Antibody-drug conjugate (ADC) has revolutionized the field of cancer treatment in the era of precision medicine due to their ability to precisely target cancer cells and release highly effective drug. Nevertheless, the realization of rational design of ADC is very difficult because the relationship between their structures and activities is difficult to understand. In the present study, we introduce a unified deep learning framework called ADCNet to help design potential ADCs. The ADCNet highly integrates the protein representation learning language model ESM-2 and small-molecule representation learning language model FG-BERT models to achieve activity prediction through learning meaningful features from antigen and antibody protein sequences of ADC, SMILES strings of linker and payload, and drug-antibody ratio (DAR) value. Based on a carefully designed and manually tailored ADC data set, extensive evaluation results reveal that ADCNet performs best on the test set compared to baseline machine learning models across all evaluation metrics. For example, it achieves an average prediction accuracy of 87.12%, a balanced accuracy of 0.8689, and an area under receiver operating characteristic curve of 0.9293 on the test set. In addition, cross-validation, ablation experiments, and external independent testing results further prove the stability, advancement, and robustness of the ADCNet architecture. For the convenience of the community, we develop the first online platform (//ADCNet.idruglab.cn) for the prediction of ADCs activity based on the optimal ADCNet model, and the source code is publicly available at //github.com/idrugLab/ADCNet.
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LLMs have become increasingly capable at accomplishing a range of specialized-tasks and can be utilized to expand equitable access to medical knowledge. Most medical LLMs have involved extensive fine-tuning, leveraging specialized medical data and significant, thus costly, amounts of computational power. Many of the top performing LLMs are proprietary and their access is limited to very few research groups. However, open-source (OS) models represent a key area of growth for medical LLMs due to significant improvements in performance and an inherent ability to provide the transparency and compliance required in healthcare. We present OpenMedLM, a prompting platform which delivers state-of-the-art (SOTA) performance for OS LLMs on medical benchmarks. We evaluated a range of OS foundation LLMs (7B-70B) on four medical benchmarks (MedQA, MedMCQA, PubMedQA, MMLU medical-subset). We employed a series of prompting strategies, including zero-shot, few-shot, chain-of-thought (random selection and kNN selection), and ensemble/self-consistency voting. We found that OpenMedLM delivers OS SOTA results on three common medical LLM benchmarks, surpassing the previous best performing OS models that leveraged computationally costly extensive fine-tuning. The model delivers a 72.6% accuracy on the MedQA benchmark, outperforming the previous SOTA by 2.4%, and achieves 81.7% accuracy on the MMLU medical-subset, establishing itself as the first OS LLM to surpass 80% accuracy on this benchmark. Our results highlight medical-specific emergent properties in OS LLMs which have not yet been documented to date elsewhere, and showcase the benefits of further leveraging prompt engineering to improve the performance of accessible LLMs for medical applications.
In several countries, including Italy, a prominent approach to population health surveillance involves conducting repeated cross-sectional surveys at short intervals of time. These surveys gather information on the health status of individual respondents, including details on their behaviors, risk factors, and relevant socio-demographic information. While the collected data undoubtedly provides valuable information, modeling such data presents several challenges. For instance, in health risk models, it is essential to consider behavioral information, spatio-temporal dynamics, and disease co-occurrence. In response to these challenges, our work proposes a multivariate spatio-temporal logistic model for chronic disease diagnoses. Predictors are modeled using individual risk factor covariates and a latent individual propensity to the disease. Leveraging a state space formulation of the model, we construct a framework in which spatio-temporal heterogeneity in regression parameters is informed by exogenous spatial information, corresponding to different spatial contextual risk factors that may affect health and the occurrence of chronic diseases in different ways. To explore the utility and the effectiveness of our method, we analyze behavioral and risk factor surveillance data collected in Italy (PASSI), which is well-known as a country characterized by high peculiar administrative, social and territorial diversities reflected on high variability in morbidity among population subgroups.
