Deep Phenotyping of Non-Alcoholic Fatty Liver Disease Patients with Genetic Factors for Insights into the Complex Disease

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder characterized by the excessive accumulation of fat in the liver in individuals who do not consume significant amounts of alcohol, including risk factors like obesity, insulin resistance, type 2 diabetes, etc. We aim to identify subgroups of NAFLD patients based on demographic, clinical, and genetic characteristics for precision medicine. The genomic and phenotypic data (3,408 cases and 4,739 controls) for this study were gathered from participants in Mayo Clinic Tapestry Study (IRB#19-000001) and their electric health records, including their demographic, clinical, and comorbidity data, and the genotype information through whole exome sequencing performed at Helix using the Exome+$^\circledR$ Assay according to standard procedure (www$.$helix$.$com). Factors highly relevant to NAFLD were determined by the chi-square test and stepwise backward-forward regression model. Latent class analysis (LCA) was performed on NAFLD cases using significant indicator variables to identify subgroups. The optimal clustering revealed 5 latent subgroups from 2,013 NAFLD patients (mean age 60.6 years and 62.1% women), while a polygenic risk score based on 6 single-nucleotide polymorphism (SNP) variants and disease outcomes were used to analyze the subgroups. The groups are characterized by metabolic syndrome, obesity, different comorbidities, psychoneurological factors, and genetic factors. Odds ratios were utilized to compare the risk of complex diseases, such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), as well as liver failure between the clusters. Cluster 2 has a significantly higher complex disease outcome compared to other clusters. Keywords: Fatty liver disease; Polygenic risk score; Precision medicine; Deep phenotyping; NAFLD comorbidities; Latent class analysis.

REMEDI: REinforcement learning-driven adaptive MEtabolism modeling of primary sclerosing cholangitis DIsease progression

Primary sclerosing cholangitis (PSC) is a rare disease wherein altered bile acid metabolism contributes to sustained liver injury. This paper introduces REMEDI, a framework that captures bile acid dynamics and the body's adaptive response during PSC progression that can assist in exploring treatments. REMEDI merges a differential equation (DE)-based mechanistic model that describes bile acid metabolism with reinforcement learning (RL) to emulate the body's adaptations to PSC continuously. An objective of adaptation is to maintain homeostasis by regulating enzymes involved in bile acid metabolism. These enzymes correspond to the parameters of the DEs. REMEDI leverages RL to approximate adaptations in PSC, treating homeostasis as a reward signal and the adjustment of the DE parameters as the corresponding actions. On real-world data, REMEDI generated bile acid dynamics and parameter adjustments consistent with published findings. Also, our results support discussions in the literature that early administration of drugs that suppress bile acid synthesis may be effective in PSC treatment.