arXiv subjects

Jingyi Jessica Li

Publications and source records attributed to Jingyi Jessica Li.

At least 19 recordsLinked to original sources

arXiv2026

Nullstrap-DE: A General Framework for Calibrating FDR and Preserving Power in DE Methods, with Applications to DESeq2 and edgeR

Differential expression (DE) analysis is a key task in RNA-seq studies, aiming to identify genes with expression differences across conditions. A central challenge is balancing false discovery rate (FDR) control with statistical power. Parametric methods such as DESeq2 and edgeR achieve high power by modeling gene-level counts using negative binomial distributions and applying empirical Bayes shrinkage. However, these methods may suffer from FDR inflation when model assumptions are mildly violated, especially in large-sample settings. In contrast, non-parametric tests like Wilcoxon offer more robust FDR control but often lack power and do not support covariate adjustment. We propose Nullstrap-DE, a general add-on framework that combines the strengths of both approaches. Designed to augment tools like DESeq2 and edgeR, Nullstrap-DE calibrates FDR while preserving power, without modifying the original method's implementation. It generates synthetic null data from a model fitted under the gene-specific null (no DE), applies the same test statistic to both observed and synthetic data, and derives a threshold that satisfies the target FDR level. We show theoretically that Nullstrap-DE asymptotically controls FDR while maintaining power consistency. Simulations confirm that it achieves reliable FDR control and high power across diverse settings, where DESeq2, edgeR, or Wilcoxon often show inflated FDR or low power. Applications to real datasets show that Nullstrap-DE enhances statistical rigor and identifies biologically meaningful genes.

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arXiv2025

Nullstrap: A Simple, High-Power, and Fast Framework for FDR Control in Variable Selection for Diverse High-Dimensional Models

Balancing false discovery rate (FDR) control with high statistical power remains a central challenge in high-dimensional variable selection. While several FDR-controlling methods have been proposed, many degrade the original data -- by adding knockoff variables or splitting the data -- which often leads to substantial power loss and hampers detection of true signals. We introduce Nullstrap, a novel framework that controls FDR without altering the original data. Nullstrap generates synthetic null data by fitting a null model under the global null hypothesis that no variables are important. It then applies the same estimation procedure in parallel to both the original and synthetic data. This parallel approach mirrors that of the classical likelihood ratio test, making Nullstrap its numerical analog. By adjusting the synthetic null coefficient estimates through a data-driven correction procedure, Nullstrap identifies important variables while controlling the FDR. We provide theoretical guarantees for asymptotic FDR control at any desired level and show that power converges to one in probability. Nullstrap is simple to implement and broadly applicable to high-dimensional linear models, generalized linear models, Cox models, and Gaussian graphical models. Simulations and real-data applications show that Nullstrap achieves robust FDR control and consistently outperforms leading methods in both power and efficiency.

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arXiv2025

Spatial Transcriptomics Iterative Hierarchical Clustering (stIHC): A Novel Method for Identifying Spatial Gene Co-Expression Modules

Recent advancements in spatial transcriptomics technologies allow researchers to simultaneously measure RNA expression levels for hundreds to thousands of genes while preserving spatial information within tissues, providing critical insights into spatial gene expression patterns, tissue organization, and gene functionality. However, existing methods for clustering spatially variable genes (SVGs) into co-expression modules often fail to detect rare or unique spatial expression patterns. To address this, we present spatial transcriptomics iterative hierarchical clustering (stIHC), a novel method for clustering SVGs into co-expression modules, representing groups of genes with shared spatial expression patterns. Through three simulations and applications to spatial transcriptomics datasets from technologies such as 10x Visium, 10x Xenium, and Spatial Transcriptomics, stIHC outperforms clustering approaches used by popular SVG detection methods, including SPARK, SPARK-X, MERINGUE, and SpatialDE. Gene Ontology enrichment analysis confirms that genes within each module share consistent biological functions, supporting the functional relevance of spatial co-expression. Robust across technologies with varying gene numbers and spatial resolution, stIHC provides a powerful tool for decoding the spatial organization of gene expression and the functional structure of complex tissues.

