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Gene set analysis is a mainstay of functional genomics, but it relies on manually curated databases of gene functions that are incomplete and unaware of biological context. Here we evaluate the ability of OpenAI's GPT-4, a Large Language Model (LLM), to develop hypotheses about common gene functions from its embedded biomedical knowledge. We created a GPT-4 pipeline to label gene sets with names that summarize their consensus functions, substantiated by analysis text and citations. Benchmarking against named gene sets in the Gene Ontology, GPT-4 generated very similar names in 50% of cases, while in most remaining cases it recovered the name of a more general concept. In gene sets discovered in 'omics data, GPT-4 names were more informative than gene set enrichment, with supporting statements and citations that largely verified in human review. The ability to rapidly synthesize common gene functions positions LLMs as valuable functional genomics assistants.

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We present a streamlined and simplified exponential lower bound on the length of proofs in intuitionistic implicational logic, adapted to Gordeev and Haeusler's dag-like natural deduction.

Recently it has become common for applied works to combine commonly used survival analysis modeling methods, such as the multivariable Cox model, and propensity score weighting with the intention of forming a doubly robust estimator that is unbiased in large samples when either the Cox model or the propensity score model is correctly specified. This combination does not, in general, produce a doubly robust estimator, even after regression standardization, when there is truly a causal effect. We demonstrate via simulation this lack of double robustness for the semiparametric Cox model, the Weibull proportional hazards model, and a simple proportional hazards flexible parametric model, with both the latter models fit via maximum likelihood. We provide a novel proof that the combination of propensity score weighting and a proportional hazards survival model, fit either via full or partial likelihood, is consistent under the null of no causal effect of the exposure on the outcome under particular censoring mechanisms if either the propensity score or the outcome model is correctly specified and contains all confounders. Given our results suggesting that double robustness only exists under the null, we outline two simple alternative estimators that are doubly robust for the survival difference at a given time point (in the above sense), provided the censoring mechanism can be correctly modeled, and one doubly robust method of estimation for the full survival curve. We provide R code to use these estimators for estimation and inference in the supplementary materials.

Benchmark suites are crucial for assessing the performance of evolutionary algorithms, but the constituent problems are often too complex to provide clear intuition about an algorithm's strengths and weaknesses. To address this gap, we introduce DOSSIER ("Diagnostic Overview of Selection Schemes In Evolutionary Runs"), a diagnostic suite initially composed of eight handcrafted metrics. These metrics are designed to empirically measure specific capacities for exploitation, exploration, and their interactions. We consider exploitation both with and without constraints, and we divide exploration into two aspects: diversity exploration (the ability to simultaneously explore multiple pathways) and valley-crossing exploration (the ability to cross wider and wider fitness valleys). We apply DOSSIER to six popular selection schemes: truncation, tournament, fitness sharing, lexicase, nondominated sorting, and novelty search. Our results confirm that simple schemes (e.g., tournament and truncation) emphasized exploitation. For more sophisticated schemes, however, our diagnostics revealed interesting dynamics. Lexicase selection performed moderately well across all diagnostics that did not incorporate valley crossing, but faltered dramatically whenever valleys were present, performing worse than even random search. Fitness sharing was the only scheme to effectively contend with valley crossing but it struggled with the other diagnostics. Our study highlights the utility of using diagnostics to gain nuanced insights into selection scheme characteristics, which can inform the design of new selection methods.

The case-cohort design is a commonly used cost-effective sampling strategy for large cohort studies, where some covariates are expensive to measure or obtain. In this paper, we consider regression analysis under a case-cohort study with interval-censored failure time data, where the failure time is only known to fall within an interval instead of being exactly observed. A common approach to analyze data from a case-cohort study is the inverse probability weighting approach, where only subjects in the case-cohort sample are used in estimation, and the subjects are weighted based on the probability of inclusion into the case-cohort sample. This approach, though consistent, is generally inefficient as it does not incorporate information outside the case-cohort sample. To improve efficiency, we first develop a sieve maximum weighted likelihood estimator under the Cox model based on the case-cohort sample, and then propose a procedure to update this estimator by using information in the full cohort. We show that the update estimator is consistent, asymptotically normal, and more efficient than the original estimator. The proposed method can flexibly incorporate auxiliary variables to further improve estimation efficiency. We employ a weighted bootstrap procedure for variance estimation. Simulation results indicate that the proposed method works well in practical situations. A real study on diabetes is provided for illustration.

Cosine similarity is an established similarity metric for computing associations on vectors, and it is commonly used to identify related samples from biological perturbational data. The distribution of cosine similarity changes with the covariance of the data, and this in turn affects the statistical power to identify related signals. The relationship between the mean and covariance of the distribution of the data and the distribution of cosine similarity is poorly understood. In this work, we derive the asymptotic moments of cosine similarity as a function of the data and identify the criteria of the data covariance matrix that minimize the variance of cosine similarity. We find that the variance of cosine similarity is minimized when the eigenvalues of the covariance matrix are equal for centered data. One immediate application of this work is characterizing the null distribution of cosine similarity over a dataset with non-zero covariance structure. Furthermore, this result can be used to optimize over a set of transformations or representations on a dataset to maximize power, recall, or other discriminative metrics, with direct application to noisy biological data. While we consider the specific biological domain of perturbational data analysis, our result has potential application for any use of cosine similarity or Pearson's correlation on data with covariance structure.

