Increases in throughput and installed base of biomedical research equipment led to a massive accumulation of -omics data known to be highly variable, high-dimensional, and sourced from multiple often incompatible data platforms. While this data may be useful for biomarker identification and drug discovery, the bulk of it remains underutilized. Deep neural networks (DNNs) are efficient algorithms based on the use of compositional layers of neurons, with advantages well matched to the challenges -omics data presents. While achieving state-of-the-art results and even surpassing human accuracy in many challenging tasks, the adoption of deep learning in biomedicine has been comparatively slow. Here, we discuss key features of deep learning that may give this approach an edge over other machine learning methods. We then consider limitations and review a number of applications of deep learning in biomedical studies demonstrating proof of concept and practical utility.
One of the major impediments in human aging research is the absence of a comprehensive and actionable set of biomarkers that may be targeted and measured to track the effectiveness of therapeutic interventions. In this study, we designed a modular ensemble of 21 deep neural networks (DNNs) of varying depth, structure and optimization to predict human chronological age using a basic blood test. To train the DNNs, we used over 60,000 samples from common blood biochemistry and cell count tests from routine health exams performed by a single laboratory and linked to chronological age and sex. The best performing DNN in the ensemble demonstrated 81.5 % epsilon-accuracy r = 0.90 with R2 = 0.80 and MAE = 6.07 years in predicting chronological age within a 10 year frame, while the entire ensemble achieved 83.5% epsilon-accuracy r = 0.91 with R2 = 0.82 and MAE = 5.55 years. The ensemble also identified the 5 most important markers for predicting human chronological age: albumin, glucose, alkaline phosphatase, urea and erythrocytes. To allow for public testing and evaluate real-life performance of the predictor, we developed an online system available at http://www.aging.ai. The ensemble approach may facilitate integration of multi-modal data linked to chronological age and sex that may lead to simple, minimally invasive, and affordable methods of tracking integrated biomarkers of aging in humans and performing cross-species feature importance analysis.
In silico modeling is a crucial milestone in modern drug design and development. Although computer-aided approaches in this field are well-studied, the application of deep learning methods in this research area is at the beginning. In this work, we present an original deep neural network (DNN) architecture named RANC (Reinforced Adversarial Neural Computer) for the de novo design of novel small-molecule organic structures based on the generative adversarial network (GAN) paradigm and reinforcement learning (RL). As a generator RANC uses a differentiable neural computer (DNC), a category of neural networks, with increased generation capabilities due to the addition of an explicit memory bank, which can mitigate common problems found in adversarial settings. The comparative results have shown that RANC trained on the SMILES string representation of the molecules outperforms its first DNN-based counterpart ORGANIC by several metrics relevant to drug discovery: the number of unique structures, passing medicinal chemistry filters (MCFs), Muegge criteria, and high QED scores. RANC is able to generate structures that match the distributions of the key chemical features/descriptors (e.g., MW, logP, TPSA) and lengths of the SMILES strings in the training data set. Therefore, RANC can be reasonably regarded as a promising starting point to develop novel molecules with activity against different biological targets or pathways. In addition, this approach allows scientists to save time and covers a broad chemical space populated with novel and diverse compounds.
Accurate and physiologically meaningful biomarkers for human aging are key to assessing antiaging therapies. Given ethnic differences in health, diet, lifestyle, behavior, environmental exposures, and even average rate of biological aging, it stands to reason that aging clocks trained on datasets obtained from specific ethnic populations are more likely to account for these potential confounding factors, resulting in an enhanced capacity to predict chronological age and quantify biological age. Here, we present a deep learning-based hematological aging clock modeled using the large combined dataset of Canadian, South Korean, and Eastern European population blood samples that show increased predictive accuracy in individual populations compared to population specific hematologic aging clocks. The performance of models was also evaluated on publicly available samples of the American population from the National Health and Nutrition Examination Survey (NHANES). In addition, we explored the association between age predicted by both population specific and combined hematological clocks and all-cause mortality. Overall, this study suggests (a) the population specificity of aging patterns and (b) hematologic clocks predicts all-cause mortality. The proposed models were added to the freely-available Aging.AI system expanding the range of tools for analysis of human aging.
