Successful pharmaceutical drug development requires finding correct doses that provide an optimum balance between efficacy and toxicity. Competing responses to dose such as efficacy and toxicity often will increase with dose, and it is important to identify a range of doses to provide an acceptable efficacy response (minimum effective dose) while not causing unacceptable intolerance or toxicity (maximum tolerated dose). How this should be done is not self-evident. Relating efficacy to dose conditionally on possible toxicity may be problematic because whether toxicity occurs will not be known when a dose for a patient needs to be chosen. Copula models provide an appealing approach for incorporating an efficacy-toxicity association when the functional forms of the efficacy and toxicity dose-response models are known but may be less appealing in practice when the functional forms of the dose-response models and the particular copula association model are unknown. This paper explores the use of the BMA-Mod Bayesian model averaging framework that accommodates efficacy and toxicity responses to provide a statistically valid, distributionally flexible, and operationally practical model-agnostic strategy for predicting efficacy and toxicity outcomes both in terms of expected responses and in terms of predictions for individual patients. The performance of the approach is evaluated via simulation when efficacy and toxicity outcomes are considered marginally, when they are associated via gaussian and Archimedean copulas, and when they are expressed in terms of clinically meaningful categories. In all cases, the BMA-Mod strategy identified consistent ranges of acceptable doses.
相關內容
The discovery of clinical biomarkers requires large patient cohorts and is aided by a pooled data approach across institutions. In many countries, data protection constraints, especially in the clinical environment, forbid the exchange of individual-level data between different research institutes, impeding the conduct of a joint analyses. To circumvent this problem, only non-disclosive aggregated data is exchanged, which is often done manually and requires explicit permission before transfer, i.e., the number of data calls and the amount of data should be limited. This does not allow for more complex tasks such as variable selection, as only simple aggregated summary statistics are typically transferred. Other methods have been proposed that require more complex aggregated data or use input data perturbation, but these methods can either not deal with a high number of biomarkers or lose information. Here, we propose a multivariable regression approach for identifying biomarkers by automatic variable selection based on aggregated data in iterative calls, which can be implemented under data protection constraints. The approach can be used to jointly analyze data distributed across several locations. To minimize the amount of transferred data and the number of calls, we also provide a heuristic variant of the approach. When performing global data standardization, the proposed method yields the same results as pooled individual-level data analysis. In a simulation study, the information loss introduced by local standardization is seen to be minimal. In a typical scenario, the heuristic decreases the number of data calls from more than 10 to 3, rendering manual data releases feasible. To make our approach widely available for application, we provide an implementation of the heuristic version incorporated in the DataSHIELD framework.\
The massive interest in deep neural networks (DNNs) for both computer vision and natural language processing has been sparked by the growth in computational power. However, this led to an increase in the memory footprint, to a point where it can be challenging to simply load a model on commodity devices such as mobile phones. To address this limitation, quantization is a favored solution as it maps high precision tensors to a low precision, memory efficient format. In terms of memory footprint reduction, its most effective variants are based on codebooks. These methods, however, suffer from two limitations. First, they either define a single codebook for each tensor, or use a memory-expensive mapping to multiple codebooks. Second, gradient descent optimization of the mapping favors jumps toward extreme values, hence not defining a proximal search. In this work, we propose to address these two limitations. First, we initially group similarly distributed neurons and leverage the re-ordered structure to either apply different scale factors to the different groups, or map weights that fall in these groups to several codebooks, without any mapping overhead. Second, stemming from this initialization, we propose a joint learning of the codebook and weight mappings that bears similarities with recent gradient-based post-training quantization techniques. Third, drawing estimation from straight-through estimation techniques, we introduce a novel gradient update definition to enable a proximal search of the codebooks and their mappings. The proposed jointly learnable codebooks and mappings (JLCM) method allows a very efficient approximation of any DNN: as such, a Llama 7B can be compressed down to 2Go and loaded on 5-year-old smartphones.
