Identifying preclinical biomarkers of neurodegenerative diseases remains a major challenge in aging research. In this study, we demonstrate that frequent "Don't know/can't remember" (DK) responses, often treated as missing data in touchscreen questionnaires, serve as a novel digital behavioral biomarker of early cognitive vulnerability and neurodegenerative disease risk. Using data from 502,234 UK Biobank participants, we stratified individuals based on DK response frequency (0-1, 2-4, 5-7, >7) and observed a robust, dose-dependent association with an increased risk of Alzheimer's disease (HR = 1.64, 95% CI: 1.26-2.14) and vascular dementia (HR = 1.93, 95% CI: 1.37-2.72), independent of established risk factors. As DK response frequency increased, participants exhibited higher BMI, reduced physical activity, higher smoking rates, and a higher prevalence of chronic diseases, particularly hypertension, diabetes, and depression. Further analysis revealed a dose-dependent relationship between DK response frequency and the risk of Alzheimer's disease and vascular dementia, with high DK responders showing early neurodegenerative changes, marked by elevated levels of Abeta40, Abeta42, NFL, and pTau-181. Metabolomic analysis also revealed lipid metabolism abnormalities, which may mediate this relationship. Together, these findings reframe DK response patterns as clinically meaningful signals of multidimensional neurobiological alterations, offering a scalable, low-cost, non-invasive tool for early risk identification and prevention at the population level.
Convolutional neural networks are continually evolving, with some efforts aimed at improving accuracy, others at increasing speed, and some at enhancing accessibility. Improving accessibility broadens the application of neural networks across a wider range of tasks, including the detection of eye diseases. Early diagnosis of eye diseases and consulting an ophthalmologist can prevent many vision disorders. Given the importance of this issue, various datasets have been collected from the cornea to facilitate the process of making neural network models. However, most of the methods introduced in the past are computationally complex. In this study, we tried to increase the accessibility of deep neural network models. We did this at the most fundamental level, specifically by redesigning and optimizing the convolutional layers. By doing so, we created a new general model that incorporates our novel convolutional layer named ArConv layers. Thanks to the efficient performance of this new layer, the model has suitable complexity for use in mobile phones and can perform the task of diagnosing the presence of disease with high accuracy. The final model we present contains only 1.3 million parameters. In comparison to the MobileNetV2 model, which has 2.2 million parameters, our model demonstrated better accuracy when trained and evaluated on the RfMiD dataset under identical conditions, achieving an accuracy of 0.9328 versus 0.9266 on the RfMiD test set.
Recent studies on plant disease diagnosis using machine learning (ML) have highlighted concerns about the overestimated diagnostic performance due to inappropriate data partitioning, where training and test datasets are derived from the same source (domain). Plant disease diagnosis presents a challenging classification task, characterized by its fine-grained nature, vague symptoms, and the extensive variability of image features within each domain. In this study, we propose the concept of Discriminative Difficulty Distance (DDD), a novel metric designed to quantify the domain gap between training and test datasets while assessing the classification difficulty of test data. DDD provides a valuable tool for identifying insufficient diversity in training data, thus supporting the development of more diverse and robust datasets. We investigated multiple image encoders trained on different datasets and examined whether the distances between datasets, measured using low-dimensional representations generated by the encoders, are suitable as a DDD metric. The study utilized 244,063 plant disease images spanning four crops and 34 disease classes collected from 27 domains. As a result, we demonstrated that even if the test images are from different crops or diseases than those used to train the encoder, incorporating them allows the construction of a distance measure for a dataset that strongly correlates with the difficulty of diagnosis indicated by the disease classifier developed independently. Compared to the base encoder, pre-trained only on ImageNet21K, the correlation higher by 0.106 to 0.485, reaching a maximum of 0.909.
Josué Pagán, José L. Risco-Martín, José M. Moya
et al.