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arXiv2024

Categorization of 33 computational methods to detect spatially variable genes from spatially resolved transcriptomics data

In the analysis of spatially resolved transcriptomics data, detecting spatially variable genes (SVGs) is crucial. Numerous computational methods exist, but varying SVG definitions and methodologies lead to incomparable results. We review 33 state-of-the-art methods, categorizing SVGs into three types: overall, cell-type-specific, and spatial-domain-marker SVGs. Our review explains the intuitions underlying these methods, summarizes their applications, and categorizes the hypothesis tests they use in the trade-off between generality and specificity for SVG detection. We discuss challenges in SVG detection and propose future directions for improvement. Our review offers insights for method developers and users, advocating for category-specific benchmarking.

q-bio.QM↗

arXiv2024

Categorization and analysis of 14 computational methods for estimating cell potency from single-cell RNA-seq data

In single-cell RNA sequencing (scRNA-seq) analysis, a key challenge is inferring hidden cellular dynamics from static cell snapshots. Various computational methods have been developed to address this, focusing on perspectives like pseudotime trajectories, RNA velocities, and estimating the differentiation potential of cells, often referred to as "cell potency." This review summarizes 14 methods for defining cell potency from scRNA-seq data, categorizing them into average-based, entropy-based, and correlation-based methods based on how they summarize gene expression levels into a potency measure. We highlight the key similarities and differences within and between these categories, offering a high-level intuition for each method. Additionally, we use unified mathematical notations to detail each method's methodology and summarize their usage complexities, including parameters, required inputs, and differences between published descriptions and software implementations. We conclude that cell potency estimation remains an open question without a consensus on the optimal approach, emphasizing the need for benchmark datasets and studies. This review aims to provide a foundation for future benchmark studies, while also addressing the broader challenge of comparing methods that infer cellular dynamics from scRNA-seq data through various perspectives, including pseudotime trajectories, RNA velocities, and cell potency.

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arXiv2024

Question-Score Identity Detection (Q-SID): A Statistical Algorithm to Detect Collusion Groups with Error Quantification from Exam Question Scores

Collusion between students in online exams is a major problem that undermines the integrity of the exam results. Although there exist methods that use exam data to identify pairs of students who have likely copied each other's answers, these methods are restricted to specific formats of multiple-choice exams. Here we present a statistical algorithm, Q-SID, that efficiently detects groups of students who likely have colluded, i.e., collusion groups, with error quantification. Q-SID uses graded numeric question scores only, so it works for many formats of multiple-choice and non-multiple-choice exams. Q-SID reports two false-positive rates (FPRs) for each collusion group: (1) empirical FPR, whose null data are from 36 strictly proctored exam datasets independent of the user-input exam data and (2) synthetic FPR, whose null data are simulated from a copula-based probabilistic model, which is first fitted to the user-input exam data and then modified to have no collusion. On 34 unproctored exam datasets, including two benchmark datasets with true positives and negatives verified by textural analysis, we demonstrate that Q-SID is a collusion detection algorithm with powerful and robust performance across exam formats, numbers of questions and students, and exam complexity.

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arXiv2023

Hierarchical Neyman-Pearson Classification for Prioritizing Severe Disease Categories in COVID-19 Patient Data

COVID-19 has a spectrum of disease severity, ranging from asymptomatic to requiring hospitalization. Understanding the mechanisms driving disease severity is crucial for developing effective treatments and reducing mortality rates. One way to gain such understanding is using a multi-class classification framework, in which patients' biological features are used to predict patients' severity classes. In this severity classification problem, it is beneficial to prioritize the identification of more severe classes and control the "under-classification" errors, in which patients are misclassified into less severe categories. The Neyman-Pearson (NP) classification paradigm has been developed to prioritize the designated type of error. However, current NP procedures are either for binary classification or do not provide high probability controls on the prioritized errors in multi-class classification. Here, we propose a hierarchical NP (H-NP) framework and an umbrella algorithm that generally adapts to popular classification methods and controls the under-classification errors with high probability. On an integrated collection of single-cell RNA-seq (scRNA-seq) datasets for 864 patients, we explore ways of featurization and demonstrate the efficacy of the H-NP algorithm in controlling the under-classification errors regardless of featurization. Beyond COVID-19 severity classification, the H-NP algorithm generally applies to multi-class classification problems, where classes have a priority order.

