arXiv subjects

Charles Kooperberg

Publications and source records attributed to Charles Kooperberg.

4 recordsLinked to original sources

arXiv2026

Modeling Physical Activity Change as Smooth Transformations: Temporal and Amplitude Patterns Associated with Physical Function in Older Women

Purpose: To investigate whether longitudinal changes in timing and magnitude of PA are associated with physical function (PF) in older women. Methods: Women from OPACH study with accelerometry at baseline and WHISH study W1 and W2 were included. Minute-level PA counts were averaged and smoothed as diurnal PA curves. Consecutive-visit change was modeled within periods (baseline--W1 and W1--W2) as a Riemannian deformation from earlier to later curves, with two-dimensional initial momenta characterizing timing and magnitude shifts. Multivariate functional principal component analysis (MFPCA) summarized coupled timing-magnitude patterns, and principal component (PC) scores and deformation energy were derived for each participant-period. Linear mixed-effects models related these features to RAND-36 PF, adjusting for baseline PF and covariates. Results: Mean PA deformation in both periods showed downward shifts in PA magnitude and temporal redistribution after 10:00. Top 15 PCs explained at least 90% of variability in both periods. PC1 captured diurnal PA increase/decrease, explaining 22.4% of variability for baseline--W1 and 20.8% for W1--W2. Among participants with complete PF scores and baseline covariates (N=1,157), higher PC1 scores, reflecting relative increase/maintenance of PA across day, were positively associated with PF (P<0.0001). Deformation energy, a metric for overall diurnal pattern change between visits, showed a significant interaction with period for PF (P=0.003), with a larger positive association during W1--W2 than during baseline--W1. Conclusions: In older women, longitudinal changes in diurnal PA accumulation were associated with PF. Riemannian deformation analysis identified clinically interpretable markers of PA pattern change that may capture functional-aging information not represented by conventional PA summaries.

stat.AP↗

arXiv2023

Heterogeneity-aware integrative regression for ancestry-specific association studies

Ancestry-specific proteome-wide association studies (PWAS) based on genetically predicted protein expression can reveal complex disease etiology specific to certain ancestral groups. These studies require ancestry-specific models for protein expression as a function of SNP genotypes. In order to improve protein expression prediction in ancestral populations historically underrepresented in genomic studies, we propose a new penalized maximum likelihood estimator for fitting ancestry-specific joint protein quantitative trait loci models. Our estimator borrows information across ancestral groups, while simultaneously allowing for heterogeneous error variances and regression coefficients. We propose an alternative parameterization of our model which makes the objective function convex and the penalty scale invariant. To improve computational efficiency, we propose an approximate version of our method and study its theoretical properties. Our method provides a substantial improvement in protein expression prediction accuracy in individuals of African ancestry, and in a downstream PWAS analysis, leads to the discovery of multiple associations between protein expression and blood lipid traits in the African ancestry population.

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arXiv2013

Meta-Analysis of Gene Level Association Tests

The vast majority of connections between complex disease and common genetic variants were identified through meta-analysis, a powerful approach that enables large samples sizes while protecting against common artifacts due to population structure, repeated small sample analyses, and/or limitations with sharing individual level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the unit of analysis. Here, we propose and evaluate new approaches for meta-analysis of rare variant association. We show that our approach retains useful features of single variant meta-analytic approaches and demonstrate its utility in a study of blood lipid levels in ~18,500 individuals genotyped with exome arrays.

stat.ME↗

arXiv2010

Structures and Assumptions: Strategies to Harness Gene $\times$ Gene and Gene $\times$ Environment Interactions in GWAS

Genome-wide association studies, in which as many as a million single nucleotide polymorphisms (SNP) are measured on several thousand samples, are quickly becoming a common type of study for identifying genetic factors associated with many phenotypes. There is a strong assumption that interactions between SNPs or genes and interactions between genes and environmental factors substantially contribute to the genetic risk of a disease. Identification of such interactions could potentially lead to increased understanding about disease mechanisms; drug $\times$ gene interactions could have profound applications for personalized medicine; strong interaction effects could be beneficial for risk prediction models. In this paper we provide an overview of different approaches to model interactions, emphasizing approaches that make specific use of the structure of genetic data, and those that make specific modeling assumptions that may (or may not) be reasonable to make. We conclude that to identify interactions it is often necessary to do some selection of SNPs, for example, based on prior hypothesis or marginal significance, but that to identify SNPs that are marginally associated with a disease it may also be useful to consider larger numbers of interactions.

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