We introduce a clipping strategy for Stochastic Gradient Descent (SGD) which uses quantiles of the gradient norm as clipping thresholds. We prove that this new strategy provides a robust and efficient optimization algorithm for smooth objectives (convex or non-convex), that tolerates heavy-tailed samples (including infinite variance) and a fraction of outliers in the data stream akin to Huber contamination. Our mathematical analysis leverages the connection between constant step size SGD and Markov chains and handles the bias introduced by clipping in an original way. For strongly convex objectives, we prove that the iteration converges to a concentrated distribution and derive high probability bounds on the final estimation error. In the non-convex case, we prove that the limit distribution is localized on a neighborhood with low gradient. We propose an implementation of this algorithm using rolling quantiles which leads to a highly efficient optimization procedure with strong robustness properties, as confirmed by our numerical experiments.
In the rapidly evolving field of medical imaging, machine learning algorithms have become indispensable for enhancing diagnostic accuracy. However, the effectiveness of these algorithms is contingent upon the availability and organization of high-quality medical imaging datasets. Traditional Digital Imaging and Communications in Medicine (DICOM) data management systems are inadequate for handling the scale and complexity of data required to be facilitated in machine learning algorithms. This paper introduces an innovative data curation tool, developed as part of the Kaapana open-source toolkit, aimed at streamlining the organization, management, and processing of large-scale medical imaging datasets. The tool is specifically tailored to meet the needs of radiologists and machine learning researchers. It incorporates advanced search, auto-annotation and efficient tagging functionalities for improved data curation. Additionally, the tool facilitates quality control and review, enabling researchers to validate image and segmentation quality in large datasets. It also plays a critical role in uncovering potential biases in datasets by aggregating and visualizing metadata, which is essential for developing robust machine learning models. Furthermore, Kaapana is integrated within the Radiological Cooperative Network (RACOON), a pioneering initiative aimed at creating a comprehensive national infrastructure for the aggregation, transmission, and consolidation of radiological data across all university clinics throughout Germany. A supplementary video showcasing the tool's functionalities can be accessed at //bit.ly/MICCAI-DEMI2023.
Estimating causal effects from observational data is a central problem in many domains. A general approach is to balance covariates with weights such that the distribution of the data mimics randomization. We present generalized balancing weights, Neural Balancing Weights (NBW), to estimate the causal effects of an arbitrary mixture of discrete and continuous interventions. The weights were obtained through direct estimation of the density ratio between the source and balanced distributions by optimizing the variational representation of $f$-divergence. For this, we selected $\alpha$-divergence as it presents efficient optimization because it has an estimator whose sample complexity is independent of its ground truth value and unbiased mini-batch gradients; moreover, it is advantageous for the vanishing-gradient problem. In addition, we provide the following two methods for estimating the balancing weights: improving the generalization performance of the balancing weights and checking the balance of the distribution changed by the weights. Finally, we discuss the sample size requirements for the weights as a general problem of a curse of dimensionality when balancing multidimensional data. Our study provides a basic approach for estimating the balancing weights of multidimensional data using variational $f$-divergences.
Rolling bearing fault diagnosis has garnered increased attention in recent years owing to its presence in rotating machinery across various industries, and an ever increasing demand for efficient operations. Prompt detection and accurate prediction of bearing failures can help reduce the likelihood of unexpected machine downtime and enhance maintenance schedules, averting lost productivity. Recent technological advances have enabled monitoring the health of these assets at scale using a variety of sensors, and predicting the failures using modern Machine Learning (ML) approaches including deep learning architectures. Vibration data has been collected using accelerated run-to-failure of overloaded bearings, or by introducing known failure in bearings, under a variety of operating conditions such as rotating speed, load on the bearing, type of bearing fault, and data acquisition frequency. However, in the development of bearing failure classification models using vibration data there is a lack of consensus in the metrics used to evaluate the models, data partitions used to evaluate models, and methods used to generate failure labels in run-to-failure experiments. An understanding of the impact of these choices is important to reliably develop models, and deploy them in practical settings. In this work, we demonstrate the significance of these choices on the performance of the models using publicly-available vibration datasets, and suggest model development considerations for real world scenarios. Our experimental findings demonstrate that assigning vibration data from a given bearing across training and evaluation splits leads to over-optimistic performance estimates, PCA-based approach is able to robustly generate labels for failure classification in run-to-failure experiments, and $F$ scores are more insightful to evaluate the models with unbalanced real-world failure data.