Bayes factors for composite hypotheses have difficulty in encoding vague prior knowledge, as improper priors cannot be used and objective priors may be subjectively unreasonable. To address these issues I revisit the posterior Bayes factor, in which the posterior distribution from the data at hand is re-used in the Bayes factor for the same data. I argue that this is biased when calibrated against proper Bayes factors, but propose adjustments to allow interpretation on the same scale. In the important case of a regular normal model, the bias in log scale is half the number of parameters. The resulting empirical Bayes factor is closely related to the widely applicable information criterion. I develop test-based empirical Bayes factors for several standard tests and propose an extension to multiple testing closely related to the optimal discovery procedure. When only a P-value is available, an approximate empirical Bayes factor is 10p. I propose interpreting the strength of Bayes factors on a logarithmic scale with base 3.73, reflecting the sharpest distinction between weaker and stronger belief. This provides an objective framework for interpreting statistical evidence, and realises a Bayesian/frequentist compromise.
Calibration of fixtures in robotic work cells is essential but also time consuming and error-prone, and poor calibration can easily lead to wasted debugging time in downstream tasks. Contact-based calibration methods let the user measure points on the fixture's surface with a tool tip attached to the robot's end effector. Most methods require the user to manually annotate correspondences on the CAD model, however, this is error-prone and a cumbersome user experience. We propose a correspondence-free alternative: The user simply measures a few points from the fixture's surface, and our method provides a tight superset of the poses which could explain the measured points. This naturally detects ambiguities related to symmetry and uninformative points and conveys this uncertainty to the user. Perhaps more importantly, it provides guaranteed bounds on the pose. The computation of such bounds is made tractable by the use of a hierarchical grid on SE(3). Our method is evaluated both in simulation and on a real collaborative robot, showing great potential for easier and less error-prone fixture calibration.
Machine learning (ML) is set to accelerate innovations in clinical microbiomics, such as in disease diagnostics and prognostics. This will require high-quality, reproducible, interpretable workflows whose predictive capabilities meet or exceed the high thresholds set for clinical tools by regulatory agencies. Here, we capture a snapshot of current practices in the application of supervised ML to microbiomics data, through an in-depth analysis of 100 peer-reviewed journal articles published in 2021-2022. We apply a data-driven approach to steer discussion of the merits of varied approaches to experimental design, including key considerations such as how to mitigate the effects of small dataset size while avoiding data leakage. We further provide guidance on how to avoid common experimental design pitfalls that can hurt model performance, trustworthiness, and reproducibility. Discussion is accompanied by an interactive online tutorial that demonstrates foundational principles of ML experimental design, tailored to the microbiomics community. Formalizing community best practices for supervised ML in microbiomics is an important step towards improving the success and efficiency of clinical research, to the benefit of patients and other stakeholders.
Many biological systems such as cell aggregates, tissues or bacterial colonies behave as unconventional systems of particles that are strongly constrained by volume exclusion and shape interactions. Understanding how these constraints lead to macroscopic self-organized structures is a fundamental question in e.g. developmental biology. To this end, various types of computational models have been developed: phase fields, cellular automata, vertex models, level-set, finite element simulations, etc. We introduce a new framework based on optimal transport theory to model particle systems with arbitrary dynamical shapes and deformability. Our method builds upon the pioneering work of Brenier on incompressible fluids and its recent applications to materials science. It lets us specify the shapes of individual cells and supports a wide range of interaction mechanisms, while automatically taking care of the volume exclusion constraint at an affordable numerical cost. We showcase the versatility of this approach by reproducing several classical systems in computational biology. Our Python code is freely available at: www.github.com/antoinediez/ICeShOT
Behavior can be described as a temporal sequence of actions driven by neural activity. To learn complex sequential patterns in neural networks, memories of past activities need to persist on significantly longer timescales than relaxation times of single-neuron activity. While recurrent networks can produce such long transients, training these networks in a biologically plausible way is challenging. One approach has been reservoir computing, where only weights from a recurrent network to a readout are learned. Other models achieve learning of recurrent synaptic weights using propagated errors. However, their biological plausibility typically suffers from issues with locality, resource allocation or parameter scales and tuning. We suggest that many of these issues can be alleviated by considering dendritic information storage and computation. By applying a fully local, always-on plasticity rule we are able to learn complex sequences in a recurrent network comprised of two populations. Importantly, our model is resource-efficient, enabling the learning of complex sequences using only a small number of neurons. We demonstrate these features in a mock-up of birdsong learning, in which our networks first learn a long, non-Markovian sequence that they can then reproduce robustly despite external disturbances.
