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Given the ubiquity of modularity in biological systems, module-level regulation analysis is vital for understanding biological systems across various levels and their dynamics. Current statistical analysis on biological modules predominantly focuses on either detecting the functional modules in biological networks or sub-group regression on the biological features without using the network data. This paper proposes a novel network-based neighborhood regression framework whose regression functions depend on both the global community-level information and local connectivity structures among entities. An efficient community-wise least square optimization approach is developed to uncover the strength of regulation among the network modules while enabling asymptotic inference. With random graph theory, we derive non-asymptotic estimation error bounds for the proposed estimator, achieving exact minimax optimality. Unlike the root-n consistency typical in canonical linear regression, our model exhibits linear consistency in the number of nodes n, highlighting the advantage of incorporating neighborhood information. The effectiveness of the proposed framework is further supported by extensive numerical experiments. Application to whole-exome sequencing and RNA-sequencing Autism datasets demonstrates the usage of the proposed method in identifying the association between the gene modules of genetic variations and the gene modules of genomic differential expressions.

With the evolution of single-cell RNA sequencing techniques into a standard approach in genomics, it has become possible to conduct cohort-level causal inferences based on single-cell-level measurements. However, the individual gene expression levels of interest are not directly observable; instead, only repeated proxy measurements from each individual's cells are available, providing a derived outcome to estimate the underlying outcome for each of many genes. In this paper, we propose a generic semiparametric inference framework for doubly robust estimation with multiple derived outcomes, which also encompasses the usual setting of multiple outcomes when the response of each unit is available. To reliably quantify the causal effects of heterogeneous outcomes, we specialize the analysis to standardized average treatment effects and quantile treatment effects. Through this, we demonstrate the use of the semiparametric inferential results for doubly robust estimators derived from both Von Mises expansions and estimating equations. A multiple testing procedure based on Gaussian multiplier bootstrap is tailored for doubly robust estimators to control the false discovery exceedance rate. Applications in single-cell CRISPR perturbation analysis and individual-level differential expression analysis demonstrate the utility of the proposed methods and offer insights into the usage of different estimands for causal inference in genomics., Comment: 26 pages and 6 figures for the main text, 30 pages and 3 figures for the supplement

We study the behavior of optimal ridge regularization and optimal ridge risk for out-of-distribution prediction, where the test distribution deviates arbitrarily from the train distribution. We establish general conditions that determine the sign of the optimal regularization level under covariate and regression shifts. These conditions capture the alignment between the covariance and signal structures in the train and test data and reveal stark differences compared to the in-distribution setting. For example, a negative regularization level can be optimal under covariate shift or regression shift, even when the training features are isotropic or the design is underparameterized. Furthermore, we prove that the optimally-tuned risk is monotonic in the data aspect ratio, even in the out-of-distribution setting and when optimizing over negative regularization levels. In general, our results do not make any modeling assumptions for the train or the test distributions, except for moment bounds, and allow for arbitrary shifts and the widest possible range of (negative) regularization levels., Comment: 59 pages, 14 figures

Quantitative measurements produced by mass spectrometry proteomics experiments offer a direct way to explore the role of proteins in molecular mechanisms. However, analysis of such data is challenging due to the large proportion of missing values. A common strategy to address this issue is to utilize an imputed dataset, which often introduces systematic bias into downstream analyses if the imputation errors are ignored. In this paper, we propose a statistical framework inspired by doubly robust estimators that offers valid and efficient inference for proteomic data. Our framework combines powerful machine learning tools, such as variational autoencoders, to augment the imputation quality with high-dimensional peptide data, and a parametric model to estimate the propensity score for debiasing imputed outcomes. Our estimator is compatible with the double machine learning framework and has provable properties. In application to both single-cell and bulk-cell proteomic data our method utilizes the imputed data to gain additional, meaningful discoveries and yet maintains good control of false positives.

Generalized cross-validation (GCV) is a widely-used method for estimating the squared out-of-sample prediction risk that employs a scalar degrees of freedom adjustment (in a multiplicative sense) to the squared training error. In this paper, we examine the consistency of GCV for estimating the prediction risk of arbitrary ensembles of penalized least-squares estimators. We show that GCV is inconsistent for any finite ensemble of size greater than one. Towards repairing this shortcoming, we identify a correction that involves an additional scalar correction (in an additive sense) based on degrees of freedom adjusted training errors from each ensemble component. The proposed estimator (termed CGCV) maintains the computational advantages of GCV and requires neither sample splitting, model refitting, or out-of-bag risk estimation. The estimator stems from a finer inspection of the ensemble risk decomposition and two intermediate risk estimators for the components in this decomposition. We provide a non-asymptotic analysis of the CGCV and the two intermediate risk estimators for ensembles of convex penalized estimators under Gaussian features and a linear response model. Furthermore, in the special case of ridge regression, we extend the analysis to general feature and response distributions using random matrix theory, which establishes model-free uniform consistency of CGCV., Comment: 91 pages, 34 figures; this version adds general proof outlines (in Sections 4.3 and 5.3), add more experiments with non-Gaussian data (in Sections D and E), relaxes an assumption (in Section A.7), clarifies explanations at several places, and corrects minor typos at several places

