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Zhonghua Liu

Publications and source records attributed to Zhonghua Liu.

At least 19 recordsLinked to original sources

Gradient-Flow Optimization as Dynamic Random-Effects Inference: Testing and Early Stopping with Applications to Deep Learning

Gradient-flow optimization is usually viewed as an algorithmic procedure for minimizing empirical loss, with training duration selected by validation or heuristic early stopping rules. We develop a statistical inference framework for gradient-flow training. We show that whenever fitted values evolve through a time-invariant positive semidefinite training operator, the output at each time is equivalent to the best linear unbiased predictor under a corresponding random-effects model. Training time then becomes a variance-component parameter governing variance reallocation from residual noise to structured signal. This turns two training decisions into inferential problems: whether training is needed becomes a variance-component test for signal beyond initialization, and how long to train becomes restricted maximum likelihood (REML) estimation of the training-time variance component. We show that the REML-guided early stopping rule selects the time at which optimized spectral losses become decorrelated from the training-operator eigenvalues. The asymptotic prediction optimality of the REML-guided early stopping time is established for fixed-design in-sample risk and random-design out-of-sample risk. Deep learning models in fixed-kernel gradient regimes provide canonical instantiations for our results. Numerical experiments and a UK Biobank proteomics application show competitive accuracy of the REML-guided early stopping time with reduced reliance on validation splits and repeated checkpoint evaluation.

stat.ML

Identification and Inference for Structural Accelerated Failure Time Models via Instrument Interactions

We study causal inference for time-to-event outcomes under right censoring in the presence of unmeasured confounding. Focusing on structural accelerated failure time models, we develop an identification and inference framework that exploits interactions among instrumental variables. The proposed approach does not rely on classical instrumental variable validity and yields valid causal inference under both valid and invalid instruments, provided that the interaction-based identification condition holds. To accommodate right censoring, we construct a censoring-adjusted observed data moment function using an augmented inverse probability censoring weighting approach. The resulting moment function is Neyman orthogonal with respect to nuisance functions and enjoys a double robustness property, enabling valid inference under flexible nuisance estimation. Estimation and inference are conducted using generalized empirical likelihood, which is well suited to settings with many potentially weak interaction-based moment conditions. We establish consistency, and asymptotic normality under many weak moment asymptotics, and develop diagnostic tools to assess interaction-based identification strength and overidentifying restrictions. Simulation studies demonstrate favorable finite sample performance across a range of censoring rates and instrument configurations. An application to UK Biobank data illustrates the practical relevance of the proposed method for causal survival analysis in large-scale observational studies.

stat.ME

Constructive Instrumental Variable Identification and Inference with Many Weak Interaction Moments

Instrumental variable methods are widely used for causal inference, but identification becomes especially challenging when instruments are weak and potentially invalid. These challenges are particularly pronounced in Mendelian randomization, where genetic variants serve as instruments and violations of exclusion restriction or independence assumptions are common. We propose MAGIC, a constructive and assumption-lean framework that achieves identification even when all candidate instruments may be invalid. The method exploits pairwise and higher-order interactions among mutually independent instruments to construct moment conditions orthogonal to both unmeasured confounding and direct effects under a linear structural model. The resulting estimation problem involves many potentially weak interaction moments with unknown nuisance parameters. We develop a semiparametric generalized method of moments estimator and introduce a global Neyman orthogonality condition to ensure robustness of both the moment function and its derivative to nuisance estimation under many weak moment asymptotics. We establish consistency and asymptotic normality when the number of moments diverges with sample size and characterize the semiparametric efficiency bound under fixed dimension. Simulations and an application to UK Biobank data illustrate the method.

stat.ME

Mendelian Randomization Methods for Causal Inference: Estimands, Identification and Inference

