Ryosuke Kojima

Yuji Okamoto, Ryosuke Kojima

Learning stable dynamics from observed time-series data is an essential problem in robotics, physical modeling, and systems biology. Many of these dynamics are represented as an inputs-output system to communicate with the external environment. In this study, we focus on input-output stable systems, exhibiting robustness against unexpected stimuli and noise. We propose a method to learn nonlinear systems guaranteeing the input-output stability. Our proposed method utilizes the differentiable projection onto the space satisfying the Hamilton-Jacobi inequality to realize the input-output stability. The problem of finding this projection can be formulated as a quadratic constraint quadratic programming problem, and we derive the particular solution analytically. Also, we apply our method to a toy bistable model and the task of training a benchmark generated from a glucose-insulin simulator. The results show that the nonlinear system with neural networks by our method achieves the input-output stability, unlike naive neural networks. Our code is available at https://github.com/clinfo/DeepIOStability.

Aya Nakamura, Ryosuke Kojima, Yuji Okamoto et al.

Many diseases, including cancer and chronic conditions, require extended treatment periods and long-term strategies. Machine learning and AI research focusing on electronic health records (EHRs) have emerged to address this need. Effective treatment strategies involve more than capturing sequential changes in patient test values. It requires an explainable and clinically interpretable model by capturing the patient's internal state over time. In this study, we propose the "deep state-space analysis framework," using time-series unsupervised learning of EHRs with a deep state-space model. This framework enables learning, visualizing, and clustering of temporal changes in patient latent states related to disease progression. We evaluated our framework using time-series laboratory data from 12,695 cancer patients. By estimating latent states, we successfully discover latent states related to prognosis. By visualization and cluster analysis, the temporal transition of patient status and test items during state transitions characteristic of each anticancer drug were identified. Our framework surpasses existing methods in capturing interpretable latent space. It can be expected to enhance our comprehension of disease progression from EHRs, aiding treatment adjustments and prognostic determinations.

Kazuki Nakamura, Eiichiro Uchino, Noriaki Sato et al.

Early disease detection and prevention methods based on effective interventions are gaining attention. Machine learning technology has enabled precise disease prediction by capturing individual differences in multivariate data. Progress in precision medicine has revealed that substantial heterogeneity exists in health data at the individual level and that complex health factors are involved in the development of chronic diseases. However, it remains a challenge to identify individual physiological state changes in cross-disease onset processes because of the complex relationships among multiple biomarkers. Here, we present the health-disease phase diagram (HDPD), which represents a personal health state by visualizing the boundary values of multiple biomarkers that fluctuate early in the disease progression process. In HDPDs, future onset predictions are represented by perturbing multiple biomarker values while accounting for dependencies among variables. We constructed HDPDs for 11 non-communicable diseases (NCDs) from a longitudinal health checkup cohort of 3,238 individuals, comprising 3,215 measurement items and genetic data. Improvement of biomarker values to the non-onset region in HDPD significantly prevented future disease onset in 7 out of 11 NCDs. Our results demonstrate that HDPDs can represent individual physiological states in the onset process and be used as intervention goals for disease prevention.

Atsuko Takagi, Mayumi Kamada, Eri Hamatani et al.

Drug repositioning holds great promise because it can reduce the time and cost of new drug development. While drug repositioning can omit various R&D processes, confirming pharmacological effects on biomolecules is essential for application to new diseases. Biomedical explainability in a drug repositioning model can support appropriate insights in subsequent in-depth studies. However, the validity of the XAI methodology is still under debate, and the effectiveness of XAI in drug repositioning prediction applications remains unclear. In this study, we propose GraphIX, an explainable drug repositioning framework using biological networks, and quantitatively evaluate its explainability. GraphIX first learns the network weights and node features using a graph neural network from known drug indication and knowledge graph that consists of three types of nodes (but not given node type information): disease, drug, and protein. Analysis of the post-learning features showed that node types that were not known to the model beforehand are distinguished through the learning process based on the graph structure. From the learned weights and features, GraphIX then predicts the disease-drug association and calculates the contribution values of the nodes located in the neighborhood of the predicted disease and drug. We hypothesized that the neighboring protein node to which the model gave a high contribution is important in understanding the actual pharmacological effects. Quantitative evaluation of the validity of protein nodes' contribution using a real-world database showed that the high contribution proteins shown by GraphIX are reasonable as a mechanism of drug action. GraphIX is a framework for evidence-based drug discovery that can present to users new disease-drug associations and identify the protein important for understanding its pharmacological effects from a large and complex knowledge base.

Kazuma Inoue, Ryosuke Kojima, Mayumi Kamada et al.

