Nathan J Morris

Eli Lilly · Lilly Research Laboratories

Structural equation modeling (SEM) is a very general approach to analyzing data in the presence of measurement error and complex causal relationships. In this tutorial, we describe SEM, with special attention to exploratory factor analysis, confirmatory factor analysis, and multiple indicator multiple cause modeling. The tutorial is motivated by a...

Structural equation modeling (SEM) is an extremely general and powerful approach to account for measurement error and causal pathways when analyzing data, and it has been used in wide range of applied sciences. There are many commercial and freely available software packages for SEM. However, it is difficult to use any of the packages to analyze ge...

mRNA degradation represents a critical regulated step in gene expression. Although the major pathways in turnover have been identified, accounting for disparate half-lives has been elusive. We show that codon optimality is one feature that contributes greatly to mRNA stability. Genome-wide RNA decay analysis revealed that stable mRNAs are enriched...

Background Mirikizumab (miri) is a selective IL23p19 monoclonal antibody approved for the treatment of ulcerative colitis. The primary focus of the VIVID-1 trial (NCT03926130) was to demonstrate the efficacy and safety of mirikizumab (miri) compared to placebo (PBO) in patients (pts) with moderate-to-severe Crohn’s disease. Here we present primary...

Background The primary objective of the VIVID-1 trial (NCT03926130) was to demonstrate efficacy and safety of mirikizumab (miri), a p19-directed anti-IL-23 antibody, compared to placebo (PBO) in patients (pts) with moderate-to-severe Crohn’s disease. Miri demonstrated statistically significant improvements in co-primary and all key secondary endpoi...

Background Mirikizumab (miri), an anti-IL-23p19 antibody, is approved for the treatment of ulcerative colitis and under development for Crohn’s disease (CD). We investigated how miri impacted fatigue, bowel urgency, and health-related quality of life (HRQoL) through 52 weeks in patients with moderately to severely active CD in the Phase 3 VIVID-1 s...

Background Mirikizumab (miri) improved symptom control in a Phase 3, multicenter, randomized, double-blind, parallel, placebo-controlled induction study at Week (W)12, in patients (pts) with moderately-to-severely active ulcerative colitis (UC; LUCENT-1). Purpose This analysis assessed sustained symptom control during the maintenance phase through...

Background Mirikizumab (miri), an anti-IL23/p19 monoclonal antibody, demonstrated efficacy compared with placebo (PBO) in the Phase 3, multicentre, randomized, double-blind LUCENT-1 induction study in patients with moderately to severely active ulcerative colitis (UC, NCT03518086). Purpose This analysis assessed early onset of symptomatic improvem...

Background The inflammatory bowel disease questionnaire (IBDQ) is a measure of health-related quality of life (QoL), with higher scores indicating greater QoL. In a prior phase 2 study (NCT02589665), mirikizumab, an anti-IL23p19 antibody, demonstrated efficacy and improvement in IBDQ scores in participants with moderately to severely active ulcerat...

Background Mirikizumab (miri), a p19-directed IL-23 antibody, showed efficacy in ulcerative colitis (UC)1. Miri modulates transcripts associated with disease activity and anti-TNF resistance in UC and increases expression of transcripts associated with healthy mucosa2. Here, we evaluate the transcription profile of patients with UC who respond to p...

Background The efficacy and safety of mirikizumab (miri) for moderately to severely active ulcerative colitis (UC) was demonstrated in the Phase 3 LUCENT trials (LUCENT-1 and -2; NCT03518086, NCT03524092).1,2 Some patients may improve more slowly and require a prolonged course of induction before achieving clinical response. Therefore, we evaluated...

Background Anti-IL23p19 inhibitors are emerging as promising treatment options for ulcerative colitis (UC). Mirikizumab (miri) is a humanized, IgG4 monoclonal antibody directed against the p19 subunit of IL-23, a key mediator in the pathogenesis of inflammatory bowel diseases. We assessed the induction efficacy and safety of miri with a Phase 3, mu...