Mendelian randomization (MR) has become an essential tool for causal inference in biomedical and public health research. By using genetic variants as instrumental variables, MR helps address unmeasured confounding and reverse causation, offering a quasi-experimental framework to evaluate causal effects of modifiable exposures on health outcomes. Despite its promise, MR faces substantial methodological challenges, including invalid instruments, weak instrument bias, and design complexities across different data structures. In this tutorial review, we provide a comprehensive overview of MR methods for causal inference, emphasizing clarity of causal interpretation, study design comparisons, availability of software tools, and practical guidance for applied scientists. We organize the review around causal estimands, ensuring that analyses are anchored to well-defined causal questions. We discuss the problems of invalid and weak instruments, comparing available strategies for their detection and correction. We integrate discussions of population-based versus family-based MR designs, analyses based on individual-level versus summary-level data, and one-sample versus two-sample MR designs, highlighting their relative advantages and limitations. We also summarize recent methodological advances and software developments that extend MR to settings with many weak or invalid instruments and to modern high-dimensional omics data. Real-data applications, including UK Biobank and Alzheimer's disease proteomics studies, illustrate the use of these methods in practice. This review aims to serve as a tutorial-style reference for both methodologists and applied scientists.

stat.ME

Semiparametric Causal Inference for Right-Censored Outcomes with Many Weak Invalid Instruments

We propose a semiparametric framework for causal inference with right-censored survival outcomes and many weak invalid instruments, motivated by Mendelian randomization in biobank studies where classical methods may fail. We adopt an accelerated failure time model and construct a moment condition based on augmented inverse probability of censoring weighting, incorporating both uncensored and censored observations. Under a heteroscedasticity-based condition on the treatment model, we establish point identification of the causal effect despite censoring and invalid instruments. We propose GEL-NOW (Generalized Empirical Likelihood with Non-Neyman Orthogonal and Weak moments) for valid inference under these conditions. A divergent number of Neyman orthogonal nuisance functions is estimated using deep neural networks. A key challenge is that the conditional censoring distribution is a non-Neyman orthogonal nuisance, contributing to the first-order asymptotics of the estimator for the target causal effect parameter. We derive the asymptotic distribution and explicitly incorporate this additional uncertainty into the asymptotic variance formula. We also introduce a censoring-adjusted over-identification test that accounts for this new variance component. Simulation studies and UK Biobank applications demonstrate the method's robustness and practical utility.

stat.ME

Quasi Instrumental Variable Methods for Stable Hidden Confounding and Binary Outcome

Instrumental variable (IV) methods are central to causal inference from observational data, particularly when a randomized experiment is not feasible. However, of the three conventional core IV identification conditions, only one, IV relevance, is empirically verifiable; often one or both of the other conditions, exclusion restriction and IV independence from unmeasured confounders, are unmet in real-world applications. These challenges are compounded when the outcome is binary, a setting for which robust IV methods remain underdeveloped. A fundamental contribution of this paper is the development of a general identification strategy justified under a structural equilibrium dynamic generative model of so-called stable confounding and a quasi instrumental variable (QIV), i.e. a variable that is only assumed to be predictive of the outcome. Such a model implies (a) stability of confounding on the multiplicative scale, and (b) stability of the additive average treatment effect among the treated (ATT), across levels of that QIV. The former is all that is necessary to ensure a valid test of the causal null hypothesis; together those two conditions establish nonparametric identification and estimation of the conditional and marginal ATT. To address the statistical challenges posed by the need for boundedness in binary outcomes, we introduce a generalized odds product re-parametrization of the observed data distribution, and we develop both a principled maximum likelihood estimator and a triply robust semiparametric locally efficient estimator, which we evaluate through simulations and an empirical application to the UK Biobank.

