Pocock and Simon's minimization method is a popular approach for covariate-adaptive randomization in clinical trials. Valid statistical inference with data collected under the minimization method requires the knowledge of the limiting covariance matrix of within-stratum imbalances, whose existence is only recently established. In this work, we propose a bootstrap-based estimator for this limit and establish its consistency, in particular, by Le Cam's third lemma. As an application, we consider in simulation studies adjustments to existing robust tests for treatment effects with survival data by the proposed estimator. It shows that the adjusted tests achieve a size close to the nominal level, and unlike other designs, the robust tests without adjustment may have an asymptotic size inflation issue under the minimization method.
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The morphology and hierarchy of the vascular systems are essential for perfusion in supporting metabolism. In human retina, one of the most energy-demanding organs, retinal circulation nourishes the entire inner retina by an intricate vasculature emerging and remerging at the optic nerve head (ONH). Thus, tracing the vascular branching from ONH through the vascular tree can illustrate vascular hierarchy and allow detailed morphological quantification, and yet remains a challenging task. Here, we presented a novel approach for a robust semi-automatic vessel tracing algorithm on human fundus images by an instance segmentation neural network (InSegNN). Distinct from semantic segmentation, InSegNN separates and labels different vascular trees individually and therefore enable tracing each tree throughout its branching. We have built-in three strategies to improve robustness and accuracy with temporal learning, spatial multi-sampling, and dynamic probability map. We achieved 83% specificity, and 50% improvement in Symmetric Best Dice (SBD) compared to literature, and outperformed baseline U-net. We have demonstrated tracing individual vessel trees from fundus images, and simultaneously retain the vessel hierarchy information. InSegNN paves a way for any subsequent morphological analysis of vascular morphology in relation to retinal diseases.
Non-Hermitian topological phases can produce some remarkable properties, compared with their Hermitian counterpart, such as the breakdown of conventional bulk-boundary correspondence and the non-Hermitian topological edge mode. Here, we introduce several algorithms with multi-layer perceptron (MLP), and convolutional neural network (CNN) in the field of deep learning, to predict the winding of eigenvalues non-Hermitian Hamiltonians. Subsequently, we use the smallest module of the periodic circuit as one unit to construct high-dimensional circuit data features. Further, we use the Dense Convolutional Network (DenseNet), a type of convolutional neural network that utilizes dense connections between layers to design a non-Hermitian topolectrical Chern circuit, as the DenseNet algorithm is more suitable for processing high-dimensional data. Our results demonstrate the effectiveness of the deep learning network in capturing the global topological characteristics of a non-Hermitian system based on training data.
Retinopathy of prematurity (ROP) is a severe condition affecting premature infants, leading to abnormal retinal blood vessel growth, retinal detachment, and potential blindness. While semi-automated systems have been used in the past to diagnose ROP-related plus disease by quantifying retinal vessel features, traditional machine learning (ML) models face challenges like accuracy and overfitting. Recent advancements in deep learning (DL), especially convolutional neural networks (CNNs), have significantly improved ROP detection and classification. The i-ROP deep learning (i-ROP-DL) system also shows promise in detecting plus disease, offering reliable ROP diagnosis potential. This research comprehensively examines the contemporary progress and challenges associated with using retinal imaging and artificial intelligence (AI) to detect ROP, offering valuable insights that can guide further investigation in this domain. Based on 89 original studies in this field (out of 1487 studies that were comprehensively reviewed), we concluded that traditional methods for ROP diagnosis suffer from subjectivity and manual analysis, leading to inconsistent clinical decisions. AI holds great promise for improving ROP management. This review explores AI's potential in ROP detection, classification, diagnosis, and prognosis.
Combinatorial optimization - a field of research addressing problems that feature strongly in a wealth of scientific and industrial contexts - has been identified as one of the core potential fields of applicability of quantum computers. It is still unclear, however, to what extent quantum algorithms can actually outperform classical algorithms for this type of problems. In this work, by resorting to computational learning theory and cryptographic notions, we prove that quantum computers feature an in-principle super-polynomial advantage over classical computers in approximating solutions to combinatorial optimization problems. Specifically, building on seminal work by Kearns and Valiant and introducing a new reduction, we identify special types of problems that are hard for classical computers to approximate up to polynomial factors. At the same time, we give a quantum algorithm that can efficiently approximate the optimal solution within a polynomial factor. The core of the quantum advantage discovered in this work is ultimately borrowed from Shor's quantum algorithm for factoring. Concretely, we prove a super-polynomial advantage for approximating special instances of the so-called integer programming problem. In doing so, we provide an explicit end-to-end construction for advantage bearing instances. This result shows that quantum devices have, in principle, the power to approximate combinatorial optimization solutions beyond the reach of classical efficient algorithms. Our results also give clear guidance on how to construct such advantage-bearing problem instances.
The log-rank test and the Cox proportional hazards model are commonly used to compare time-to-event data in clinical trials, as they are most powerful under proportional hazards. But there is a loss of power if this assumption is violated, which is the case for some new oncology drugs like immunotherapies. We consider a two-stage test procedure, in which the weighting of the log-rank test statistic depends on a pre-test of the proportional hazards assumption. I.e., depending on the pre-test either the log-rank or an alternative test is used to compare the survival probabilities. We show that if naively implemented this can lead to a substantial inflation of the type-I error rate. To address this, we embed the two-stage test in a permutation test framework to keep the nominal level alpha. We compare the operating characteristics of the two-stage test with the log-rank test and other tests by clinical trial simulations.