Tens of thousands of simultaneous hypothesis tests are routinely performed in genomic studies to identify differentially expressed genes. However, due to unmeasured confounders, many standard statistical approaches may be substantially biased. This paper investigates the large-scale hypothesis testing problem for multivariate generalized linear models in the presence of confounding effects. Under arbitrary confounding mechanisms, we propose a unified statistical estimation and inference framework that harnesses orthogonal structures and integrates linear projections into three key stages. It begins by disentangling marginal and uncorrelated confounding effects to recover the latent coefficients. Subsequently, latent factors and primary effects are jointly estimated through lasso-type optimization. Finally, we incorporate projected and weighted bias-correction steps for hypothesis testing. Theoretically, we establish the identification conditions of various effects and non-asymptotic error bounds. We show effective Type-I error control of asymptotic $z$-tests as sample and response sizes approach infinity. Numerical experiments demonstrate that the proposed method controls the false discovery rate by the Benjamini-Hochberg procedure and is more powerful than alternative methods. By comparing single-cell RNA-seq counts from two groups of samples, we demonstrate the suitability of adjusting confounding effects when significant covariates are absent from the model., Comment: Main text: 28 pages and 7 figures; appendix: 48 pages and 8 figures

We establish precise structural and risk equivalences between subsampling and ridge regularization for ensemble ridge estimators. Specifically, we prove that linear and quadratic functionals of subsample ridge estimators, when fitted with different ridge regularization levels $\lambda$ and subsample aspect ratios $\psi$, are asymptotically equivalent along specific paths in the $(\lambda,\psi)$-plane (where $\psi$ is the ratio of the feature dimension to the subsample size). Our results only require bounded moment assumptions on feature and response distributions and allow for arbitrary joint distributions. Furthermore, we provide a data-dependent method to determine the equivalent paths of $(\lambda,\psi)$. An indirect implication of our equivalences is that optimally tuned ridge regression exhibits a monotonic prediction risk in the data aspect ratio. This resolves a recent open problem raised by Nakkiran et al. for general data distributions under proportional asymptotics, assuming a mild regularity condition that maintains regression hardness through linearized signal-to-noise ratios., Comment: Fixed typos; add an figure to illustrate the risk monotonicity of optimal ridge

We study subsampling-based ridge ensembles in the proportional asymptotics regime, where the feature size grows proportionally with the sample size such that their ratio converges to a constant. By analyzing the squared prediction risk of ridge ensembles as a function of the explicit penalty $\lambda$ and the limiting subsample aspect ratio $\phi_s$ (the ratio of the feature size to the subsample size), we characterize contours in the $(\lambda, \phi_s)$-plane at any achievable risk. As a consequence, we prove that the risk of the optimal full ridgeless ensemble (fitted on all possible subsamples) matches that of the optimal ridge predictor. In addition, we prove strong uniform consistency of generalized cross-validation (GCV) over the subsample sizes for estimating the prediction risk of ridge ensembles. This allows for GCV-based tuning of full ridgeless ensembles without sample splitting and yields a predictor whose risk matches optimal ridge risk., Comment: 47 pages, 11 figures; this version fixes minor typos. arXiv admin note: text overlap with arXiv:2210.11445

Ensemble methods such as bagging and random forests are ubiquitous in various fields, from finance to genomics. Despite their prevalence, the question of the efficient tuning of ensemble parameters has received relatively little attention. This paper introduces a cross-validation method, ECV (Extrapolated Cross-Validation), for tuning the ensemble and subsample sizes in randomized ensembles. Our method builds on two primary ingredients: initial estimators for small ensemble sizes using out-of-bag errors and a novel risk extrapolation technique that leverages the structure of prediction risk decomposition. By establishing uniform consistency of our risk extrapolation technique over ensemble and subsample sizes, we show that ECV yields $\delta$-optimal (with respect to the oracle-tuned risk) ensembles for squared prediction risk. Our theory accommodates general ensemble predictors, only requires mild moment assumptions, and allows for high-dimensional regimes where the feature dimension grows with the sample size. As a practical case study, we employ ECV to predict surface protein abundances from gene expressions in single-cell multiomics using random forests. In comparison to sample-split cross-validation and $K$-fold cross-validation, ECV achieves higher accuracy avoiding sample splitting. At the same time, its computational cost is considerably lower owing to the use of the risk extrapolation technique. Additional numerical results validate the finite-sample accuracy of ECV for several common ensemble predictors under a computational constraint on the maximum ensemble size., Comment: Accepted by the Journal of Computational and Graphical Statistics