Decision-making algorithms are being used in important decisions, such as who should be enrolled in health care programs and be hired. Even though these systems are currently deployed in high-stakes scenarios, many of them cannot explain their decisions. This limitation has prompted the Explainable Artificial Intelligence (XAI) initiative, which aims to make algorithms explainable to comply with legal requirements, promote trust, and maintain accountability. This paper questions whether and to what extent explainability can help solve the responsibility issues posed by autonomous AI systems. We suggest that XAI systems that provide post-hoc explanations could be seen as blameworthy agents, obscuring the responsibility of developers in the decision-making process. Furthermore, we argue that XAI could result in incorrect attributions of responsibility to vulnerable stakeholders, such as those who are subjected to algorithmic decisions (i.e., patients), due to a misguided perception that they have control over explainable algorithms. This conflict between explainability and accountability can be exacerbated if designers choose to use algorithms and patients as moral and legal scapegoats. We conclude with a set of recommendations for how to approach this tension in the socio-technical process of algorithmic decision-making and a defense of hard regulation to prevent designers from escaping responsibility.
Causality can be described in terms of a structural causal model (SCM) that carries information on the variables of interest and their mechanistic relations. For most processes of interest the underlying SCM will only be partially observable, thus causal inference tries to leverage any exposed information. Graph neural networks (GNN) as universal approximators on structured input pose a viable candidate for causal learning, suggesting a tighter integration with SCM. To this effect we present a theoretical analysis from first principles that establishes a novel connection between GNN and SCM while providing an extended view on general neural-causal models. We then establish a new model class for GNN-based causal inference that is necessary and sufficient for causal effect identification. Our empirical illustration on simulations and standard benchmarks validate our theoretical proofs.
Analyzing observational data from multiple sources can be useful for increasing statistical power to detect a treatment effect; however, practical constraints such as privacy considerations may restrict individual-level information sharing across data sets. This paper develops federated methods that only utilize summary-level information from heterogeneous data sets. Our federated methods provide doubly-robust point estimates of treatment effects as well as variance estimates. We derive the asymptotic distributions of our federated estimators, which are shown to be asymptotically equivalent to the corresponding estimators from the combined, individual-level data. We show that to achieve these properties, federated methods should be adjusted based on conditions such as whether models are correctly specified and stable across heterogeneous data sets.
Human doctors with well-structured medical knowledge can diagnose a disease merely via a few conversations with patients about symptoms. In contrast, existing knowledge-grounded dialogue systems often require a large number of dialogue instances to learn as they fail to capture the correlations between different diseases and neglect the diagnostic experience shared among them. To address this issue, we propose a more natural and practical paradigm, i.e., low-resource medical dialogue generation, which can transfer the diagnostic experience from source diseases to target ones with a handful of data for adaptation. It is capitalized on a commonsense knowledge graph to characterize the prior disease-symptom relations. Besides, we develop a Graph-Evolving Meta-Learning (GEML) framework that learns to evolve the commonsense graph for reasoning disease-symptom correlations in a new disease, which effectively alleviates the needs of a large number of dialogues. More importantly, by dynamically evolving disease-symptom graphs, GEML also well addresses the real-world challenges that the disease-symptom correlations of each disease may vary or evolve along with more diagnostic cases. Extensive experiment results on the CMDD dataset and our newly-collected Chunyu dataset testify the superiority of our approach over state-of-the-art approaches. Besides, our GEML can generate an enriched dialogue-sensitive knowledge graph in an online manner, which could benefit other tasks grounded on knowledge graph.
注冊地址： 北京市海淀區羊坊店路18號2幢3層301-191