Biology subjects

Hyams, J.

Publications and source records attributed to Hyams, J..

3 recordsLinked to original sources

bioRxiv2025

Model-informed Deep Q-Networks to Guide Infliximab Dosing in Pediatric Crohn's Disease

Model-informed precision dosing (MIPD) utilizes pharmacokinetic/pharmacodynamic (PK/PD) models to optimize drug therapy. However, conventional MIPD often requires manual simulation and regimen selection, which are time-consuming and demand specialized expertise. Reinforcement learning (RL), in which an agent learns optimal decisions through iterative interactions with an environment, offers a scalable and automated alternative. In this study, we developed a model-informed Deep Q-Network (DQN) to personalize infliximab dosing for patients with Crohns disease. The DQN was trained in a simulation environment incorporating a population PK model, inter-individual variability, and assay error. Virtual patients with randomly sampled covariates were used to explore dosing strategies at infusions 1, 3, and 4. Doses ranged from 1 to 10 mg/kg at infusion 1 and from 1 to 20 mg/kg thereafter, with intervals of 4 to 12 weeks. The reward function prioritized achieving trough concentrations of 18-26 {micro}g/mL before infusion 3 and 5-10 {micro}g/mL before infusions 4 and 5, while penalizing overtreatment and additional infusions. The DQN policy converged after 80,000 episodes, yielding target attainment probabilities (PTAs) of 92.9% and 98.4% at infusions 4 and 5, respectively, in 1,000 virtual patients. High doses (11-20 mg/kg) were selected in only 0.2% of cases. At infusion 4, 66.8% of patients received an 8-week interval, and 57.3% at infusion 5. Retrospective real-world validation showed that patients whose actual doses matched DQN recommendations had trough levels significantly closer to target ranges. These findings support the feasibility of using DQN-based agents to enhance and automate infliximab individualized dosing in pediatric populations.

pharmacology and toxicology↗

bioRxiv2023

Identification of arginine-vasopressin receptor 1a (Avpr1a/AVPR1A) as a novel candidate gene for chronic visceral pain.

Chronic abdominal pain in the absence of ongoing disease is the hallmark of disorders of gut-brain interaction (DGBIs), including irritable bowel syndrome (IBS). While the etiology of DGBIs remains poorly understood, there is evidence that both genetic and environmental factors play a role. In this study, we report the identification and validation of Avpr1a as a novel candidate gene for visceral hypersensitivity (VH), a primary peripheral mechanism underlying abdominal pain in DGBI/IBS. Comparing two C57BL/6 (BL/6) substrains (C57BL/6NTac and C57BL/6J) revealed differential susceptibility to the development of chronic VH following intrarectal zymosan (ZYM) instillation, a validated preclinical model for post-inflammatory IBS. Using whole genome sequencing, we identified a SNP differentiating the two strains in the 5 intergenic region upstream of Avpr1a, encoding the protein arginine-vasopressin receptor 1A (AVPR1A). We used behavioral, histological, and molecular approaches to identify distal colon- specific gene expression differences and neuronal hyperresponsiveness covarying with Avpr1a genotype and VH susceptibility. While the two BL/6 substrains did not differ across other gastrointestinal (GI) phenotypes (e.g., GI motility), VH-susceptible BL/6NTac mice had higher colonic Avpr1a mRNA and protein expression. Moreover, neurons of the enteric nervous system were hyperresponsive to the AVPR1A agonist AVP, suggesting a role for enteric neurons in the pathology underlying VH. These results parallel our findings that patients colonic Avpr1a mRNA expression was higher in patients with higher pain ratings. Taken together, these findings implicate differential regulation of Avpr1a as a novel mechanism of VH-susceptibility as well as a potential therapeutic target specific to VH. SummaryA combination of approaches, from genomic analysis to functional analyses, confirm Avpr1a as a high priority candidate gene for visceral pain.

genetics↗

bioRxiv2018

Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy

Clinical benefits to cytokine blockade in ileal Crohns disease (iCD) have been limited to a subset of patients. Whether cellular and molecular heterogeneity contributes to variability in treatment responses has been unclear. Using single cell technologies combining scRNAseq, CyTOF and multiplex tissue imaging, we mapped the cellular landscape of inflamed ileum lesions, adjacent non-inflamed ileum and matched circulating blood cells of iCD patients. In inflamed tissues, we identified a pathogenic module characterized by an inflammatory mononuclear phagocyte (Inf.MNP)-associated cellular response organized around inflammatory macrophages and mature dendritic cells in a subset of iCD patients. We confirmed the Inf.MNP-associated cellular response in 4 independent iCD cohorts (n=441) and showed that presence of this pathogenic module at diagnosis correlated with primary resistance to anti-TNF therapy. Single cell mapping of iCD tissues identifies a complex cellular signature of anti-TNF resistance thereby revealing novel biomarkers of treatment response and tailored therapeutic opportunities.

immunology↗