Obtaining the solutions of partial differential equations based on machine learning methods has drawn more and more attention in the fields of scientific computation and engineering applications. In this work, we first propose a coupled Extreme Learning Machine(called CELM) method incorporated with the physical laws to solve a class of fourth-order biharmonic equations by reformulating it into two well-posed Poisson problems. In addition, some activation functions including tangent, gaussian, sine, and trigonometric functions are introduced to assess our CELM method. Furthermore, we introduce several activation functions, such as tangent, Gaussian, sine, and trigonometric functions, to evaluate the performance of our CELM method. Notably, the sine and trigonometric functions demonstrate a remarkable ability to effectively minimize the approximation error of the CELM model. In the end, several numerical experiments are performed to study the initializing ways for both the weights and biases of the hidden units in our CELM model and explore the required number of hidden units. Numerical results show the proposed CELM algorithm is high-precision and efficient to address the biharmonic equations on both regular and irregular domains.

Symmetry is a cornerstone of much of mathematics, and many probability distributions possess symmetries characterized by their invariance to a collection of group actions. Thus, many mathematical and statistical methods rely on such symmetry holding and ostensibly fail if symmetry is broken. This work considers under what conditions a sequence of probability measures asymptotically gains such symmetry or invariance to a collection of group actions. Considering the many symmetries of the Gaussian distribution, this work effectively proposes a non-parametric type of central limit theorem. That is, a Lipschitz function of a high dimensional random vector will be asymptotically invariant to the actions of certain compact topological groups. Applications of this include a partial law of the iterated logarithm for uniformly random points in an $\ell_p^n$-ball and an asymptotic equivalence between classical parametric statistical tests and their randomization counterparts even when invariance assumptions are violated.

Robust generalization is a major challenge in deep learning, particularly when the number of trainable parameters is very large. In general, it is very difficult to know if the network has memorized a particular set of examples or understood the underlying rule (or both). Motivated by this challenge, we study an interpretable model where generalizing representations are understood analytically, and are easily distinguishable from the memorizing ones. Namely, we consider two-layer neural networks trained on modular arithmetic tasks where ($\xi \cdot 100\%$) of labels are corrupted (\emph{i.e.} some results of the modular operations in the training set are incorrect). We show that (i) it is possible for the network to memorize the corrupted labels \emph{and} achieve $100\%$ generalization at the same time; (ii) the memorizing neurons can be identified and pruned, lowering the accuracy on corrupted data and improving the accuracy on uncorrupted data; (iii) regularization methods such as weight decay, dropout and BatchNorm force the network to ignore the corrupted data during optimization, and achieve $100\%$ accuracy on the uncorrupted dataset; and (iv) the effect of these regularization methods is (``mechanistically'') interpretable: weight decay and dropout force all the neurons to learn generalizing representations, while BatchNorm de-amplifies the output of memorizing neurons and amplifies the output of the generalizing ones. Finally, we show that in the presence of regularization, the training dynamics involves two consecutive stages: first, the network undergoes the \emph{grokking} dynamics reaching high train \emph{and} test accuracy; second, it unlearns the memorizing representations, where train accuracy suddenly jumps from $100\%$ to $100 (1-\xi)\%$.

We hypothesize that due to the greedy nature of learning in multi-modal deep neural networks, these models tend to rely on just one modality while under-fitting the other modalities. Such behavior is counter-intuitive and hurts the models' generalization, as we observe empirically. To estimate the model's dependence on each modality, we compute the gain on the accuracy when the model has access to it in addition to another modality. We refer to this gain as the conditional utilization rate. In the experiments, we consistently observe an imbalance in conditional utilization rates between modalities, across multiple tasks and architectures. Since conditional utilization rate cannot be computed efficiently during training, we introduce a proxy for it based on the pace at which the model learns from each modality, which we refer to as the conditional learning speed. We propose an algorithm to balance the conditional learning speeds between modalities during training and demonstrate that it indeed addresses the issue of greedy learning. The proposed algorithm improves the model's generalization on three datasets: Colored MNIST, Princeton ModelNet40, and NVIDIA Dynamic Hand Gesture.

Graph representation learning for hypergraphs can be used to extract patterns among higher-order interactions that are critically important in many real world problems. Current approaches designed for hypergraphs, however, are unable to handle different types of hypergraphs and are typically not generic for various learning tasks. Indeed, models that can predict variable-sized heterogeneous hyperedges have not been available. Here we develop a new self-attention based graph neural network called Hyper-SAGNN applicable to homogeneous and heterogeneous hypergraphs with variable hyperedge sizes. We perform extensive evaluations on multiple datasets, including four benchmark network datasets and two single-cell Hi-C datasets in genomics. We demonstrate that Hyper-SAGNN significantly outperforms the state-of-the-art methods on traditional tasks while also achieving great performance on a new task called outsider identification. Hyper-SAGNN will be useful for graph representation learning to uncover complex higher-order interactions in different applications.

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