vital sign monitoring, particularly beneficial for elderly individuals or during outbreaks of contagious diseases like COVID-19. The proposed models were only validated on one dataset. However, the dataset (size, representation, diversity, balance, and processing) plays an important role in any data-driven models including ours. Conclusions: Through experiments, we observed the hybrid model’s efficacy in predicting vital signs such as HR, SpO2, SBP, and DBP, along with demographic variables like sex and age. There is potential for extending the hybrid model to estimate additional vital signs such as body temperature and respiration rate. Full article

Background: Human emotions are subjective psychophysiological processes that play an important role in the daily interactions of human life. Emotions often do not manifest themselves in isolation; people can experience a mixture of them and may not express them in a visible or perceptible way; Methods: This study seeks to uncover EEG patterns linked to emotions, as well as to examine brain activity across emotional states and optimise machine learning techniques for accurate emotion classification. For these purposes, the DEAP dataset was used to comprehensively analyse electroencephalogram (EEG) data and understand how emotional patterns can be observed. Machine learning algorithms, such as SVM, MLP, and RF, were implemented to predict valence and arousal classifications for different combinations of frequency bands and brain regions; Results: The analysis reaffirms the value of EEG as a tool for objective emotion detection, demonstrating its potential in both clinical and technological contexts. By highlighting the benefits of using fewer electrodes, this study emphasises the feasibility of creating more accessible and user-friendly emotion recognition systems; Conclusions: Further improvements in feature extraction and model generalisation are necessary for clinical applications. This study highlights not only the potential of emotion classification to develop biomedical applications, but also to enhance human–machine interaction systems. Full article

Background: The advent of virtual reality in psychiatry presents a wealth of opportunities for a variety of psychopathologies. Avatar Interventions are dialogic and experiential treatments integrating personalized medicine with virtual reality (VR), which have shown promising results by enhancing the emotional regulation of their participants. Notably, Avatar Therapy for the treatment of auditory hallucinations (i.e., voices) allows patients to engage in dialogue with an avatar representing their most persecutory voice. In addition, Avatar Intervention for cannabis use disorder involves an avatar representing a significant person in the patient’s consumption. In both cases, the main goal is to modify the problematic relationship and allow patients to regain control over their symptoms. While results are promising, its potential to be applied to other psychopathologies, such as major depression, is an exciting area for further exploration. In an era where VR interventions are gaining popularity, the present study aims to investigate whether technological advancements could overcome current limitations, such as avatar realism, and foster a deeper immersion into virtual environments, thereby enhancing participants’ sense of presence within the virtual world. A newly developed virtual reality platform was compared to the current platform used by our research team in past and ongoing studies. Methods: This study involved 43 subjects: 20 healthy subjects and 23 subjects diagnosed with severe mental disorders. Each participant interacted with an avatar using both platforms. After each immersive session, questionnaires were administered by a graduate student in a double-blind manner to evaluate technological advancements and user experiences. Results: The findings indicate that the new technological improvements allow the new platform to significantly surpass the current platform as per multiple subjective parameters. Notably, the new platform was associated with superior realism of the avatar (d = 0.574; p < 0.001) and the voice (d = 1.035; p < 0.001), as well as enhanced lip synchronization (d = 0.693; p < 0.001). Participants reported a significantly heightened sense of presence (d = 0.520; p = 0.002) and an overall better immersive experience (d = 0.756; p < 0.001) with the new VR platform. These observations were true in both healthy subjects and participants with severe mental disorders. Conclusions: The technological improvements generated a heightened sense of presence among participants, thus improving their immersive experience. These two parameters could be associated with the effectiveness of VR interventions and future studies should be undertaken to evaluate their impact on outcomes. Full article

