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Tran, P. P.

Publications and source records attributed to Tran, P. P..

2 recordsLinked to original sources

Information Bottleneck Dominates Adversarial Training for Ancestry-Invariant Polygenic Risk Prediction: Dimensionality, Not Gradient Reversal, Controls the Fairness-Accuracy Tradeoff

In adversarial representation learning for fair prediction, the gradient reversal coefficient ({lambda}) is widely treated as the primary control for sensitive-attribute invariance. We show this assumption is wrong. Using a dual-stream architecture for cross-ancestry polygenic risk score (PRS) prediction, we demonstrate that latent dimensionality -- the information bottleneck -- accounts for 8-27 x more variance in ancestry leakage than adversarial strength. Varying{lambda} across a 20 x range changes leakage by only 2.2 percentage points; varying dimensionality across a 16 x range changes it by 46.6 pp. At dimension 8 with no adversarial training ({lambda} = 0), ancestry leakage is 32.9% (chance = 20%): the bottleneck alone achieves near-invariance. The adversary architecture (linear vs deep MLP) is equally irrelevant (0.6 pp range). We validate this finding across two unrelated domains -- genomic ancestry invariance (6 clinical traits, 1000 Genomes, n = 2,504) and EEG subject invariance (pretrained HFTP + Braindecode dual-domain model, 20 subjects) -- observing consistent dimensionality dominance (12.7:1 ratio in EEG). For the genomic application, Stream 1 encodes population structure via DCT-II frequencydomain features (136 coefficients); Stream 2 encodes phenotype signal from top PRS SNPs (PCA to 128 dimensions). The architecture works equally well with standard genomic PCA as the ancestry stream (R2 = 0.217 vs 0.222), confirming the contribution is architectural, not encoding-specific. African-ancestry PRS reconstruction R2 improves on all six traits (e.g., +5.1 pp for coronary artery disease). Linear models achieve higher aggregate R2 but fail catastrophically on cross-ancestry transfer (R2 = - 12.45 for African-ancestry CAD). We emphasize that we predict PRS (a computed score), not disease phenotypes; validation on biobank-scale phenotype data is ongoing. These results suggest the adversarial fairness community has been over-investing in adversary engineering relative to simple capacity control. Practitioners should select latent dimensionality first to set the information budget for the fairness-accuracy tradeoff, then optionally use adversarial training for marginal refinement.

genomics↗

Multiparametric Assessment of TNNI3 Variant Phenotypes in Human iPSC-Cardiomyocytes Correlates with Disease Severity in Patients

BackgroundThe routine genetic testing of cardiomyopathy patients has significantly accelerated the identification of causative cardiomyopathy variants. However, translating these genetic insights into effective patient management poses significant challenges, since the impact of gene variants on physiological function and clinical outcomes is not yet fully understood. Therefore, there is an urgent need for large-scale methods to assess the effects of genetic variants on cardiomyocyte physiology and to establish correlations between functional phenotypes and clinical severity. MethodsWe developed a high throughput imaging platform to measure force generation and calcium handling throughout the cardiac cycle of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). By expressing variants of a sarcomeric protein [cardiac Troponin-I (TNNI3)] in a healthy genetic background, we were able to assess sarcomeric calcium sensitivity as well as systolic and diastolic function. Analysis of these parameters distinguished subgroups of variants, and permitted the correlation of in vitro physiological effects with a measure of disease severity in a single-center cardiomyopathy cohort. ResultsCombining contractile force and calcium cycling measurements accurately distinguished known pathogenic from non-pathogenic TNNI3 variants and also revealed pathogenicity of two variants of unknown significance (VUS) that occurred in two families, suggesting the ability to prospectively discern pathogenicity. Clustering of TNNI3 variants based on quantitative physiological phenotypes identified subgroups that correlated with age of disease onset across a well-characterized cardiomyopathy patient cohort, showing clinical relevance of the in vitro phenotypes. Interestingly, normalized measures of in vitro diastolic function correlated with age of onset (R2 = 0.6), but calcium sensitivity, which accurately predicted pathogenicity, did not translate into disease severity. ConclusionsA high throughput in vitro platform that measures multidimensional cardiomyocyte function can link subgroups of human genetic variants in TNNI3 with differential patient outcomes. Comprehensive determination of variant effects on disease-relevant cardiomyocyte function will help classify variants into different pathogenic mechanisms leading to variable disease severity, and potentially lead to class-targeted ameliorative strategies.

genetics↗