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arXiv2022

Information-theoretic Classification Accuracy: A Criterion that Guides Data-driven Combination of Ambiguous Outcome Labels in Multi-class Classification

Outcome labeling ambiguity and subjectivity are ubiquitous in real-world datasets. While practitioners commonly combine ambiguous outcome labels for all data points (instances) in an ad hoc way to improve the accuracy of multi-class classification, there lacks a principled approach to guide the label combination for all data points by any optimality criterion. To address this problem, we propose the information-theoretic classification accuracy (ITCA), a criterion that balances the trade-off between prediction accuracy (how well do predicted labels agree with actual labels) and classification resolution (how many labels are predictable), to guide practitioners on how to combine ambiguous outcome labels. To find the optimal label combination indicated by ITCA, we propose two search strategies: greedy search and breadth-first search. Notably, ITCA and the two search strategies are adaptive to all machine-learning classification algorithms. Coupled with a classification algorithm and a search strategy, ITCA has two uses: improving prediction accuracy and identifying ambiguous labels. We first verify that ITCA achieves high accuracy with both search strategies in finding the correct label combinations on synthetic and real data. Then we demonstrate the effectiveness of ITCA in diverse applications including medical prognosis, cancer survival prediction, user demographics prediction, and cell type classification. We also provide theoretical insights into ITCA by studying the oracle and the linear discriminant analysis classification algorithms. Python package itca (available at https://github.com/JSB-UCLA/ITCA) implements ITCA and search strategies.

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arXiv2021

Protocol for Executing and Benchmarking Eight Computational Doublet-Detection Methods in Single-Cell RNA Sequencing Data Analysis

The existence of doublets is a key confounder in single-cell RNA sequencing (scRNA-seq) data analysis. Computational methods have been developed for detecting doublets from scRNA-seq data. We developed an R package DoubletCollection to integrate the installation and execution of eight doublet-detection methods. DoubletCollection also provides a unified interface to perform and visualize downstream analysis after doublet detection. Here, we present a protocol of using DoubletCollection to benchmark doublet-detection methods. This protocol can automatically accommodate new doublet-detection methods in the fast-growing scRNA-seq field.

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arXiv2021

A flexible model-free prediction-based framework for feature ranking

Despite the availability of numerous statistical and machine learning tools for joint feature modeling, many scientists investigate features marginally, i.e., one feature at a time. This is partly due to training and convention but also roots in scientists' strong interests in simple visualization and interpretability. As such, marginal feature ranking for some predictive tasks, e.g., prediction of cancer driver genes, is widely practiced in the process of scientific discoveries. In this work, we focus on marginal ranking for binary prediction, the arguably most common predictive tasks. We argue that the most widely used marginal ranking criteria, including the Pearson correlation, the two-sample t test, and two-sample Wilcoxon rank-sum test, do not fully take feature distributions and prediction objectives into account. To address this gap in practice, we propose two ranking criteria corresponding to two prediction objectives: the classical criterion (CC) and the Neyman-Pearson criterion (NPC), both of which use model-free nonparametric implementations to accommodate diverse feature distributions. Theoretically, we show that under regularity conditions both criteria achieve sample-level ranking consistent with their population-level counterpart with high probability. Moreover, NPC is robust to sampling bias when the two class proportions in a sample deviate from those in the population. This property endows NPC good potential in biomedical research where sampling bias is common. We demonstrate the use and relative advantages of CC and NPC in simulation and real data studies. Our model-free objective-based ranking idea is extendable to ranking feature subsets and generalizable to other prediction tasks and learning objectives.

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arXiv2020

Bridging Cost-sensitive and Neyman-Pearson Paradigms for Asymmetric Binary Classification

Asymmetric binary classification problems, in which the type I and II errors have unequal severity, are ubiquitous in real-world applications. To handle such asymmetry, researchers have developed the cost-sensitive and Neyman-Pearson paradigms for training classifiers to control the more severe type of classification error, say the type I error. The cost-sensitive paradigm is widely used and has straightforward implementations that do not require sample splitting; however, it demands an explicit specification of the costs of the type I and II errors, and an open question is what specification can guarantee a high-probability control on the population type I error. In contrast, the Neyman-Pearson paradigm can train classifiers to achieve a high-probability control of the population type I error, but it relies on sample splitting that reduces the effective training sample size. Since the two paradigms have complementary strengths, it is reasonable to combine their strengths for classifier construction. In this work, we for the first time study the methodological connections between the two paradigms, and we develop the TUBE-CS algorithm to bridge the two paradigms from the perspective of controlling the population type I error.