Background Urgency, also referred to as bowel movement urgency or bowel urgency, is the sudden need for a bowel movement. Bowel urgency is one of the most bothersome and important symptoms experienced by patients with ulcerative colitis (UC), contributing to decrements in quality of life. Bowel urgency is distinct from the common symptoms associate...

Background Mirikizumab (miri; LY3074828) is a humanized monoclonal antibody directed against the p19 subunit of IL-23, which demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial (NCT02589665) in patients with ulcerative colitis (UC). Bowel movement urgency is one of the most bothersome symptoms experienced by patients...

Background Mirikizumab (LY3074828) is a humanized monoclonal antibody directed against the p19 subunit of IL-23, and had demonstrated efficacy in psoriasis, ulcerative colitis (UC), and Crohn’s disease. The effect of miri on health-related quality of life (HRQoL) as measured by the 36-Item Short Form Health Survey v2 Standard (SF-36) was examined i...

Background Interleukin (IL)-23 is a key cytokine in inflammatory bowel disease pathogenesis. Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in patients with moderate-to-severely active ulcerative colitis (UC) during 52 weeks of a Phase 2 randomised clinical trial (AMAC, NCT02589665). The effects of m...

Structural equation modeling (SEM) is a powerful, comprehensive, and flexible multivariate statistical method for modeling relationships between observed and latent variables. However, in genetic association analysis, frequentist approaches to fitting SEMs do not always lead to convergence and admissible solutions for complex models, categorical va...

CD4⁺ effector/memory T cells (Tem) represent a leading edge of the adaptive immune system responsible for protecting the body from infection, cancer, and other damaging processes. However, a subset of Tem cells with low expression of CD45Rb (RbLoTem) has been shown to suppress inflammation despite their effector surface phenotype and the lack of Fo...

Despite effective control of HIV infection with antiretroviral drugs, individuals with HIV have high incidences of secondary diseases. These sequelae, such as cardiovascular disease (CVD), are poorly understood and represent a major health burden. To date, predictive biomarkers of HIV‐associated secondary disease have been elusive, making preventat...

Messenger RNA (mRNA) degradation plays a critical role in regulating transcript levels in eukaryotic cells. Previous work by us and others has shown that codon identity exerts a powerful influence on mRNA stability. In Saccharomyces cerevisiae, studies using a handful of reporter mRNAs show that optimal codons increase translation elongation rate,...

This study examined the spelling skills in middle childhood and adolescence in individuals with histories of early childhood speech sound disorders (SSD) with and without language impairment (LI). Youth without such histories were also included (No SSD/LI group). The heritability of spelling skills at each age level was estimated. Children with SSD...

Messenger RNA (mRNA) degradation plays a critical role in regulating transcript levels in eukaryotic cells. Previous work by us and others has shown that codon identity exerts a powerful influence on mRNA stability. In Saccharomyces cerevisiae , studies using a handful of reporter mRNAs show that optimal codons increase translation elongation rate,...

Background: Antenatal exposure to parasites can affect infants' subsequent responses to vaccination. The present study investigated how maternal prenatal infections and newborns' anti-parasite cytokine profiles relate to IgG responses to standard vaccination during infancy. Methods: 450 Kenyan women were tested for parasitic infections during pr...

: The conventional D-dimer cut-off value of at least 500 μg FEU/l has good sensitivity but poor specificity for identifying pulmonary embolism. An elevated age-adjusted D-dimer value (age in years × 10 μg FEU/l) for patients at least 50 years old has been recommended as a better cut-off with adequate sensitivity and improved specificity for identif...

Objectives: To identify associations between use of ipratropium and/or intravenous magnesium and outcomes of children hospitalized with acute asthma exacerbations and treated with continuous albuterol. Methods: Secondary analysis of data from children prospectively enrolled in the multicenter Ohio Pediatric Asthma Repository restricted to only c...