stat.ME

TastepepAI, An artificial intelligence platform for taste peptide de novo design

Taste peptides have emerged as promising natural flavoring agents attributed to their unique organoleptic properties, high safety profile, and potential health benefits. However, the de novo identification of taste peptides derived from animal, plant, or microbial sources remains a time-consuming and resource-intensive process, significantly impeding their widespread application in the food industry. Here, we present TastePepAI, a comprehensive artificial intelligence framework for customized taste peptide design and safety assessment. As the key element of this framework, a loss-supervised adaptive variational autoencoder (LA-VAE) is implemented to efficiently optimizes the latent representation of sequences during training and facilitates the generation of target peptides with desired taste profiles. Notably, our model incorporates a novel taste-avoidance mechanism, allowing for selective flavor exclusion. Subsequently, our in-house developed toxicity prediction algorithm (SpepToxPred) is integrated in the framework to undergo rigorous safety evaluation of generated peptides. Using this integrated platform, we successfully identified 73 peptides exhibiting sweet, salty, and umami, significantly expanding the current repertoire of taste peptides. This work demonstrates the potential of TastePepAI in accelerating taste peptide discovery for food applications and provides a versatile framework adaptable to broader peptide engineering challenges.

cs.LG

BioTD: an online database of biotoxins

Biotoxins, mainly produced by venomous animals, plants and microorganisms, exhibit high physiological activity and unique effects such as lowering blood pressure and analgesia. A number of venom-derived drugs are already available on the market, with many more candidates currently undergoing clinical and laboratory studies. However, drug design resources related to biotoxins are insufficient, particularly a lack of accurate and extensive activity data. To fulfill this demand, we develop the Biotoxins Database (BioTD). BioTD is the largest open-source database for toxins, offering open access to 14,607 data records (8,185 activity records), covering 8,975 toxins sourced from 5,220 references and patents across over 900 species. The activity data in BioTD is categorized into five groups: Activity, Safety, Kinetics, Hemolysis and other physiological indicators. Moreover, BioTD provides data on 986 mutants, refines the whole sequence and signal peptide sequences of toxins, and annotates disulfide bond information. Given the importance of biotoxins and their associated data, this new database was expected to attract broad interests from diverse research fields in drug discovery. BioTD is freely accessible at http://biotoxin.net/.

q-bio.BM

Post-selection inference for high-dimensional mediation analysis with survival outcomes

It is of substantial scientific interest to detect mediators that lie in the causal pathway from an exposure to a survival outcome. However, with high-dimensional mediators, as often encountered in modern genomic data settings, there is a lack of powerful methods that can provide valid post-selection inference for the identified marginal mediation effect. To resolve this challenge, we develop a post-selection inference procedure for the maximally selected natural indirect effect using a semiparametric efficient influence function approach. To this end, we establish the asymptotic normality of a stabilized one-step estimator that takes the selection of the mediator into account. Simulation studies show that our proposed method has good empirical performance. We further apply our proposed approach to a lung cancer dataset and find multiple DNA methylation CpG sites that might mediate the effect of cigarette smoking on lung cancer survival.

stat.ME

DNA-SE: Towards Deep Neural-Nets Assisted Semiparametric Estimation

Semiparametric statistics play a pivotal role in a wide range of domains, including but not limited to missing data, causal inference, and transfer learning, to name a few. In many settings, semiparametric theory leads to (nearly) statistically optimal procedures that yet involve numerically solving Fredholm integral equations of the second kind. Traditional numerical methods, such as polynomial or spline approximations, are difficult to scale to multi-dimensional problems. Alternatively, statisticians may choose to approximate the original integral equations by ones with closed-form solutions, resulting in computationally more efficient, but statistically suboptimal or even incorrect procedures. To bridge this gap, we propose a novel framework by formulating the semiparametric estimation problem as a bi-level optimization problem; and then we develop a scalable algorithm called Deep Neural-Nets Assisted Semiparametric Estimation (DNA-SE) by leveraging the universal approximation property of Deep Neural-Nets (DNN) to streamline semiparametric procedures. Through extensive numerical experiments and a real data analysis, we demonstrate the numerical and statistical advantages of $\dnase$ over traditional methods. To the best of our knowledge, we are the first to bring DNN into semiparametric statistics as a numerical solver of integral equations in our proposed general framework.