Principal component analysis (PCA) is a longstanding and well-studied approach for dimension reduction. It rests upon the assumption that the underlying signal in the data has low rank, and thus can be well-summarized using a small number of dimensions. The output of PCA is typically represented using a scree plot, which displays the proportion of variance explained (PVE) by each principal component. While the PVE is extensively reported in routine data analyses, to the best of our knowledge the notion of inference on the PVE remains unexplored. In this paper, we consider inference on the PVE. We first introduce a new population quantity for the PVE with respect to an unknown matrix mean. Critically, our interest lies in the PVE of the sample principal components (as opposed to unobserved population principal components); thus, the population PVE that we introduce is defined conditional on the sample singular vectors. We show that it is possible to conduct inference, in the sense of confidence intervals, p-values, and point estimates, on this population quantity. Furthermore, we can conduct valid inference on the PVE of a subset of the principal components, even when the subset is selected using a data-driven approach such as the elbow rule. We demonstrate the proposed approach in simulation and in an application to a gene expression dataset.
The Laplace eigenvalue problem on circular sectors has eigenfunctions with corner singularities. Standard methods may produce suboptimal approximation results. To address this issue, a novel numerical algorithm that enhances standard isogeometric analysis is proposed in this paper by using a single-patch graded mesh refinement scheme. Numerical tests demonstrate optimal convergence rates for both the eigenvalues and eigenfunctions. Furthermore, the results show that smooth splines possess a superior approximation constant compared to their $C^0$-continuous counterparts for the lower part of the Laplace spectrum. This is an extension of previous findings about excellent spectral approximation properties of smooth splines on rectangular domains to circular sectors. In addition, graded meshes prove to be particularly advantageous for an accurate approximation of a limited number of eigenvalues. The novel algorithm applied here has a drawback in the singularity of the isogeometric parameterization. It results in some basis functions not belonging to the solution space of the corresponding weak problem, which is considered a variational crime. However, the approach proves to be robust. Finally, a hierarchical mesh structure is presented to avoid anisotropic elements, omit redundant degrees of freedom and keep the number of basis functions contributing to the variational crime constant, independent of the mesh size. Numerical results validate the effectiveness of hierarchical mesh grading for the simulation of eigenfunctions with and without corner singularities.
Breast cancer remains a global challenge, causing over 1 million deaths globally in 2018. To achieve earlier breast cancer detection, screening x-ray mammography is recommended by health organizations worldwide and has been estimated to decrease breast cancer mortality by 20-40%. Nevertheless, significant false positive and false negative rates, as well as high interpretation costs, leave opportunities for improving quality and access. To address these limitations, there has been much recent interest in applying deep learning to mammography; however, obtaining large amounts of annotated data poses a challenge for training deep learning models for this purpose, as does ensuring generalization beyond the populations represented in the training dataset. Here, we present an annotation-efficient deep learning approach that 1) achieves state-of-the-art performance in mammogram classification, 2) successfully extends to digital breast tomosynthesis (DBT; "3D mammography"), 3) detects cancers in clinically-negative prior mammograms of cancer patients, 4) generalizes well to a population with low screening rates, and 5) outperforms five-out-of-five full-time breast imaging specialists by improving absolute sensitivity by an average of 14%. Our results demonstrate promise towards software that can improve the accuracy of and access to screening mammography worldwide.
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