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arXiv2020

Statistical hypothesis testing versus machine-learning binary classification: distinctions and guidelines

Making binary decisions is a common data analytical task in scientific research and industrial applications. In data sciences, there are two related but distinct strategies: hypothesis testing and binary classification. In practice, how to choose between these two strategies can be unclear and rather confusing. Here we summarize key distinctions between these two strategies in three aspects and list five practical guidelines for data analysts to choose the appropriate strategy for specific analysis needs. We demonstrate the use of those guidelines in a cancer driver gene prediction example.

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arXiv2020

Generalized Pearson correlation squares for capturing mixtures of bivariate linear dependences

Motivated by the pressing needs for capturing complex but interpretable variable relationships in scientific research, here we generalize the squared Pearson correlation to capture a mixture of linear dependences between two real-valued random variables, with or without an index variable that specifies the line memberships. We construct generalized Pearson correlation squares by focusing on three aspects: the exchangeability of the two variables, the independence of parametric model assumptions, and the availability of population-level parameters. For the computation of the generalized Pearson correlation square from a sample without line-membership specification, we develop a K-lines clustering algorithm, where K, the number of lines, can be chosen in a data-adaptive way. With our defined population-level generalized Pearson correlation squares, we derive the asymptotic distributions of the sample-level statistics to enable efficient statistical inference. Simulation studies verify the theoretical results and compare the generalized Pearson correlation squares with other widely-used association measures in terms of power. Gene expression data analysis demonstrates the effectiveness of the generalized Pearson correlation squares in capturing interpretable gene-gene relationships missed by other measures. We implement the estimation and inference procedures in an R package gR2.

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arXiv2020

A Bootstrap Lasso + Partial Ridge Method to Construct Confidence Intervals for Parameters in High-dimensional Sparse Linear Models

Constructing confidence intervals for the coefficients of high-dimensional sparse linear models remains a challenge, mainly because of the complicated limiting distributions of the widely used estimators, such as the lasso. Several methods have been developed for constructing such intervals. Bootstrap lasso+ols is notable for its technical simplicity, good interpretability, and performance that is comparable with that of other more complicated methods. However, bootstrap lasso+ols depends on the beta-min assumption, a theoretic criterion that is often violated in practice. Thus, we introduce a new method, called bootstrap lasso+partial ridge, to relax this assumption. Lasso+partial ridge is a two-stage estimator. First, the lasso is used to select features. Then, the partial ridge is used to refit the coefficients. Simulation results show that bootstrap lasso+partial ridge outperforms bootstrap lasso+ols when there exist small, but nonzero coefficients, a common situation that violates the beta-min assumption. For such coefficients, the confidence intervals constructed using bootstrap lasso+partial ridge have, on average, $50\%$ larger coverage probabilities than those of bootstrap lasso+ols. Bootstrap lasso+partial ridge also has, on average, $35\%$ shorter confidence interval lengths than those of the de-sparsified lasso methods, regardless of whether the linear models are misspecified. Additionally, we provide theoretical guarantees for bootstrap lasso+partial ridge under appropriate conditions, and implement it in the R package "HDCI."

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arXiv2019

Issues arising from benchmarking single-cell RNA sequencing imputation methods

On June 25th, 2018, Huang et al. published a computational method SAVER on Nature Methods for imputing dropout gene expression levels in single cell RNA sequencing (scRNA-seq) data. Huang et al. performed a set of comprehensive benchmarking analyses, including comparison with the data from RNA fluorescence in situ hybridization, to demonstrate that SAVER outperformed two existing scRNA-seq imputation methods, scImpute and MAGIC. However, their computational analyses were based on semi-synthetic data that the authors had generated following the Poisson-Gamma model used in the SAVER method. We have therefore re-examined Huang et al.'s study. We find that the semi-synthetic data have very different properties from those of real scRNA-seq data and that the cell clusters used for benchmarking are inconsistent with the cell types labeled by biologists. We show that a reanalysis based on real scRNA-seq data and grounded on biological knowledge of cell types leads to different results and conclusions from those of Huang et al.