(1) Background: The exploration of various machine learning (ML) algorithms for classifying the state of Lumbar Intervertebral Discs (IVD) in orthopedic patients is the focus of this study. The classification is based on six key biomechanical features of the pelvis and lumbar spine. Although previous research has demonstrated the effectiveness of ML models in diagnosing IVD pathology using imaging modalities, there is a scarcity of studies using biomechanical features. (2) Methods: The study utilizes a dataset that encompasses two classification tasks. The first task classifies patients into Normal and Abnormal based on their IVDs (2C). The second task further classifies patients into three groups: Normal, Disc Hernia, and Spondylolisthesis (3C). The performance of various ML models, including decision trees, support vector machines, and neural networks, is evaluated using metrics such as accuracy, AUC, recall, precision, F1, Kappa, and MCC. These models are trained on two open-source datasets, using the PyCaret library in Python. (3) Results: The findings suggest that an ensemble of Random Forest and Logistic Regression models performs best for the 2C classification, while the Extra Trees classifier performs best for the 3C classification. The models demonstrate an accuracy of up to 90.83% and a precision of up to 91.86%, highlighting the effectiveness of ML models in diagnosing IVD pathology. The analysis of the weight of different biomechanical features in the decision-making processes of the models provides insights into the biomechanical changes involved in the pathogenesis of Lumbar IVD abnormalities. (4) Conclusions: This research contributes to the ongoing efforts to leverage data-driven ML models in improving patient outcomes in orthopedic care. The effectiveness of the models for both diagnosis and furthering understanding of Lumbar IVD herniations and spondylolisthesis is outlined. The limitations of AI use in clinical settings are discussed, and areas for future improvement to create more accurate and informative models are suggested. Full article

Background: This study aims to revolutionize traditional pediatric vaccination protocols by integrating virtual reality (VR) technology. The purpose is to minimize discomfort in children, ages 2–12, during vaccinations by immersing them in a specially designed VR short story that aligns with the various stages of the clinical vaccination process. In our approach, the child dons a headset during the vaccination procedure and engages with a virtual reality (VR) short story that is specifically designed to correspond with the stages of a typical vaccination process in a clinical setting. Methods: A two-phase clinical trial was conducted to evaluate the effectiveness of the VR intervention. The first phase included 242 children vaccinated without VR, serving as a control group, while the second phase involved 97 children who experienced VR during vaccination. Discomfort levels were measured using the VACS (VAccination disComfort Scale) tool. Statistical analyses were performed to compare discomfort levels based on age, phases of vaccination, and overall experience. Results: The findings revealed significant reductions in discomfort among children who experienced VR compared to those in the control group. The VR intervention demonstrated superiority across multiple dimensions, including age stratification and different stages of the vaccination process. Conclusions: The proposed VR framework significantly reduces vaccination-related discomfort in children. Its cost-effectiveness, utilizing standard or low-cost headsets like Cardboard devices, makes it a feasible and innovative solution for pediatric practices. This approach introduces a novel, child-centric enhancement to vaccination protocols, improving the overall experience for young patients. Full article

Objective: This study aimed to investigate the utilization of patterns derived from physical activity monitoring (PAM) for the identification of individuals at risk of type 2 diabetes mellitus (T2DM) through an at-home screening approach employing machine learning techniques. Methods: Data from the 2011–2014 National Health and Nutrition Examination Survey (NHANES) were scrutinized, focusing on the PAM component. The primary objective involved the identification of diabetes, characterized by an HbA1c ≥ 6.5% (48 mmol/mol), while the secondary objective included individuals with prediabetes, defined by an HbA1c ≥ 5.7% (39 mmol/mol). Features derived from PAM, along with age, were utilized as inputs for an XGBoost classification model. SHapley Additive exPlanations (SHAP) was employed to enhance the interpretability of the models. Results: The study included 7532 subjects with both PAM and HbA1c data. The model, which solely included PAM features, had a test dataset ROC-AUC of 0.74 (95% CI = 0.72–0.76). When integrating the PAM features with age, the model’s ROC-AUC increased to 0.79 (95% CI = 0.78–0.80) in the test dataset. When addressing the secondary target of prediabetes, the XGBoost model exhibited a test dataset ROC-AUC of 0.80 [95% CI; 0.79–0.81]. Conclusions: The objective quantification of physical activity through PAM yields valuable information that can be employed in the identification of individuals with undiagnosed diabetes and prediabetes. Full article