Project 3: Biomarkers

University Of Colorado Denver, Aurora CO

Investigators

Abstract

PROJECT 3 ABSTRACT Accurate assessment of the multisystem phenotypic implications of an abnormal number of sex chromosomes, or sex chromosome aneuploidy (SCA), is a current limitation that needs to be overcome to facilitate effective clinical trials with targeted interventions and appropriate biomarkers. NASCARR Research Project 3, “Establishing Severity Scores and Predictive Biomarkers in SCA” will address this limitation by defining the dominant axes of clinical variation (ACV’s) for individuals with SCA and genomic biomarkers associated with ACV severity. In Aim 1, define dominant ACVs across SCA clinical domains and develop person-level outcome severity scores, we will apply our novel research methods for ACV discovery to Project 1 data – ~1,000 multidisciplinary outcome variables from ~1,000 karyotypically diverse individuals with SCA. Aim 1 will use cutting edge network science and machine learning methods to resolve dominant ACVs in SCA; differentiate shared vs distinct ACVs across medical specialties and SCA karyotypes; and enable rapid and standardized person-level measurement of outcome severity in SCA - for individual ACVs as well as all ACVs combined (global ACV severity). Crucially, our approach overcomes the siloing of information from different medical disciplines and SCA karyotypes that has impeded ACV definition and measurement in SCA to date. For Aim 2, specify genomic biomarkers for ACV severity in SCA, we will test the hypothesis that ACV severity can be predicted by sex chromosome gene expression. RNAseq will measure sex chromosome gene expression in individuals with the lowest and highest severity scores from four of the most common SCA karyotypes (X, XXX, XXY, XYY). Successful completion of aim 2 will result in the development of tools for genomic outcome prediction, identification of molecular predictors of outcome severity that could be measured or manipulated in clinical trials, and collection of polymorphic blood mononuclear cells (PMBCs) for future generation of stem cells for tissue-specific analyses. This project will be made possible through intramural NIH collaboration with extramural investigators in the NASCARR consortium, with the resources made possible through the RDCRN infrastructure.