Biological data may be separated into primary data, such as gene expression, and secondary data, such as pathways and protein-protein interactions. Methods using secondary data to enhance the analysis of primary data are promising, because secondary data have background information that is not included in primary data. In this study, we proposed an end-to-end framework to integrally handle secondary data to construct a classification model for primary data. We applied this framework to cancer prognosis prediction using gene expression data and a biological network. Cross-validation results indicated that our model achieved higher accuracy compared with a deep neural network model without background biological network information. Experiments conducted in patient groups by cancer type showed improvement in ROC-area under the curve for many groups. Visualizations of high accuracy cancer types identified contributing genes and pathways by enrichment analysis. Known biomarkers and novel biomarker candidates were identified through these experiments.

Yuji Okamoto, Ryosuke Kojima

This study challenges strictly guaranteeing ``dissipativity'' of a dynamical system represented by neural networks learned from given time-series data. Dissipativity is a crucial indicator for dynamical systems that generalizes stability and input-output stability, known to be valid across various systems including robotics, biological systems, and molecular dynamics. By analytically proving the general solution to the nonlinear Kalman-Yakubovich-Popov (KYP) lemma, which is the necessary and sufficient condition for dissipativity, we propose a differentiable projection that transforms any dynamics represented by neural networks into dissipative ones and a learning method for the transformed dynamics. Utilizing the generality of dissipativity, our method strictly guarantee stability, input-output stability, and energy conservation of trained dynamical systems. Finally, we demonstrate the robustness of our method against out-of-domain input through applications to robotic arms and fluid dynamics. Code is https://github.com/kojima-r/DeepDissipativeModel

Tatsuya Sagawa, Ryosuke Kojima

Transformer-based deep neural networks have revolutionized the field of molecular-related prediction tasks by treating molecules as symbolic sequences. These models have been successfully applied in various organic chemical applications by pretraining them with extensive compound libraries and subsequently fine-tuning them with smaller in-house datasets for specific tasks. However, many conventional methods primarily focus on single molecules, with limited exploration of pretraining for reactions involving multiple molecules. In this paper, we propose ReactionT5, a novel model that leverages pretraining on the Open Reaction Database (ORD), a publicly available large-scale resource. We further fine-tune this model for yield prediction and product prediction tasks, demonstrating its impressive performance even with limited fine-tuning data compared to traditional models. The pre-trained ReactionT5 model is publicly accessible on the Hugging Face platform.

Tatsuya Sagawa, Ryosuke Kojima

Chemical Language Models (CLMs) pre-trained on large scale molecular data are widely used for molecular property prediction. However, the common belief that increasing training resources such as model size, dataset size, and training compute improves both pretraining loss and downstream task performance has not been systematically validated in the chemical domain. In this work, we evaluate this assumption by pretraining CLMs while scaling training resources and measuring transfer performance across diverse molecular property prediction (MPP) tasks. We find that while pretraining loss consistently decreases with increased training resources, downstream task performance shows limited improvement. Moreover, alternative metrics based on the Hessian or loss landscape also fail to estimate downstream performance in CLMs. We further identify conditions under which downstream performance saturates or degrades despite continued improvements in pretraining metrics, and analyze the underlying task dependent failure modes through parameter space visualizations. These results expose a gap between pretraining based evaluation and downstream performance, and emphasize the need for model selection and evaluation strategies that explicitly account for downstream task characteristics.

Sho Oshima, Yuji Okamoto, Taisei Tosaki et al.

Graph Contrastive Learning (GCL) is a powerful self-supervised learning framework that performs data augmentation through graph perturbations, with growing applications in the analysis of biological networks such as Gene Regulatory Networks (GRNs). The artificial perturbations commonly used in GCL, such as node dropping, induce structural changes that can diverge from biological reality. This concern has contributed to a broader trend in graph representation learning toward augmentation-free methods, which view such structural changes as problematic and to be avoided. However, this trend overlooks the fundamental insight that structural changes from biologically meaningful perturbations are not a problem to be avoided but a rich source of information, thereby ignoring the valuable opportunity to leverage data from real biological experiments. Motivated by this insight, we propose SupGCL (Supervised Graph Contrastive Learning), a new GCL method for GRNs that directly incorporates biological perturbations from gene knockdown experiments as supervision. SupGCL is a probabilistic formulation that continuously generalizes conventional GCL, linking artificial augmentations with real perturbations measured in knockdown experiments and using the latter as explicit supervisory signals. To assess effectiveness, we train GRN representations with SupGCL and evaluate their performance on downstream tasks. The evaluation includes both node-level tasks, such as gene function classification, and graph-level tasks on patient-specific GRNs, such as patient survival hazard prediction. Across 13 tasks built from GRN datasets derived from patients with three cancer types, SupGCL consistently outperforms state-of-the-art baselines.

