Biology subjects

Ford, J.

Publications and source records attributed to Ford, J..

23 records · Page 2Linked to original sources

bioRxiv2020

Reward processing electrophysiology in schizophrenia: Effects of age and illness phase

BackgroundReward processing abnormalities may underlie characteristic pleasure and motivational impairments in schizophrenia. Some neural measures of reward processing show strong age-related modulation, highlighting the importance of considering age effects on reward sensitivity. We compared event-related potentials (ERPs) reflecting reward anticipation (stimulus-preceding negativity, SPN) and evaluation (reward positivity, RewP; late-positive potential, LPP) across individuals with schizophrenia (SZ) and healthy controls (HC), with an emphasis on examining effects of chronological age, brain age (i.e., predicted age based on neurobiological measures), and illness phase. MethodsSubjects underwent EEG while completing a slot-machine task for which rewards were not dependent on performance accuracy, speed, or other preparatory demands. Slot-machine task EEG responses were compared between 54 SZ and 54 HC individuals, ages 19 to 65. Reward-related ERPs were analyzed with respect to chronological age, categorically-defined illness phase (early; ESZ versus chronic schizophrenia; CSZ), and were used to model brain age relative to chronological age. ResultsIllness phase-focused analyses indicated there were no group differences in average SPN or RewP amplitudes. However, a group x reward outcome interaction revealed that ESZ differed from HC in later outcome processing, reflected by greater LPP responses following loss versus reward (a reversal of the HC pattern). While brain age estimates did not differ among groups, depressive symptoms in SZ were associated with older brain age estimates while controlling for negative symptoms. ConclusionsESZ and CSZ did not differ from HC in reward anticipation or early outcome processing during a cognitively undemanding reward task, highlighting areas of preserved functioning. However, ESZ showed altered later reward outcome evaluation, pointing to selective reward deficits during the early illness phase of schizophrenia. Further, an association between ERP-derived brain age and depressive symptoms in SZ extends prior findings linking depression with reward-related ERP blunting. Taken together, both illness phase and age may impact reward processing in SZ, and brain aging may offer a promising, novel marker of reward dysfunction that warrants further study.

neuroscience↗

bioRxiv2019

Whole genome analysis identifies the association of TP53 genomic deletions with lower survival in Stage III colorectal cancer

DNA copy number aberrations (CNA) were frequently observed in colorectal cancers (CRC). There is an urgent call for CNA-based biomarkers in clinics, in particular for Stage III CRC, if combined with imaging or pathologic evidence, promise more precise care at the timing. We conducted this Stage III specific biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA profiling protocol. Specifically, we developed the profiling protocol for tumor-normal matched tissue samples based on low-coverage clinical whole-genome sequencing (WGS). We demonstrated the protocols accuracy and robustness by a systematic benchmark with microarray, high-coverage whole-exome and -genome approaches, where the low-coverage WGS-derived CNA segments were highly accordant (PCC>0.95) with those derived from microarray, and they were substantially less variable if compared to exome-derived segments. A lasso-based model and multivariate cox regression analysis identified a chromosome 17p loss, containing the TP53 tumor suppressor gene, that was significantly associated with reduced survival (P=0.0139, HR=1.688, 95% CI = [1.112-2.562]), which was validated by an independent cohort of 187 Stage III CRCs. In summary, the new low-coverage WGS protocol has high sensitivity, high resolution and low cost and the identified 17p-loss is an effective poor prognosis marker for Stage III patients.

genomics↗

bioRxiv2018

The spatial chronnectome reveals a dynamic interplay between functional segregation and integration