Disruption of microvascular blood flow is a common cause of tissue hypoxia in disease, yet no therapies are available that directly target the microvasculature to improve tissue oxygenation. Red blood cells (RBCs) auto-regulate blood flow through S-nitroso-hemoglobin (SNO-Hb)-mediated export of nitric oxide (NO) bioactivity. We therefore tested the...

Objectives: We assessed characteristics that may predict outpatient appointment attendance in outpatient medical clinics among patients comorbid for serious mental illness (SMI) and type 2 diabetes (DM). Methods: Baseline covariate data from 200 individuals with SMI-DM enrolled in a randomized controlled trial (RCT) were used to examine characte...

Model-free methods of linkage analysis for quantitative traits are a class of easily implemented, computationally efficient and statistically robust approaches to searching for linkage to a quantitative trait. By “model-free” we refer to methods of linkage analysis that do not fully specify a genetic model (i.e., the causal allele frequency, and pe...

Structural equation modeling (SEM) is a multivariate statistical framework that is used to model complex relationships between directly observed and indirectly observed (latent) variables. SEM is a general framework that involves simultaneously solving systems of linear equations and encompasses other techniques such as regression, factor analysis,...

The relative contributions of additive versus non-additive interactions in the regulation of complex traits remains controversial. This may be in part because large-scale epistasis has traditionally been difficult to detect in complex, multi-cellular organisms. We hypothesized that it would be easier to detect interactions using mouse chromosome su...

Positive correlation between cis-meQTLs and trans-meQTLs. (A) Scatter plot of the relationship between the percentage of cis-meQTLs and trans-meQTLs in each of 8 CSS strains with one substituted chromosome. The strains are labelled on the graph with only their substituted chromosome, for example strain (B6 x B6.A8)F1 is shown for simplicity as A8....

Regulation of hepatic Zkscan3 expression by additive meQTLs. (A) Gene expression of Zkscan3 in the liver was analyzed by (A) RNA-Seq and (B) RT-qPCR. Each dot represents Zkscan3 expression levels in an individual mouse. RT-qPCR data shown is relative to the control gene Rplp0. The mean value for each strain is indicated by a black line. The expecte...

Schematic diagram illustrating the categorization of epistasis as either synergistic or antagonistic. Hypothetical mean expression levels are shown with black lines for the strains B6 and the two single CSS strains (CSSa x B6)F1 and (B6 x CSSb)F1, where a and b represent any two different substituted chromosomes. The predicted expression levels bas...

Number of mice used for analysis of body weight and plasma glucose. (XLSX)

Identification of fasting glucose QTLs using a combined linear model. (XLSX)

No differences in mapping efficiency of RNA-Seq reads between B6 and CSSs. (A) Genome-wide mapping efficiency was calculated as the number of unique reads mapped to the GENCODE coding portion of the genome divided by the total number of reads per sample. (B) Mapping efficiency was calculated as above for the individual substituted chromosomes in ea...

Summary of metabolic data for 766 mice used in analysis of body weight and plasma glucose. (XLSX)

Main and average effects on phenotypes. (XLSX)

List of ieQTLs in CSSs. (XLSX)

Primer sequences for RT-qPCR detection. (XLSX)

Body weight and glucose levels in all CSS and control mice. Body weight and plasma glucose levels were measured in 5-week-old mice that were fasted overnight. Each dot represents the data from an individual mouse. Females (F) are shown in red. Males (M) are shown in blue. Outliers, as described in the Trait Analysis paragraph in the Methods section...

Positive correlation between cis-ieQTLs and trans-ieQTLs. (A) Scatter plot of the relationship between the percentage of cis-ieQTLs and trans-ieQTLs identified among 15 pairwise CSS crosses. The data points are labelled on the graph with the two substituted chromosomes for each pairwise cross. Data is shown on a log scale. (B) Histogram illustratin...

