arXiv subjects

Keshav Motwani

Publications and source records attributed to Keshav Motwani.

5 recordsLinked to original sources

arXiv2025

Genetic Regression Analysis of Human Brain Connectivity Using an Efficient Estimator of Genetic Covariance

Non-invasive measurements of the human brain using magnetic resonance imaging (MRI) have significantly improved our understanding the brain's network organization by enabling measurement of anatomical connections between brain regions (structural connectivity) and their coactivation (functional connectivity). Heritability analyses have established that genetics account for considerable intersubject variability in structural and functional connectivity. However, characterizing how genetics shape the relationship between structural and functional connectomes remains challenging, since this association is obscured by unique environmental exposures in observed data. To address this, we develop a regression analysis framework that enables characterization of the relationship between latent genetic contributions to structural and functional connectivity. Implementing the proposed framework requires estimating genetic covariance matrices in multivariate random effects models, which is computationally intractable for high-dimensional connectome data using existing methods. We introduce a constrained method-of-moments estimator that is several orders of magnitude faster than existing methods without sacrificing estimation accuracy. For the genetic regression analysis, we develop regularized estimation approaches, including ridge, lasso, and tensor regression. Applying our method to Human Connectome Project data, we find that functional connectivity is moderately predictable from structure at the genetic level (max R^2 = 0.34), though it is not directly predictable in the observed data (max R^2 = 0.03). This stark contrast suggests that unique environmental factors mask strong genetically-encoded structure-function relationships.

stat.AP↗

arXiv2024

Revisiting inference after prediction

Recent work has focused on the very common practice of prediction-based inference: that is, (i) using a pre-trained machine learning model to predict an unobserved response variable, and then (ii) conducting inference on the association between that predicted response and some covariates. As pointed out by Wang et al. (2020), applying a standard inferential approach in (ii) does not accurately quantify the association between the unobserved (as opposed to the predicted) response and the covariates. In recent work, Wang et al. (2020) and Angelopoulos et al. (2023) propose corrections to step (ii) in order to enable valid inference on the association between the unobserved response and the covariates. Here, we show that the method proposed by Angelopoulos et al. (2023) successfully controls the type 1 error rate and provides confidence intervals with correct nominal coverage, regardless of the quality of the pre-trained machine learning model used to predict the unobserved response. However, the method proposed by Wang et al. (2020) provides valid inference only under very strong conditions that rarely hold in practice: for instance, if the machine learning model perfectly estimates the true regression function in the study population of interest.

stat.ML↗

arXiv2023

Multiresolution categorical regression for interpretable cell type annotation

In many categorical response regression applications, the response categories admit a multiresolution structure. That is, subsets of the response categories may naturally be combined into coarser response categories. In such applications, practitioners are often interested in estimating the resolution at which a predictor affects the response category probabilities. In this article, we propose a method for fitting the multinomial logistic regression model in high dimensions that addresses this problem in a unified and data-driven way. In particular, our method allows practitioners to identify which predictors distinguish between coarse categories but not fine categories, which predictors distinguish between fine categories, and which predictors are irrelevant. For model fitting, we propose a scalable algorithm that can be applied when the coarse categories are defined by either overlapping or nonoverlapping sets of fine categories. Statistical properties of our method reveal that it can take advantage of this multiresolution structure in a way existing estimators cannot. We use our method to model cell type probabilities as a function of a cell's gene expression profile (i.e., cell type annotation). Our fitted model provides novel biological insights which may be useful for future automated and manual cell type annotation methodology.

stat.ME↗

arXiv2023

Generalized Data Thinning Using Sufficient Statistics

Our goal is to develop a general strategy to decompose a random variable $X$ into multiple independent random variables, without sacrificing any information about unknown parameters. A recent paper showed that for some well-known natural exponential families, $X$ can be "thinned" into independent random variables $X^{(1)}, \ldots, X^{(K)}$, such that $X = \sum_{k=1}^K X^{(k)}$. These independent random variables can then be used for various model validation and inference tasks, including in contexts where traditional sample splitting fails. In this paper, we generalize their procedure by relaxing this summation requirement and simply asking that some known function of the independent random variables exactly reconstruct $X$. This generalization of the procedure serves two purposes. First, it greatly expands the families of distributions for which thinning can be performed. Second, it unifies sample splitting and data thinning, which on the surface seem to be very different, as applications of the same principle. This shared principle is sufficiency. We use this insight to perform generalized thinning operations for a diverse set of families.

stat.ME↗

arXiv2021

Binned multinomial logistic regression for integrative cell type annotation

Categorizing individual cells into one of many known cell type categories, also known as cell type annotation, is a critical step in the analysis of single-cell genomics data. The current process of annotation is time-intensive and subjective, which has led to different studies describing cell types with labels of varying degrees of resolution. While supervised learning approaches have provided automated solutions to annotation, there remains a significant challenge in fitting a unified model for multiple datasets with inconsistent labels. In this article, we propose a new multinomial logistic regression estimator which can be used to model cell type probabilities by integrating multiple datasets with labels of varying resolution. To compute our estimator, we solve a nonconvex optimization problem using a blockwise proximal gradient descent algorithm. We show through simulation studies that our approach estimates cell type probabilities more accurately than competitors in a wide variety of scenarios. We apply our method to ten single-cell RNA-seq datasets and demonstrate its utility in predicting fine resolution cell type labels on unlabeled data as well as refining cell type labels on data with existing coarse resolution annotations. An R package implementing the method is available at https://github.com/keshav-motwani/IBMR and the collection of datasets we analyze is available at https://github.com/keshav-motwani/AnnotatedPBMC.

stat.AP↗