The brain is highly dynamic, reorganizing its activity at different interacting spatial and temporal scales including variation within and between brain networks. The chronnectome is a model of the brain in which nodal activity and connectivity patterns are changing in fundamental and recurring ways through time. Most previous work has assumed fixed spatial nodes/networks, ignoring the possibility that spatial nodes or networks may vary in time, particularly at the level of the voxel. Here, we introduce an approach allowing for a spatially fluid chronnectome (called the spatial chronnectome for clarity), which focuses on the variation in spatiotemporal coupling at the voxel level within each network. We identify a novel set of spatially dynamic features which can be obtained and evaluated under different conditions. Results reveal transient spatially fluid interactions between intra- and inter-network relationships in which brain networks transiently merge and then separate again, emphasizing the dynamic interplay between segregation and integration. We also show that brain networks exhibit distinct spatial patterns with unique temporal characteristics, potentially explaining a broad spectrum of inconsistencies in previous studies which assumed static networks. Moreover, we show for the first time that anticorrelative connections to the default mode network, are transient as opposed to constant across the entire scan. Preliminary assessments of the approach using a multi-site dataset collected from 160 healthy subjects and 149 patients with schizophrenia (SZ) revealed the ability of the approach to obtain new information and nuanced alterations of brain networks that remain undetected during static analysis. For example, patients with SZ display transient decreases in voxel-wise network coupling including within visual and auditory networks that are not detectable in a spatially static analysis. Our approach also enabled calculation of a novel parameter, the intra-domain coupling variability which was higher within patients with SZ. The significant association between spatiotemporal uniformity and attention/vigilance cognitive domain highlights the cognitive relevance of the spatial chronnectome. In summary, the spatial chronnectome represents a new direction of research enabling the study of functional networks that are transient at the voxel level and identification of mechanisms for within and between-subject spatial variability to study functional brain homeostasis.

neuroscience↗

bioRxiv2018

Comprehensive Genomic Characterization of Breast Tumors with BRCA1 and BRCA2 Mutations

BackgroundGermline mutations in the BRCA1 and BRCA2 genes predispose carriers to breast and ovarian cancer, and there remains a need to identify the specific genomic mechanisms by which cancer evolves in these patients. Here we present a systematic genomic analysis of breast tumors with BRCA1 and BRCA2 mutations.\n\nMethodsWe analyzed genomic data from breast tumors, with a focus on comparing tumors with BRCA1/BRCA2 gene mutations with common classes of sporadic breast tumors.\n\nResultsWe identify differences between BRCA-mutated and sporadic breast tumors in patterns of point mutation, DNA methylation and structural variation. We show that structural variation disproportionately affects tumor suppressor genes and identify specific driver gene candidates that are enriched for structural variation.\n\nConclusionsCompared to sporadic tumors, BRCA-mutated breast tumors show signals of reduced DNA methylation, more ancestral cell divisions, and elevated rates of structural variation that tend to disrupt highly expressed protein-coding genes and known tumor suppressors. Our analysis suggests that BRCA-mutated tumors are more aggressive than sporadic breast cancers because loss of the BRCA pathway causes multiple processes of mutagenesis and gene dysregulation.

cancer biology↗

bioRxiv2016

Long-read whole genome sequencing identifies causal structural variation in a Mendelian disease

Current clinical genomics assays primarily utilize short-read sequencing (SRS), which offers high throughput, high base accuracy, and low cost per base. SRS has, however, limited ability to evaluate tandem repeats, regions with high [GC] or [AT] content, highly polymorphic regions, highly paralogous regions, and large-scale structural variants. Long-read sequencing (LRS) has complementary strengths and offers a means to discover overlooked genetic variation in patients undiagnosed by SRS. To evaluate LRS, we selected a patient who presented with multiple neoplasia and cardiac myxomata suggestive of Carney complex for whom targeted clinical gene testing and whole genome SRS were negative. Low coverage whole genome LRS was performed on the PacBio Sequel system and structural variants were called, yielding 6,971 deletions and 6,821 insertions > 50bp. Filtering for variants that are absent in an unrelated control and that overlap a coding exon of a disease gene identified three deletions and three insertions. One of these, a heterozygous 2,184 bp deletion, overlaps the first coding exon of PRKAR1A, which is implicated in autosomal dominant Carney complex. This variant was confirmed by Sanger sequencing and was classified as pathogenic using standard criteria for the interpretation of sequence variants. This first successful application of whole genome LRS to identify a pathogenic variant suggests that LRS has significant potential to identify disease-causing structural variation. We recommend larger studies to evaluate the diagnostic yield of LRS, and the development of a comprehensive catalog of common human structural variation to support future studies.

genomics↗