Prediction of symptomatic crises in chronic diseases allows to take decisions before the symptoms occur, such as the intake of drugs to avoid the symptoms or the activation of medical alarms. The prediction horizon is in this case an important parameter in order to fulfill the pharmacokinetics of medications, or the time response of medical services. This paper presents a study about the prediction limits of a chronic disease with symptomatic crises: the migraine. For that purpose, this work develops a methodology to build predictive migraine models and to improve these predictions beyond the limits of the initial models. The maximum prediction horizon is analyzed, and its dependency on the selected features is studied. A strategy for model selection is proposed to tackle the trade off between conservative but robust predictive models, with respect to less accurate predictions with higher horizons. The obtained results show a prediction horizon close to 40 minutes, which is in the time range of the drug pharmacokinetics. Experiments have been performed in a realistic scenario where input data have been acquired in an ambulatory clinical study by the deployment of a non-intrusive Wireless Body Sensor Network. Our results provide an effective methodology for the selection of the future horizon in the development of prediction algorithms for diseases experiencing symptomatic crises.
Identification of causal genes and pathways is a critical step for understanding the genetic underpinnings of rare diseases. We propose novel approaches to gene prioritization and pathway identification using DNA language model, graph neural networks, and genetic algorithm. Using HyenaDNA, a long-range genomic foundation model, we generated dynamic gene embeddings that reflect changes caused by deleterious variants. These gene embeddings were then utilized to identify candidate genes and pathways. We validated our method on a cohort of rare disease patients with partially known genetic diagnosis, demonstrating the re-identification of known causal genes and pathways and the detection of novel candidates. These findings have implications for the prevention and treatment of rare diseases by enabling targeted identification of new drug targets and therapeutic pathways.
The development of an intelligent agricultural decision-supporting system for crop selection and disease forecasting in Bangladesh is the main objective of this work. The economy of the nation depends heavily on agriculture. However, choosing crops with better production rates and efficiently controlling crop disease are obstacles that farmers have to face. These issues are addressed in this research by utilizing machine learning methods and real-world datasets. The recommended approach uses a variety of datasets on the production of crops, soil conditions, agro-meteorological regions, crop disease, and meteorological factors. These datasets offer insightful information on disease trends, soil nutrition demand of crops, and agricultural production history. By incorporating this knowledge, the model first recommends the list of primarily selected crops based on the soil nutrition of a particular user location. Then the predictions of meteorological variables like temperature, rainfall, and humidity are made using SARIMAX models. These weather predictions are then used to forecast the possibilities of diseases for the primary crops list by utilizing the support vector classifier. Finally, the developed model makes use of the decision tree regression model to forecast crop yield and provides a final crop list along with associated possible disease forecast. Utilizing the outcome of the model, farmers may choose the best productive crops as well as prevent crop diseases and reduce output losses by taking preventive actions. Consequently, planning and decision-making processes are supported and farmers can predict possible crop yields. Overall, by offering a detailed decision support system for crop selection and disease prediction, this work can play a vital role in advancing agricultural practices in Bangladesh.
Real-world data (RWD) and real-world evidence (RWE) have been increasingly used in medical product development and regulatory decision-making, especially for rare diseases. After outlining the challenges and possible strategies to address the challenges in rare disease drug development (see the accompanying paper), the Real-World Evidence (RWE) Scientific Working Group of the American Statistical Association Biopharmaceutical Section reviews the roles of RWD and RWE in clinical trials for drugs treating rare diseases. This paper summarizes relevant guidance documents and frameworks by selected regulatory agencies and the current practice on the use of RWD and RWE in natural history studies and the design, conduct, and analysis of rare disease clinical trials. A targeted learning roadmap for rare disease trials is described, followed by case studies on the use of RWD and RWE to support a natural history study and marketing applications in various settings.
Mehmet Yigit Avci, Emily Chan, Veronika Zimmer
et al.
With the increasing incidence of neurodegenerative diseases such as Alzheimer's Disease (AD), there is a need for further research that enhances detection and monitoring of the diseases. We present MORPHADE (Morphological Autoencoders for Alzheimer's Disease Detection), a novel unsupervised learning approach which uses deformations to allow the analysis of 3D T1-weighted brain images. To the best of our knowledge, this is the first use of deformations with deep unsupervised learning to not only detect, but also localize and assess the severity of structural changes in the brain due to AD. We obtain markedly higher anomaly scores in clinically important areas of the brain in subjects with AD compared to healthy controls, showcasing that our method is able to effectively locate AD-related atrophy. We additionally observe a visual correlation between the severity of atrophy highlighted in our anomaly maps and medial temporal lobe atrophy scores evaluated by a clinical expert. Finally, our method achieves an AUROC of 0.80 in detecting AD, out-performing several supervised and unsupervised baselines. We believe our framework shows promise as a tool towards improved understanding, monitoring and detection of AD. To support further research and application, we have made our code publicly available at github.com/ci-ber/MORPHADE.
