Biology subjects

McCarthy, P.

Publications and source records attributed to McCarthy, P..

8 recordsLinked to original sources

bioRxiv2026

Diagnose Harmonisation (DHARM): An open-source tool for the harmonisation and analysis of batch effects in MRI-derived measures.

Technical differences between scanners, acquisition protocols, machine hardware and processing pipelines can introduce systematic variation into MRI-derived measures. Numerous harmonisation methods have been developed to reduce these effects. However, validation of these methods is often performed using different criteria depending on the method itself, the datasets used and the study design. Consequently, determining whether harmonisation is required, selecting an appropriate method and establishing whether or not technical variation has been sufficiently removed without compromising biological signal remain challenging. In this manuscript, we introduce Diagnose Harmonisation (DHARM), an open-source Python toolbox for diagnosing batch effects, applying harmonisation and evaluating harmonisation performance in cross-sectional and repeated-measures settings. DHARM is user-friendly, comes with GUI-based and command-line interfaces, and has graphical reporting. It provides standardised reporting workflows combining complementary measures of batch-associated differences in feature location, scale, empirical distributions, covariance and multivariate structure, together with measures assessing preservation of biological covariate effects and repeated-measures consistency. The framework includes several established harmonisation approaches, but its evaluation workflow is method-agnostic: users can also supply data harmonised using external or newly developed methods and benchmark their outputs using the same common set of diagnostics. We demonstrate DHARM using multisite cross-sectional MRI measures from UK Biobank, Cam-CAN and OxBAC as well as travelling-heads data from the ON-Harmony dataset. Across the cross-sectional datasets, harmonisation substantially reduced additive batch effects, while residual differences in variance and empirical distributions varied between methods. Multivariate diagnostics further demonstrated that reduction of batch-associated structure can coexist with preservation or increased detectability of biologically relevant variation. In the repeated-measures example, harmonisation reduced batch-associated and within-subject variability, while broadly preserving subject-level and biological relationships. DHARM provides a reproducible framework for diagnosing batch effects, applying different harmonisation methods and evaluating harmonisation as a multi-criteria problem rather than relying on a single measure of success. By jointly characterising technical variation and preservation of biologically meaningful information, DHARM can support dataset- and objective-specific selection, benchmarking and validation of harmonisation strategies.

neuroscience↗

bioRxiv2026

A Regionally Inspired West Virginia Obesogenic Diet Induces Fat Accretion and Metabolic Dysfunction While Identifying Sex Disparity

Obesity prevalence continues to rise in the United States, with a disproportionate burden falling to West Virginia. To investigate the metabolic effects of region-specific dietary patterns, we developed the West Virginia Obesogenic Diet (WV-OD), a compositionally defined rodent diet based on nutritional analyses of meals consumed by obese individuals in the state. The WV-OD closely mirrors the macronutrient profile of the average American diet while incorporating regional features such as a greater sodium level and significantly less fiber. We compared the metabolic effects of the WV-OD to a matched control diet (WV-CD) and to a widely used high-fat diet (HFD, 60% of calories derived from fat) in male and female C57BL/6J mice. After 19 weeks, WV-OD-fed males exhibited weight gain and adiposity comparable to HFD-fed counterparts, along with glucose intolerance and hepatic triglyceride accumulation confirming the obesogenic and metabolically disruptive properties of the WV-OD. Unlike HFD-fed mice, WV-OD-fed males also displayed elevated circulating cholesterol and cholesterol esters without corresponding increases in hepatic total cholesterol. When compared to the HFD, the WV-OD did not increase uric acid or xanthine oxidoreductase (XOR) content of liver or circulation; however, both males and females on the WV-OD demonstrated trends towards elevated plasma uric acid. Interestingly, while exhibiting a similar caloric intake on either diet, the WV-OD females did not demonstrate significant fat accretion or metabolic dysfunction compared to females subjected to the 60% HFD. In toto, these findings: 1) establish the WV-OD as a regionally-grounded, yet broadly representative tool for modeling diet-induced obesity and metabolic dysfunction, 2) offer a physiologically relevant alternative to extreme-fat dietary models in preclinical research and 3) highlight sex-based differences in response to diet-induced obesity.

physiology↗

bioRxiv2024

Regulation of the Promoter for Capsular Polysaccharide Synthesis in Neisseria Meningitidis Serogroup B by HTH_XRE Family Transcription Factor

The capsular polysaccharide synthesis (cps) locus of Neisseria meningitidis is implicated in invasive meningococcal disease. The synthesis (synABCD) and transport (ctrABCD) operons are transcribed in opposite directions from a common intergenic region and expression is negatively regulated by the bacterial two-component system misR/misS and thermosensitive RNA folding. However, these mechanisms do not fully explain the stationary phase responses and the cis-acting elements remain to be fully characterized. Using GFP reporter gene and site-directed mutagenesis, cis-regulatory elements in the 134-bp intergenic region, NmIR, were investigated. While confirming a known RpoD promoter, an additional potential promoter element and putative binding sites for the transcription factors fis and lexA were identified through sequence analysis. Deletion of the putative LexA binding site led to an increase in GFP fluorescence. The N. meningitidis genome carries only one lexA homolog, the Helix-Turn-Helix regulator XRE family member (GenBank-NMB0910, HTH_XRE). Trans-complementation of the NmIR-GFP reporter with the N. meningitidis HTH_XRE expression plasmid led to increased fluorescence. Trans-complementation with either misR/misS or nusG decreased reporter gene expression. Consistent with previous reports, deletion of the RpoD promoter reduced expression by 50%, suggesting a redundancy of promoter elements in the intergenic region. Thus, the results confirm the functioning of an exogenous N. meningitidis CPS synthesis promoter in E. coli and demonstrate its regulation through trans-complementation by misR/misS, HTH_XRE, and nusG. ImportancePathogenic Neisseria meningitidis, a causal agent of bacterial meningitis, secretes capsular polysaccharides of different compositions that differentiate the serogroups. Since the capsule is an important virulence factor that determines adhesion to epithelia and ability to invade tissues, there is need to understand the underlying mechanisms for its expression. Furthermore, bacterial polysaccharides are potential sources of novel biomaterials. The expression of the capsule production genes is regulated, and this study reveals a mechanism involving a transcription factor, HTH_XRE, whose function in Neisseria meningitidis is not known. It extends the understanding of capsular expression regulation by identifying other control elements in the promoter region. The results will have applications in optimizing biomaterial production or in developing therapeutic interventions.