Bagging is a commonly used ensemble technique in statistics and machine learning to improve the performance of prediction procedures. In this paper, we study the prediction risk of variants of bagged predictors under the proportional asymptotics regime, in which the ratio of the number of features to the number of observations converges to a constant. Specifically, we propose a general strategy to analyze the prediction risk under squared error loss of bagged predictors using classical results on simple random sampling. Specializing the strategy, we derive the exact asymptotic risk of the bagged ridge and ridgeless predictors with an arbitrary number of bags under a well-specified linear model with arbitrary feature covariance matrices and signal vectors. Furthermore, we prescribe a generic cross-validation procedure to select the optimal subsample size for bagging and discuss its utility to eliminate the non-monotonic behavior of the limiting risk in the sample size (i.e., double or multiple descents). In demonstrating the proposed procedure for bagged ridge and ridgeless predictors, we thoroughly investigate the oracle properties of the optimal subsample size and provide an in-depth comparison between different bagging variants., Comment: 102 pages, 34 figures; this version add minor clarifications at few places

The expanding number of assets offers more opportunities for investors but poses new challenges for modern portfolio management (PM). As a central plank of PM, portfolio selection by expected utility maximization (EUM) faces uncontrollable estimation and optimization errors in ultrahigh-dimensional scenarios. Past strategies for high-dimensional PM mainly concern only large-cap companies and select many stocks, making PM impractical. We propose a sample-average approximation-based portfolio strategy to tackle the difficulties above with cardinality constraints. Our strategy bypasses the estimation of mean and covariance, the Chinese walls in high-dimensional scenarios. Empirical results on S&P 500 and Russell 2000 show that an appropriate number of carefully chosen assets leads to better out-of-sample mean-variance efficiency. On Russell 2000, our best portfolio profits as much as the equally-weighted portfolio but reduces the maximum drawdown and the average number of assets by 10% and 90%, respectively. The flexibility and the stability of incorporating factor signals for augmenting out-of-sample performances are also demonstrated. Our strategy balances the trade-off among the return, the risk, and the number of assets with cardinality constraints. Therefore, we provide a theoretically sound and computationally efficient strategy to make PM practical in the growing global financial market.

Camera scene detection is among the most popular computer vision problem on smartphones. While many custom solutions were developed for this task by phone vendors, none of the designed models were available publicly up until now. To address this problem, we introduce the first Mobile AI challenge, where the target is to develop quantized deep learning-based camera scene classification solutions that can demonstrate a real-time performance on smartphones and IoT platforms. For this, the participants were provided with a large-scale CamSDD dataset consisting of more than 11K images belonging to the 30 most important scene categories. The runtime of all models was evaluated on the popular Apple Bionic A11 platform that can be found in many iOS devices. The proposed solutions are fully compatible with all major mobile AI accelerators and can demonstrate more than 100-200 FPS on the majority of recent smartphone platforms while achieving a top-3 accuracy of more than 98%. A detailed description of all models developed in the challenge is provided in this paper., Comment: Mobile AI 2021 Workshop and Challenges: https://ai-benchmark.com/workshops/mai/2021/. arXiv admin note: substantial text overlap with arXiv:2105.08630; text overlap with arXiv:2105.07825, arXiv:2105.07809, arXiv:2105.08629

Depth estimation is an important computer vision problem with many practical applications to mobile devices. While many solutions have been proposed for this task, they are usually very computationally expensive and thus are not applicable for on-device inference. To address this problem, we introduce the first Mobile AI challenge, where the target is to develop an end-to-end deep learning-based depth estimation solutions that can demonstrate a nearly real-time performance on smartphones and IoT platforms. For this, the participants were provided with a new large-scale dataset containing RGB-depth image pairs obtained with a dedicated stereo ZED camera producing high-resolution depth maps for objects located at up to 50 meters. The runtime of all models was evaluated on the popular Raspberry Pi 4 platform with a mobile ARM-based Broadcom chipset. The proposed solutions can generate VGA resolution depth maps at up to 10 FPS on the Raspberry Pi 4 while achieving high fidelity results, and are compatible with any Android or Linux-based mobile devices. A detailed description of all models developed in the challenge is provided in this paper., Comment: Mobile AI 2021 Workshop and Challenges: https://ai-benchmark.com/workshops/mai/2021/. arXiv admin note: text overlap with arXiv:2105.07809