stat.ML

Identification and Inference with Invalid Instruments

Instrumental variables (IVs) are widely used to study the causal effect of an exposure on an outcome in the presence of unmeasured confounding. IVs require an instrument, a variable that is (A1) associated with the exposure, (A2) has no direct effect on the outcome except through the exposure, and (A3) is not related to unmeasured confounders. Unfortunately, finding variables that satisfy conditions (A2) or (A3) can be challenging in practice. This paper reviews works where instruments may not satisfy conditions (A2) or (A3), which we refer to as invalid instruments. We review identification and inference under different violations of (A2) or (A3), specifically under linear models, non-linear models, and heteroskedatic models. We conclude with an empirical comparison of various methods by re-analyzing the effect of body mass index on systolic blood pressure from the UK Biobank.

stat.ME

GENIUS-MAWII: For Robust Mendelian Randomization with Many Weak Invalid Instruments

Mendelian randomization (MR) has become a popular approach to study causal effects by using genetic variants as instrumental variables. We propose a new MR method, GENIUS-MAWII, which simultaneously addresses the two salient phenomena that adversely affect MR analyses: many weak instruments and widespread horizontal pleiotropy. Similar to MR GENIUS (Tchetgen Tchetgen et al., 2021), we achieve identification of the treatment effect by leveraging heteroscedasticity of the exposure. We then derive the class of influence functions of the treatment effect, based on which, we construct a continuous updating estimator and establish its consistency and asymptotic normality under a many weak invalid instruments asymptotic regime by developing novel semiparametric theory. We also provide a measure of weak identification, an overidentification test, and a graphical diagnostic tool. We demonstrate in simulations that GENIUS-MAWII has clear advantages in the presence of directional or correlated horizontal pleiotropy compared to other methods. We apply our method to study the effect of body mass index on systolic blood pressure using UK Biobank.

stat.ME

An Introduction to Causal Inference Methods with Multi-omics Data

Omics biomarkers play a pivotal role in personalized medicine by providing molecular-level insights into the etiology of diseases, guiding precise diagnostics, and facilitating targeted therapeutic interventions. Recent advancements in omics technologies have resulted in an increasing abundance of multimodal omics data, providing unprecedented opportunities for identifying novel omics biomarkers for human diseases. Mendelian randomization (MR) is a practically useful causal inference method that uses genetic variants as instrumental variables (IVs) to infer causal relationships between omics biomarkers and complex traits/diseases by removing hidden confounding bias. In this article, we first present current challenges in performing MR analysis with omics data, and then describe four MR methods for analyzing multi-omics data including epigenomics, transcriptomics, proteomics, and metabolomics data, all executable within the R software environment.

stat.AP

Ensemble methods for testing a global null

Testing a global null is a canonical problem in statistics and has a wide range of applications. In view of the fact that no uniformly most powerful test exists, prior and/or domain knowledge are commonly used to focus on a certain class of alternatives to improve the testing power. However, it is generally challenging to develop tests that are particularly powerful against a certain class of alternatives. In this paper, motivated by the success of ensemble learning methods for prediction or classification, we propose an ensemble framework for testing that mimics the spirit of random forests to deal with the challenges. Our ensemble testing framework aggregates a collection of weak base tests to form a final ensemble test that maintains strong and robust power for global nulls. We apply the framework to four problems about global testing in different classes of alternatives arising from Whole Genome Sequencing (WGS) association studies. Specific ensemble tests are proposed for each of these problems, and their theoretical optimality is established in terms of Bahadur efficiency. Extensive simulations and an analysis of a real WGS dataset are conducted to demonstrate the type I error control and/or power gain of the proposed ensemble tests.

stat.ME

Automatic Speech Disentanglement for Voice Conversion using Rank Module and Speech Augmentation