molecular biology↗

bioRxiv2023

MMORF - FSL's MultiMOdal Registration Framework

We present MMORF--FSLs MultiMOdal Registration Framework--a newly released nonlinear image registration tool designed primarily for application to MRI images of the brain. MMORF is capable of simultaneously optimising both displacement and rotational transformations within a single registration framework by leveraging rich information from multiple scalar and tensor modalities. The regularisation employed in MMORF promotes local rigidity in the deformation, and we have previously demonstrated how this effectively controls both shape and size distortion, and leads to more biologically plausible warps. The performance of MMORF is benchmarked against three established nonlinear registration methods--FNIRT, ANTs and DR-TAMAS--across four domains: FreeSurfer label overlap, DTI similarity, task-fMRI cluster mass, and distortion. Results show that MMORF performs as well as or better than all other methods across every domain--both in terms of accuracy and levels of distortion. MMORF is available as part of FSL, and its inputs and outputs are fully compatible with existing workflows. We believe that MMORF will be a valuable tool for the neuroimaging community, regardless of the domain of any downstream analysis, providing state-of-the-art registration performance that integrates into the rich and widely adopted suite of analysis tools in FSL.

neuroscience↗

bioRxiv2020

Integrating large-scale neuroimaging research datasets: harmonisation of white matter hyperintensity measurements across Whitehall and UK Biobank datasets

Large scale neuroimaging datasets present the possibility of providing normative distributions for a wide variety of neuroimaging markers, which would vastly improve the clinical utility of these measures. However, a major challenge is our current poor ability to integrate measures across different large-scale datasets, due to inconsistencies in imaging and non-imaging measures across the different protocols and populations. Here we explore the harmonisation of white matter hyperintensity (WMH) measures across two major studies of healthy elderly populations, the Whitehall II imaging sub-study and the UK Biobank. We identify pre-processing strategies that maximise the consistency across datasets and utilise multivariate regression to characterise sample differences contributing to study-level differences in WMH variations. We also present a parser to harmonise WMH-relevant non-imaging variables across the two datasets. We show that we can provide highly calibrated WMH measures from these datasets with: (1) the inclusion of a number of specific standardised processing steps; and (2) appropriate modelling of sample differences through the alignment of demographic, cognitive and physiological variables. These results open up a wide range of applications for the study of WMHs and other neuroimaging markers across extensive databases of clinical data. HIGHLIGHTSO_LIWe harmonised measures of WMHs across two studies on healthy ageing C_LIO_LISpecific pre-processing strategies can increase comparability across studies C_LIO_LIModelling of biological differences is crucial to provide calibrated measures C_LI

neuroscience↗

bioRxiv2020

Confound modelling in UK Biobank brain imaging

Dealing with confounds is an essential step in large cohort studies to address problems such as unexplained variance and spurious correlations. UK Biobank is a powerful resource for studying associations between imaging and nonimaging measures such as lifestyle factors and health outcomes, in part because of the large subject numbers. However, the resulting high statistical power also raises the sensitivity to confound effects, which therefore have to be carefully considered. In this work we describe a set of possible confounds (including non-linear effects and interactions) that researchers may wish to consider for their studies using such data. We include descriptions of how we can estimate the confounds, and study the extent to which each of these confounds affects the data, and the spurious correlations that may arise if they are not controlled. Finally, we discuss several issues that future studies should consider when dealing with confounds.

neuroscience↗

bioRxiv2019

Brain aging comprises multiple modes of structural and functional change with distinct genetic and biophysical associations

Brain imaging can be used to study how individuals brains are aging, compared against population norms. This can inform on aspects of brain health; for example, smoking and blood pressure can be seen to accelerate brain aging. Typically, a single "brain age" is estimated per subject, whereas here we we identified 62 modes of subject variability, from 21,407 subjects multimodal brain imaging data in UK Biobank. The modes represent different aspects of brain aging, showing distinct patterns of functional and structural brain change, and distinct patterns of association with genetics, lifestyle, cognition, physical measures and disease. While conventional brain-age modelling found no genetic associations, 34 modes had genetic associations. We suggest that it is important not to treat brain aging as a single homogeneous process, and that modelling of distinct patterns of structural and functional change will reveal more biologically meaningful markers of brain aging in health and disease.

neuroscience↗

bioRxiv2019

Genome-wide association analyses identify variants in IRF4 associated with Acute Myeloid Leukemia and Myelodysplastic Syndrome susceptibility

The role of common genetic variation in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts (2309 cases and 2814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). ASSET identified an increased risk for de novo AML and MDS (OR=1.38, 95% CI, 1.26-1.51, Pmeta=2.8x10-12) in patients carrying the T allele at rs12203592 in Interferon Regulatory Factor 4 (IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Our TWAS analyses showed increased IRF4 gene expression is associated with increased risk of de novo AML and MDS (OR=3.90, 95% CI, 2.36-6.44, Pmeta =1.0x10-7). The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.

genomics↗