Biomedical subjects

Michael Lee

Publications and source records attributed to Michael Lee.

3 recordsLinked to original sources

PubMed2026

Hard to Halt: Automation Bias in Agent-Driven Sequencing Prior Authorization Workflows.

PURPOSE: Prior authorization (PA) for exome or genome sequencing is a time-consuming process that impedes timely rare disease diagnosis. Large language model-based browser agents offer potential for automating these workflows, but their clinical reliability remain uncharacterized. METHODS: We developed a sandbox compromising a simulated ES/GS PA submission payer portal and a synthetic EHR containing 836 patient records spanning compliant profiles and deficient profiles with different types of issues. Gemini 3 Pro, Gemini 3 Flash, and Claude Opus 4.5 were evaluated on task completion rate, form completion accuracy, and appropriate withholding for deficient profiles. RESULTS: Larger models achieved much higher task completion rates (Gemini 3 Pro 95.45%, Claude Opus 4.5 93.67%) compared to Gemini 3 Flash (56.05%), but nearly universally failed to withhold submission for deficient profiles whereas Gemini 3 Flash ironically demonstrated superior withholding performance (17.33%). In a non-agentic setting, Gemini 3 Pro correctly identified 91% of the issues in deficient profiles, indicating that withholding failure is attributable to the browser interaction rather than the model's reasoning limitations. CONCLUSION: Current LLM-based browser agents exhibit a systematic bias towards form submission that poses risks in PA workflows. A modular, multi-agent architecture with human supervision is necessary for a safe clinical deployment.

Journal Article↗

PubMed2025

Heterochromatin-based silencing of a foreign tandem repeat in Drosophila melanogaster shows unusual biochemistry and temperature sensitivity.

Eukaryotic genomes are packaged into chromatin, a regulatory nucleoprotein assembly. Establishment, maintenance, and interconversion of chromatin states is required for correct patterns of gene expression, genome integrity, and survival. Transcriptionally repressive heterochromatin minimizes mobilization of transposable elements and limits expansion of other repetitive DNA, but mechanisms for recognition of the latter sequences are not well established. We previously demonstrated in Drosophila melanogaster that transcripts derived from 1360 and Invader4 transposon insertions can trigger local conversion of transcriptionally permissive euchromatin to heterochromatin through the piRNA system, but only in a subset of genomic locations near existing blocks of heterochromatin. Here we show that a ~9 kb tandem array of the 36-nucleotide lac operator (lacO) sequence of Escherichia coli can form ectopic heterochromatin at a similar subset of sites, resulting in variegating expression of an adjacent reporter gene. Heterochromatin Protein 1a (HP1a) and histone deacetylation are required for lacO repeat-induced silencing, but, contrasting with previously described Position Effect Variegation (PEV), we do not observe increased histone H3 lysine 9 methylation. Silencing is effective at 25°C and suppressed at 18°C (in contrast to canonical PEV, which is enhanced at 18°C), indicating involvement of a temperature-sensitive component. Temperature switching experiments show that lacO repeat-induced heterochromatin formation is reversible throughout larval development following an HP1a-dependent initiation step in the early embryo. We conclude that the Drosophila nucleus can recognize a completely foreign tandem repeat as a target for heterochromatin formation, and that the heterochromatin structure established is distinct from that of endogenous tandem arrays.

HP1a↗

PubMed2025

Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19.

The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 and donor lung tissue with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage. We identify changes in cellular composition across progressive damage, including waves of molecularly distinct macrophages and depletion of epithelial and endothelial populations. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early damage, and fibrosis-related collagens in late damage. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early steps of alveolar damage. These results provide a comprehensive, spatially resolved atlas of alveolar damage progression in COVID-19, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways in severe disease.

COVID-19↗