Voice Conversion (VC) converts the voice of a source speech to that of a target while maintaining the source's content. Speech can be mainly decomposed into four components: content, timbre, rhythm and pitch. Unfortunately, most related works only take into account content and timbre, which results in less natural speech. Some recent works are able to disentangle speech into several components, but they require laborious bottleneck tuning or various hand-crafted features, each assumed to contain disentangled speech information. In this paper, we propose a VC model that can automatically disentangle speech into four components using only two augmentation functions, without the requirement of multiple hand-crafted features or laborious bottleneck tuning. The proposed model is straightforward yet efficient, and the empirical results demonstrate that our model can achieve a better performance than the baseline, regarding disentanglement effectiveness and speech naturalness.

cs.SD

High-dimensional Feature Screening for Nonlinear Associations With Survival Outcome Using Restricted Mean Survival Time

Feature screening is an important tool in analyzing ultrahigh-dimensional data, particularly in the field of Omics and oncology studies. However, most attention has been focused on identifying features that have a linear or monotonic impact on the response variable. Detecting a sparse set of variables that have a nonlinear or non-monotonic relationship with the response variable is still a challenging task. To fill the gap, this paper proposed a robust model-free screening approach for right-censored survival data by providing a new perspective of quantifying the covariate effect on the restricted mean survival time, rather than the routinely used hazard function. The proposed measure, based on the difference between the restricted mean survival time of covariate-stratified and overall data, is able to identify comprehensive types of associations including linear, nonlinear, non-monotone, and even local dependencies like change points. This approach is highly interpretable and flexible without any distribution assumption. The sure screening property is established and an iterative screening procedure is developed to address multicollinearity between high-dimensional covariates. Simulation studies are carried out to demonstrate the superiority of the proposed method in selecting important features with a complex association with the response variable. The potential of applying the proposed method to handle interval-censored failure time data has also been explored in simulations, and the results have been promising. The method is applied to a breast cancer dataset to identify potential prognostic factors, which reveals potential associations between breast cancer and lymphoma.

stat.ME

DeepMed: Semiparametric Causal Mediation Analysis with Debiased Deep Learning

Causal mediation analysis can unpack the black box of causality and is therefore a powerful tool for disentangling causal pathways in biomedical and social sciences, and also for evaluating machine learning fairness. To reduce bias for estimating Natural Direct and Indirect Effects in mediation analysis, we propose a new method called DeepMed that uses deep neural networks (DNNs) to cross-fit the infinite-dimensional nuisance functions in the efficient influence functions. We obtain novel theoretical results that our DeepMed method (1) can achieve semiparametric efficiency bound without imposing sparsity constraints on the DNN architecture and (2) can adapt to certain low dimensional structures of the nuisance functions, significantly advancing the existing literature on DNN-based semiparametric causal inference. Extensive synthetic experiments are conducted to support our findings and also expose the gap between theory and practice. As a proof of concept, we apply DeepMed to analyze two real datasets on machine learning fairness and reach conclusions consistent with previous findings.

stat.ML

An Eigenvalue Ratio Approach to Inferring Population Structure from Whole Genome Sequencing Data

Inference of population structure from genetic data plays an important role in population and medical genetics studies. With the advancement and decreasing cost of sequencing technology, the increasingly available whole genome sequencing data provide much richer information about the underlying population structure. The traditional method (Patterson, Price, and Reich, 2006) originally developed for array-based genotype data for computing and selecting top principal components that capture population structure may not perform well on sequencing data for two reasons. First, the number of genetic variants p is much larger than the sample size n in sequencing data such that the sample-to-marker ratio n/p is nearly zero, violating the assumption of the Tracy-Widom test used in their method. Second, their method might not be able to handle the linkage disequilibrium well in sequencing data. To resolve those two practical issues, we propose a new method called ERStruct to determine the number of top informative principal components based on sequencing data. More specifically, we propose to use the ratio of consecutive eigenvalues as a more robust test statistic, and then we approximate its null distribution using modern random matrix theory. Both simulation studies and applications to two public data sets from the HapMap 3 and the 1000 Genomes Projects demonstrate the empirical performance of our ERStruct method.

stat.AP