Biology subjects

Fox, N. C.

Publications and source records attributed to Fox, N. C..

3 recordsLinked to original sources

bioRxiv2018

Integrative pathway enrichment analysis of multivariate omics data

Multi-omics datasets quantify complementary aspects of molecular biology and thus pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple omics datasets using a statistical data fusion approach, rationalizes contributing evidence and highlights associated genes. We demonstrate its utility by analyzing coding and non-coding mutations from 2,583 whole cancer genomes, revealing frequently mutated hallmark pathways and a long tail of known and putative cancer driver genes. We also studied prognostic molecular pathways in breast cancer subtypes by integrating genomic and transcriptomic features of tumors and tumor-adjacent cells and found significant associations with immune response processes and anti-apoptotic signaling pathways. ActivePathways is a versatile method that improves systems-level understanding of cellular organization in health and disease through integration of multiple molecular datasets and pathway annotations.

bioinformatics↗

bioRxiv2018

Data-driven models of dominantly-inherited Alzheimer’s disease progression

Dominantly-inherited Alzheimers disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimers disease. We use emerging techniques in generative data-driven disease-progression modelling to characterise dominantly-inherited Alzheimers disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset (EYO). We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers: 163 PSEN1; 17 PSEN2; and 31 APP) and a baseline visit (age 19-66; up to four visits each, 1{middle dot}1 {+/-} 1{middle dot}9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential-equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then sub-cortical regions (approximately 24{+/-}11 years before onset); CSF p-tau (17{+/-}8 years), tau and A{beta}42 changes; neurodegeneration first in the putamen and nucleus accumbens (up to 6 {+/-} 2 years); then cognitive decline (7 {+/-} 6 years), cerebral hypometabolism (4 {+/-} 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than EYO: root-mean-squared error of 1{middle dot}35 years versus 5{middle dot}54 years. The models reveal hidden detail on dominantly-inherited Alzheimers disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.

neuroscience↗

bioRxiv2017

Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we present a new machine learning technique - Subtype and Stage Inference (SuStaIn) - able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available crosssectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal new subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes, and characterises within-group heterogeneity for the first time. In Alzheimers disease, SuStaIn uncovers three subtypes, uniquely revealing their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p=7.18x10--4) or temporal stage (p=3.96x10-5). SuStaIn thus offers new promise for enabling disease subtype discovery and precision medicine.

neuroscience↗