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arXiv2018

Modeling and analysis of RNA-seq data: a review from a statistical perspective

Background: Since the invention of next-generation RNA sequencing (RNA-seq) technologies, they have become a powerful tool to study the presence and quantity of RNA molecules in biological samples and have revolutionized transcriptomic studies. The analysis of RNA-seq data at four different levels (samples, genes, transcripts, and exons) involve multiple statistical and computational questions, some of which remain challenging up to date. Results: We review RNA-seq analysis tools at the sample, gene, transcript, and exon levels from a statistical perspective. We also highlight the biological and statistical questions of most practical considerations. Conclusion: The development of statistical and computational methods for analyzing RNA- seq data has made significant advances in the past decade. However, methods developed to answer the same biological question often rely on diverse statical models and exhibit different performance under different scenarios. This review discusses and compares multiple commonly used statistical models regarding their assumptions, in the hope of helping users select appropriate methods as needed, as well as assisting developers for future method development.

q-bio.GN↗

arXiv2017

MSIQ: Joint Modeling of Multiple RNA-seq Samples for Accurate Isoform Quantification

Next-generation RNA sequencing (RNA-seq) technology has been widely used to assess full-length RNA isoform abundance in a high-throughput manner. RNA-seq data offer insight into gene expression levels and transcriptome structures, enabling us to better understand the regulation of gene expression and fundamental biological processes. Accurate isoform quantification from RNA-seq data is challenging due to the information loss in sequencing experiments. A recent accumulation of multiple RNA-seq data sets from the same tissue or cell type provides new opportunities to improve the accuracy of isoform quantification. However, existing statistical or computational methods for multiple RNA-seq samples either pool the samples into one sample or assign equal weights to the samples when estimating isoform abundance. These methods ignore the possible heterogeneity in the quality of different samples and could result in biased and unrobust estimates. In this article, we develop a method, which we call "joint modeling of multiple RNA-seq samples for accurate isoform quantification" (MSIQ), for more accurate and robust isoform quantification by integrating multiple RNA-seq samples under a Bayesian framework. Our method aims to (1) identify a consistent group of samples with homogeneous quality and (2) improve isoform quantification accuracy by jointly modeling multiple RNA-seq samples by allowing for higher weights on the consistent group. We show that MSIQ provides a consistent estimator of isoform abundance, and we demonstrate the accuracy and effectiveness of MSIQ compared with alternative methods through simulation studies on D. melanogaster genes. We justify MSIQ's advantages over existing approaches via application studies on real RNA-seq data from human embryonic stem cells, brain tissues, and the HepG2 immortalized cell line.

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arXiv2017

Neyman-Pearson (NP) classification algorithms and NP receiver operating characteristics (NP-ROC)

In many binary classification applications such as disease diagnosis and spam detection, practitioners often face great needs to control type I errors (i.e., the conditional probability of misclassifying a class 0 observation as class 1) so that it remains below a desired threshold. To address this need, the Neyman-Pearson (NP) classification paradigm is a natural choice; it minimizes type II error (i.e., the conditional probability of misclassifying a class 1 observation as class 0) while enforcing an upper bound, $α$, on the type I error. Although the NP paradigm has a century-long history in hypothesis testing, it has not been well recognized and implemented in classification schemes. Common practices that directly limit the empirical type I error to no more than $α$ do not satisfy the type I error control objective because the resulting classifiers are still likely to have type I errors much larger than $α$. As a result, the NP paradigm has not been properly implemented for many classification scenarios in practice. In this work, we develop the first umbrella algorithm that implements the NP paradigm for all scoring-type classification methods, including popular methods such as logistic regression, support vector machines and random forests. Powered by this umbrella algorithm, we propose a novel graphical tool for NP classification methods: NP receiver operating characteristic (NP-ROC) bands, motivated by the popular receiver operating characteristic (ROC) curves. NP-ROC bands will help choose $α$ in a data adaptive way and compare different NP classifiers. We demonstrate the use and properties of the NP umbrella algorithm and NP-ROC bands, available in the R package nproc, through simulation and real data case studies.

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