Shams Nafisa Ali, Afia Zahin, Samiul Based Shuvo
et al.
Cardiac auscultation, an integral tool in diagnosing cardiovascular diseases (CVDs), often relies on the subjective interpretation of clinicians, presenting a limitation in consistency and accuracy. Addressing this, we introduce the BUET Multi-disease Heart Sound (BMD-HS) dataset - a comprehensive and meticulously curated collection of heart sound recordings. This dataset, encompassing 864 recordings across five distinct classes of common heart sounds, represents a broad spectrum of valvular heart diseases, with a focus on diagnostically challenging cases. The standout feature of the BMD-HS dataset is its innovative multi-label annotation system, which captures a diverse range of diseases and unique disease states. This system significantly enhances the dataset's utility for developing advanced machine learning models in automated heart sound classification and diagnosis. By bridging the gap between traditional auscultation practices and contemporary data-driven diagnostic methods, the BMD-HS dataset is poised to revolutionize CVD diagnosis and management, providing an invaluable resource for the advancement of cardiac health research. The dataset is publicly available at this link: https://github.com/mHealthBuet/BMD-HS-Dataset.
Infrared hyperspectral imaging is a powerful approach in the field of materials and life sciences. However, the extension to modern sub-diffraction nanoimaging still remains a highly inefficient technique, as it acquires data via inherent sequential schemes. Here, we introduce the mathematical technique of low-rank matrix reconstruction to the sub-diffraction scheme of atomic force microscopy-based infrared spectroscopy (AFM-IR), for efficient hyperspectral infrared nanoimaging. To demonstrate its application potential, we chose the trypanosomatid unicellular parasites Leishmania species as a realistic target of biological importance. The mid-infrared spectral fingerprint window covering the spectral range from 1300 to 1900 cm$^{-1}$ was chosen and a step width of 220 nm was applied for nanoimaging of single parasites. Multivariate statistics approaches such as hierarchical cluster analysis (HCA) were used for extracting the chemically distinct spatial locations. Subsequently, we randomly selected only 5% from an originally gathered data cube of 134 (x) $\times$ 50 (y) $\times$ 148 (spectral) AFM-IR measurements and reconstructed the full data set by low-rank matrix recovery. The technique is evaluated by showing agreement in the cluster regions between full and reconstructed data cubes. We conclude that the corresponding measurement time of more than 14 hours can be reduced to less than 1 hour. These findings can significantly boost the practical applicability of hyperspectral nanoimaging in both academic and industrial settings involving nano- and bio-materials.
Growing evidence from recent studies implies that microRNA or miRNA could serve as biomarkers in various complex human diseases. Since wet-lab experiments are expensive and time-consuming, computational techniques for miRNA-disease association prediction have attracted a lot of attention in recent years. Data scarcity is one of the major challenges in building reliable machine learning models. Data scarcity combined with the use of precalculated hand-crafted input features has led to problems of overfitting and data leakage. We overcome the limitations of existing works by proposing a novel multi-tasking graph convolution-based approach, which we refer to as MuCoMiD. MuCoMiD allows automatic feature extraction while incorporating knowledge from five heterogeneous biological information sources (interactions between miRNA/diseases and protein-coding genes (PCG), interactions between protein-coding genes, miRNA family information, and disease ontology) in a multi-task setting which is a novel perspective and has not been studied before. To effectively test the generalization capability of our model, we construct large-scale experiments on standard benchmark datasets as well as our proposed larger independent test sets and case studies. MuCoMiD shows an improvement of at least 3% in 5-fold CV evaluation on HMDDv2.0 and HMDDv3.0 datasets and at least 35% on larger independent test sets with unseen miRNA and diseases over state-of-the-art approaches. We share our code for reproducibility and future research at https://git.l3s.uni-hannover.de/dong/cmtt.
Irina Georgieva, Asya Stoyanova, Svetla Angelova
et al.