Artificial intelligence (AI) systems have the potential to revolutionize clinical practices, including improving diagnostic accuracy and surgical decision-making, while also reducing costs and manpower. However, it is important to recognize that these systems may perpetuate social inequities or demonstrate biases, such as those based on race or gender. Such biases can occur before, during, or after the development of AI models, making it critical to understand and address potential biases to enable the accurate and reliable application of AI models in clinical settings. To mitigate bias concerns during model development, we surveyed recent publications on different debiasing methods in the fields of biomedical natural language processing (NLP) or computer vision (CV). Then we discussed the methods that have been applied in the biomedical domain to address bias. We performed our literature search on PubMed, ACM digital library, and IEEE Xplore of relevant articles published between January 2018 and December 2023 using multiple combinations of keywords. We then filtered the result of 10,041 articles automatically with loose constraints, and manually inspected the abstracts of the remaining 890 articles to identify the 55 articles included in this review. Additional articles in the references are also included in this review. We discuss each method and compare its strengths and weaknesses. Finally, we review other potential methods from the general domain that could be applied to biomedicine to address bias and improve fairness.The bias of AIs in biomedicine can originate from multiple sources. Existing debiasing methods that focus on algorithms can be categorized into distributional or algorithmic.
In exploratory factor analysis, model parameters are usually estimated by maximum likelihood method. The maximum likelihood estimate is obtained by solving a complicated multivariate algebraic equation. Since the solution to the equation is usually intractable, it is typically computed with continuous optimization methods, such as Newton-Raphson methods. With this procedure, however, the solution is inevitably dependent on the estimation algorithm and initial value since the log-likelihood function is highly non-concave. Particularly, the estimates of unique variances can result in zero or negative, referred to as improper solutions; in this case, the maximum likelihood estimate can be severely unstable. To delve into the issue of the instability of the maximum likelihood estimate, we compute exact solutions to the multivariate algebraic equation by using algebraic computations. We provide a computationally efficient algorithm based on the algebraic computations specifically optimized for maximum likelihood factor analysis. To be specific, Gr\"oebner basis and cylindrical decomposition are employed, powerful tools for solving the multivariate algebraic equation. Our proposed procedure produces all exact solutions to the algebraic equation; therefore, these solutions are independent of the initial value and estimation algorithm. We conduct Monte Carlo simulations to investigate the characteristics of the maximum likelihood solutions.
The integration of large language models (LLMs) into the medical field has gained significant attention due to their promising accuracy in simulated clinical decision-making settings. However, clinical decision-making is more complex than simulations because physicians' decisions are shaped by many factors, including the presence of cognitive bias. However, the degree to which LLMs are susceptible to the same cognitive biases that affect human clinicians remains unexplored. Our hypothesis posits that when LLMs are confronted with clinical questions containing cognitive biases, they will yield significantly less accurate responses compared to the same questions presented without such biases.In this study, we developed BiasMedQA, a novel benchmark for evaluating cognitive biases in LLMs applied to medical tasks. Using BiasMedQA we evaluated six LLMs, namely GPT-4, Mixtral-8x70B, GPT-3.5, PaLM-2, Llama 2 70B-chat, and the medically specialized PMC Llama 13B. We tested these models on 1,273 questions from the US Medical Licensing Exam (USMLE) Steps 1, 2, and 3, modified to replicate common clinically-relevant cognitive biases. Our analysis revealed varying effects for biases on these LLMs, with GPT-4 standing out for its resilience to bias, in contrast to Llama 2 70B-chat and PMC Llama 13B, which were disproportionately affected by cognitive bias. Our findings highlight the critical need for bias mitigation in the development of medical LLMs, pointing towards safer and more reliable applications in healthcare.
We adopt the integral definition of the fractional Laplace operator and study an optimal control problem on Lipschitz domains that involves a fractional elliptic partial differential equation (PDE) as state equation and a control variable that enters the state equation as a coefficient; pointwise constraints on the control variable are considered as well. We establish the existence of optimal solutions and analyze first and, necessary and sufficient, second order optimality conditions. Regularity estimates for optimal variables are also analyzed. We develop two finite element discretization strategies: a semidiscrete scheme in which the control variable is not discretized, and a fully discrete scheme in which the control variable is discretized with piecewise constant functions. For both schemes, we analyze the convergence properties of discretizations and derive error estimates.
In large-scale systems there are fundamental challenges when centralised techniques are used for task allocation. The number of interactions is limited by resource constraints such as on computation, storage, and network communication. We can increase scalability by implementing the system as a distributed task-allocation system, sharing tasks across many agents. However, this also increases the resource cost of communications and synchronisation, and is difficult to scale. In this paper we present four algorithms to solve these problems. The combination of these algorithms enable each agent to improve their task allocation strategy through reinforcement learning, while changing how much they explore the system in response to how optimal they believe their current strategy is, given their past experience. We focus on distributed agent systems where the agents' behaviours are constrained by resource usage limits, limiting agents to local rather than system-wide knowledge. We evaluate these algorithms in a simulated environment where agents are given a task composed of multiple subtasks that must be allocated to other agents with differing capabilities, to then carry out those tasks. We also simulate real-life system effects such as networking instability. Our solution is shown to solve the task allocation problem to 6.7% of the theoretical optimal within the system configurations considered. It provides 5x better performance recovery over no-knowledge retention approaches when system connectivity is impacted, and is tested against systems up to 100 agents with less than a 9% impact on the algorithms' performance.
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