Taisuke Sato, Ryosuke Kojima

We propose a new approach to SAT solving which solves SAT problems in vector spaces as a cost minimization problem of a non-negative differentiable cost function J^sat. In our approach, a solution, i.e., satisfying assignment, for a SAT problem in n variables is represented by a binary vector u in {0,1}^n that makes J^sat(u) zero. We search for such u in a vector space R^n by cost minimization, i.e., starting from an initial u_0 and minimizing J to zero while iteratively updating u by Newton's method. We implemented our approach as a matrix-based differential SAT solver MatSat. Although existing main-stream SAT solvers decide each bit of a solution assignment one by one, be they of conflict driven clause learning (CDCL) type or of stochastic local search (SLS) type, MatSat fundamentally differs from them in that it continuously approach a solution in a vector space. We conducted an experiment to measure the scalability of MatSat with random 3-SAT problems in which MatSat could find a solution up to n=10^5 variables. We also compared MatSat with four state-of-the-art SAT solvers including winners of SAT competition 2018 and SAT Race 2019 in terms of time for finding a solution, using a random benchmark set from SAT 2018 competition and an artificial random 3-SAT instance set. The result shows that MatSat comes in second in both test sets and outperforms all the CDCL type solvers.

Kazuki Nakamura, Ryosuke Kojima, Eiichiro Uchino et al.

Clinical decision making regarding treatments based on personal characteristics leads to effective health improvements. Machine learning (ML) has been the primary concern of diagnosis support according to comprehensive patient information. However, the remaining prominent issue is the development of objective treatment processes in clinical situations. This study proposes a novel framework to plan treatment processes in a data-driven manner. A key point of the framework is the evaluation of the "actionability" for personal health improvements by using a surrogate Bayesian model in addition to a high-performance nonlinear ML model. We first evaluated the framework from the viewpoint of its methodology using a synthetic dataset. Subsequently, the framework was applied to an actual health checkup dataset comprising data from 3,132 participants, to improve systolic blood pressure values at the individual level. We confirmed that the computed treatment processes are actionable and consistent with clinical knowledge for lowering blood pressure. These results demonstrate that our framework could contribute toward decision making in the medical field, providing clinicians with deeper insights.

Ryosuke Kojima, Taisuke Sato

We introduce a new logic programming language T-PRISM based on tensor embeddings. Our embedding scheme is a modification of the distribution semantics in PRISM, one of the state-of-the-art probabilistic logic programming languages, by replacing distribution functions with multidimensional arrays, i.e., tensors. T-PRISM consists of two parts: logic programming part and numerical computation part. The former provides flexible and interpretable modeling at the level of first order logic, and the latter part provides scalable computation utilizing parallelization and hardware acceleration with GPUs. Combing these two parts provides a remarkably wide range of high-level declarative modeling from symbolic reasoning to deep learning. To embody this programming language, we also introduce a new semantics, termed tensorized semantics, which combines the traditional least model semantics in logic programming with the embeddings of tensors. In T-PRISM, we first derive a set of equations related to tensors from a given program using logical inference, i.e., Prolog execution in a symbolic space and then solve the derived equations in a continuous space by TensorFlow. Using our preliminary implementation of T-PRISM, we have successfully dealt with a wide range of modeling. We have succeeded in dealing with real large-scale data in the declarative modeling. This paper presents a DistMult model for knowledge graphs using the FB15k and WN18 datasets.

Mizuho Nishio, Mitsuo Nishizawa, Osamu Sugiyama et al.

We aimed to evaluate computer-aided diagnosis (CADx) system for lung nodule classification focusing on (i) usefulness of gradient tree boosting (XGBoost) and (ii) effectiveness of parameter optimization using Bayesian optimization (Tree Parzen Estimator, TPE) and random search. 99 lung nodules (62 lung cancers and 37 benign lung nodules) were included from public databases of CT images. A variant of local binary pattern was used for calculating feature vectors. Support vector machine (SVM) or XGBoost was trained using the feature vectors and their labels. TPE or random search was used for parameter optimization of SVM and XGBoost. Leave-one-out cross-validation was used for optimizing and evaluating the performance of our CADx system. Performance was evaluated using area under the curve (AUC) of receiver operating characteristic analysis. AUC was calculated 10 times, and its average was obtained. The best averaged AUC of SVM and XGBoost were 0.850 and 0.896, respectively; both were obtained using TPE. XGBoost was generally superior to SVM. Optimal parameters for achieving high AUC were obtained with fewer numbers of trials when using TPE, compared with random search. In conclusion, XGBoost was better than SVM for classifying lung nodules. TPE was more efficient than random search for parameter optimization.