Acute respiratory infections cause significant morbidity and mortality even before the COVID-19 pandemic. Pandemic restrictions decreased circulation of many respiratory viruses but some less troubling infections such as common cold are still circulating.
 One of the most frequent causative agents of common cold are rhinoviruses. The fact that these pathogens have been able to slip through anti-COVID preventive measures raises the question of whether we really know this group of viruses and whether these viruses cause only common cold. The clinical impact of rhinoviruses seems to be underestimated.
 In searching of an answer how rhinoviruses have slipped through the anti-COVID precautions we referred to the work of infectious disease specialists, virologists and epidemiologists -much of it conducted decades before the current pandemic. A non-systematic search of the literature is performed. Some of the latest findings on rhinoviruses along with basic knowledge on their biology and clinical impact are summarized in this review.
Fakrul Islam Tushar, Vincent M. D'Anniballe, Rui Hou
et al.
Purpose: To design multi-disease classifiers for body CT scans for three different organ systems using automatically extracted labels from radiology text reports.Materials & Methods: This retrospective study included a total of 12,092 patients (mean age 57 +- 18; 6,172 women) for model development and testing (from 2012-2017). Rule-based algorithms were used to extract 19,225 disease labels from 13,667 body CT scans from 12,092 patients. Using a three-dimensional DenseVNet, three organ systems were segmented: lungs and pleura; liver and gallbladder; and kidneys and ureters. For each organ, a three-dimensional convolutional neural network classified no apparent disease versus four common diseases for a total of 15 different labels across all three models. Testing was performed on a subset of 2,158 CT volumes relative to 2,875 manually derived reference labels from 2133 patients (mean age 58 +- 18;1079 women). Performance was reported as receiver operating characteristic area under the curve (AUC) with 95% confidence intervals by the DeLong method. Results: Manual validation of the extracted labels confirmed 91% to 99% accuracy across the 15 different labels. AUCs for lungs and pleura labels were: atelectasis 0.77 (95% CI: 0.74, 0.81), nodule 0.65 (0.61, 0.69), emphysema 0.89 (0.86, 0.92), effusion 0.97 (0.96, 0.98), and no apparent disease 0.89 (0.87, 0.91). AUCs for liver and gallbladder were: hepatobiliary calcification 0.62 (95% CI: 0.56, 0.67), lesion 0.73 (0.69, 0.77), dilation 0.87 (0.84, 0.90), fatty 0.89 (0.86, 0.92), and no apparent disease 0.82 (0.78, 0.85). AUCs for kidneys and ureters were: stone 0.83 (95% CI: 0.79, 0.87), atrophy 0.92 (0.89, 0.94), lesion 0.68 (0.64, 0.72), cyst 0.70 (0.66, 0.73), and no apparent disease 0.79 (0.75, 0.83). Conclusion: Weakly-supervised deep learning models were able to classify diverse diseases in multiple organ systems.
The need for comprehensive and automated screening methods for retinal image classification has long been recognized. Well-qualified doctors annotated images are very expensive and only a limited amount of data is available for various retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Some studies show that AMD and DR share some common features like hemorrhagic points and exudation but most classification algorithms only train those disease models independently. Inspired by knowledge distillation where additional monitoring signals from various sources is beneficial to train a robust model with much fewer data. We propose a method called synergic adversarial label learning (SALL) which leverages relevant retinal disease labels in both semantic and feature space as additional signals and train the model in a collaborative manner. Our experiments on DR and AMD fundus image classification task demonstrate that the proposed method can significantly improve the accuracy of the model for grading diseases. In addition, we conduct additional experiments to show the effectiveness of SALL from the aspects of reliability and interpretability in the context of medical imaging application.
We develop a time and space dependent predator-prey model. The predators' equation is a non local hyperbolic balance law, while the diffusion of prey obeys a parabolic equation, so that predators "hunt" for prey, while prey diffuse. A control term allows to describe the use of predators as parasitoids to limit the growth of prey-parasites. The general well posedness and stability results here obtained ensure the existence of optimal pest control strategies, as discussed through some numerical integrations. The specific example we have in mind is that of Trichopria drosophilae used to fight against the spreading of Drosophila suzukii.