In this article, we propose the deep neural network Adversarial Threshold Neural Computer (ATNC). The ATNC model is intended for the de novo design of novel small-molecule organic structures. The model is based on generative adversarial network architecture and reinforcement learning. ATNC uses a Differentiable Neural Computer as a generator and has a new specific block, called adversarial threshold (AT). AT acts as a filter between the agent (generator) and the environment (discriminator + objective reward functions). Furthermore, to generate more diverse molecules we introduce a new objective reward function named Internal Diversity Clustering (IDC). In this work, ATNC is tested and compared with the ORGANIC model. Both models were trained on the SMILES string representation of the molecules, using four objective functions (internal similarity, Muegge druglikeness filter, presence or absence of sp-rich fragments, and IDC). The SMILES representations of 15K druglike molecules from the ChemDiv collection were used as a training data set. For the different functions, ATNC outperforms ORGANIC. Combined with the IDC, ATNC generates 72% of valid and 77% of unique SMILES strings, while ORGANIC generates only 7% of valid and 86% of unique SMILES strings. For each set of molecules generated by ATNC and ORGANIC, we analyzed distributions of four molecular descriptors (number of atoms, molecular weight, logP, and tpsa) and calculated five chemical statistical features (internal diversity, number of unique heterocycles, number of clusters, number of singletons, and number of compounds that have not been passed through medicinal chemistry filters). Analysis of key molecular descriptors and chemical statistical features demonstrated that the molecules generated by ATNC elicited better druglikeness properties. We also performed in vitro validation of the molecules generated by ATNC; results indicated that ATNC is an effective method for producing hit compounds.
For the past several decades, research in understanding the molecular basis of human muscle aging has progressed significantly. However, the development of accessible tissue-specific biomarkers of human muscle aging that may be measured to evaluate the effectiveness of therapeutic interventions is still a major challenge. Here we present a method for tracking age-related changes of human skeletal muscle. We analyzed publicly available gene expression profiles of young and old tissue from healthy donors. Differential gene expression and pathway analysis were performed to compare signatures of young and old muscle tissue and to preprocess the resulting data for a set of machine learning algorithms. Our study confirms the established mechanisms of human skeletal muscle aging, including dysregulation of cytosolic Ca2+ homeostasis, PPAR signaling and neurotransmitter recycling along with IGFR and PI3K-Akt-mTOR signaling. Applying several supervised machine learning techniques, including neural networks, we built a panel of tissue-specific biomarkers of aging. Our predictive model achieved 0.91 Pearson correlation with respect to the actual age values of the muscle tissue samples, and a mean absolute error of 6.19 years on the test set. The performance of models was also evaluated on gene expression samples of the skeletal muscles from the Gene expression Genotype-Tissue Expression (GTEx) project. The best model achieved the accuracy of 0.80 with respect to the actual age bin prediction on the external validation set. Furthermore, we demonstrated that aging biomarkers can be used to identify new molecular targets for tissue-specific anti-aging therapies.
There is an association between smoking and cancer, cardiovascular disease and all-cause mortality. However, currently, there are no affordable and informative tests for assessing the effects of smoking on the rate of biological aging. In this study we demonstrate for the first time that smoking status can be predicted using blood biochemistry and cell count results andthe recent advances in artificial intelligence (AI). By employing age-prediction models developed using supervised deep learning techniques, we found that smokers exhibited higher aging rates than nonsmokers, regardless of their cholesterol ratios and fasting glucose levels. We further used those models to quantify the acceleration of biological aging due to tobacco use. Female smokers were predicted to be twice as old as their chronological age compared to nonsmokers, whereas male smokers were predicted to be one and a half times as old as their chronological age compared to nonsmokers. Our findings suggest that deep learning analysis of routine blood tests could complement or even replace the current error-prone method of self-reporting of smoking status and could be expanded to assess the effect of other lifestyle and environmental factors on aging.
The human gut microbiome is a complex ecosystem that both affects and is affected by its host status. Previous metagenomic analyses of gut microflora revealed associations between specific microbes and host age. Nonetheless there was no reliable way to tell a host's age based on the gut community composition.Here we developed a method of predicting hosts' age based on microflora taxonomic profiles using a cross-study dataset and deep learning. Our best model has an architecture of a deep neural network that achieves the mean absolute error of 5.91 years when tested on external data. We further advance a procedure for inferring the role of particular microbes during human aging and defining them as potential aging biomarkers. The described intestinal clock represents a unique quantitative model of gut microflora aging and provides a starting point for building host aging and gut community succession into a single narrative.
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