Summary of genes with multiple meQTLs. (XLSX)

List of genes with multiple ieQTLs. (XLSX)

Schematic diagram of CSS and control crosses. Crosses were used to generate control, single CSS, and double CSS mice to examine main effects and interaction effects on various traits and gene expression levels. The four crosses used (top) to generate the control and CSS offspring (bottom) to study the substitution of chromosomes 3 and 10 are provid...

Inter-chromosomal epistasis regulates fasting glucose levels. Plots representing four out of the five CSS crosses that showed significant inter-chromosomal interactions on plasma glucose levels (The other significant CSS cross is shown in Fig 1). Each dot represents a single mouse. “Others” represents the data from all mice in this study excluding...

Identification of 5 inter-chromosomal epistatic interactions that regulate fasting glucose levels in mice. Multiple testing adjusted p-values for interaction effects on fasting plasma glucose levels among 15 crosses each involving two A/J-derived chromosome substitutions with the substituted chromosomes indicated below the chart. Inverse-variance m...

Identification of 5 trans-meQTLs that regulate the hepatic expression of Brca2. Gene expression levels of Brca2 in the liver are shown for strain B6 and 8 single CSS strains. Each dot represents Brca2 expression in an individual mouse. The mean value for each strain is indicated by a solid line. The Brca2 gene is located on mouse chromosome 5. ** i...

List of meQTLs in CSSs. (XLSX)

Main effects on gene expression. (XLSX)

List of genes with multiple meQTLs. (XLSX)

Genes examined by RNA-Seq and RT-qPCR for epistasis and additive interactions. (XLSX)

Summary of genes with multiple ieQTLs. (XLSX)

Identification of body weight QTLs using a combined linear model. (XLSX)

Objectives: The aim of this study was to test a hypothesized mediation model to explain associations between mothers' dental anxiety and children's dental utilization through the mothers' own dental utilization. Methods: Two hundred and fourteen low-income African American mothers with young children (age 31-59 months) completed a study question...

Aims This study evaluates ocular biometrics and aqueous humour dynamics (AHD) in healthy Chinese volunteers to determine how the various ocular parameters interact to maintain physiological intraocular pressure (IOP) at all ages. Methods Sixty-nine volunteers enrolled in this cross-sectional study and were categorised into young (20–30 years) and...

The relative contributions of additive versus non-additive interactions in the regulation of complex traits remains controversial. This may be in part because large-scale epistasis has traditionally been difficult to detect in complex, multi-cellular organisms. We hypothesized that it would be easier to detect interactions using mouse chromosome su...

Supplementary Figures, Supplementary Tables and Supplementary References

Gene expression over a 1-megabase window near six FECD-associated loci in normal corneal tissue.

Promoter, Enhancer and eQTL Annotations for Major Loci

Objective: To characterize actual achieved patterns of oxygenation in infants born appropriate vs small for gestational age (SGA) randomized to a lower (85-89%) vs higher (91%-95%) oxygen saturation target in the Surfactant Positive Pressure and Oxygen Trial. To determine the association between achieved oxygen saturation levels and survival in in...

The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases an...

Analysis of Bed Bug (Cimex lectularius) Introductions Into an Academic Medical Center - Johnathan Michael Sheele, Erika Barrett, Obada Farhan, Nathan Morris

Background Although disorganized, chaotic households have been linked to poorer sleep outcomes, how household chaos actually manifests itself in the behaviors of others around the bedtime of a child or adolescent is not well understood. Objective To determine whether household chaos was associated with specific, nightly sleep-disturbing activities...

Background Proton pump inhibitors (PPIs) have been shown in cell culture to kill Trichomonas vaginalis (TV) at lower half maximal inhibitory concentration values than metronidazole (Flagyl), the most common medication used to treat the infection. However, there have been no previous clinical investigations to determine if PPIs are associated with r...

The role played by epistasis between alleles at unlinked loci in shaping population fitness has been debated for many years and the existing evidence has been mainly accumulated from model organisms. In model organisms, fitness epistasis can be systematically inferred by detecting nonindependence of genotypic values between loci in a population and...