Biology subjects

McNamara, M.

Publications and source records attributed to McNamara, M..

8 recordsLinked to original sources

bioRxiv2026

stably: error-controlled stability selection for biomarker panel discovery

Motivation Data-independent acquisition mass spectrometry (DIA-MS) has become increasingly popular for clinical proteomics due to its sensitivity and reproducibility. Univariate statistical analysis tools, such as limma and MSstats, are widely used for identifying differentially abundant proteins but cannot capture multivariate relationships between proteins that may provide greater discriminatory power as a panel. Machine learning approaches can address this gap, but typically prioritise predictive performance over feature stability, producing biomarker panels for downstream validation that vary depending on data splitting and are poorly suited to clinical translation. Results We developed stably, a Python package that implements stability selection with formal false positive control for DIA proteomics data. Using synthetic data with known ground-truth biomarkers, we show that the Shah and Samworth complementary pairs stability selection framework recovers more true synthetic biomarkers than the Meinshausen and Buhlmann framework at moderate effect sizes typical of proteomics (d = 0.5 - 2.0), while both maintain false positive rates well below their theoretical guarantees. Applied to a publicly available serum proteomics dataset from patients with all stages of pancreatic ductal adenocarcinoma (n=176), stably identified a stable 17-protein biomarker panel in the discovery cohort (n=120), which achieved higher predictive power (AUC = 0.93) in the validation cohort (n=56) than the panel selected by Byeon et al. (2024)(AUC 0.82). stably represents a principled, error-controlled method for biomarker panel discovery for translation into second cohorts. Availability and implementation stably is available on GitHub (https://github.com/byrnedaniel5-eng/stably); the version used in this study is archived on PyPI (https://pypi.org/project/stably/).

bioinformatics↗

bioRxiv2025

DNA methylation signatures of frailty beyond age: a longitudinal study of female and male mice

Frailty is an age-related geriatric syndrome with largely unknown mechanisms. We conducted a longitudinal study of aging C57BL/6JNIA mice (females; n = 40, male; n = 49), measured frailty index and derived DNA methylation data from PBMCs. We selected frailty-related differentially methylated CpGs and determined differentially methylated regions (DMRs), focusing on both age-independent and -dependent frailty, and using both mixed-sex and sex-stratified subgroups. We propose a joint set of 925 frailty-related DMRs, perform an association study with frailty outcomes, build epigenetic frailty clocks and validate in mice with interventions. Notably, age-independent frailty DMRs are enriched in nervous and endocrine pathways, distinct from signaling and lipid metabolism pathways identified from age-dependent DMRs. We observe hypermethylation in signaling pathways and hypomethylation in lipid metabolism and cytochrome P450 pathways with frailty progression. 36 DMRs show consistent associations in validation. These findings highlight distinct epigenetic signatures underlying frailty and aging, with potential sex-specific mechanisms.

molecular biology↗

bioRxiv2024

Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD+ can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD+ precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD+ metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD+ boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.

pharmacology and toxicology↗

bioRxiv2022

Single molecule methylation profiles of cell-free DNA in cancer with nanopore sequencing

Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for characterizing diseases. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to hundreds of millions of reads per cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore methods. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.

genomics↗

bioRxiv2022

A phenotypic screen of Marfan syndrome iPSC-derived vascular smooth muscle cells uncovers GSK3β as a new target

Marfan syndrome (MFS) is a rare connective tissue disorder caused by mutations in FBN1. Patients with MFS notably suffer from aortic aneurysm and dissection. Despite considerable effort, animal models have proven to be poorly predictive for therapeutic intervention in human aortic disease. Using a "humanised" model system may be more appropriate in identifying new therapeutic targets. Patient-derived induced pluripotent stem cells can be differentiated into vascular smooth muscle cells (VSMCs) and recapitulate major features of MFS. We have screened 1,022 small molecules in our in vitro model, exploiting the highly-proteolytic nature of MFS-VSMCs, and identified 36 effective compounds. Further analysis identified GSK3{beta} as a recurring target in the compound screen. GSK3{beta} inhibition/knockdown did not ameliorate the proliferation defect in MFS-VSMCs but improved MFS-VSMC apoptosis and proteolysis. To conclude, we have identified GSK3{beta} as a novel target for MFS, forming the foundation for future work in MFS and other aortic diseases.

cell biology↗

bioRxiv2021

An elongated COI fragment to discriminate botryllid species and as an improved ascidian DNA barcode

Botryllids are colonial ascidians widely studied for their potential invasiveness and as model organisms, however the morphological description and discrimination of these species is very problematic, leading to frequent specimen misidentifications. To facilitate species discrimination and detection of cryptic/new species, we developed new barcoding primers for the amplification of a COI fragment of about 860 bp (860-COI), which is an extension of the common Folmers barcode region. Our 860-COI was successfully amplified in 177 worldwide-sampled botryllid colonies. Combined with morphological analyses, 860-COI allowed not only discriminating known species, but also identifying undescribed and cryptic species, resurrecting old species currently in synonymy, and proposing the assignment of clade D of the model organism Botryllus schlosseri to Botryllus renierii. Importantly, within clade A of B. schlosseri, 860-COI recognized at least two candidate species against only one recognized by the Folmers fragment, underlining the need of further genetic investigations on this clade. This result also suggests that the 860-COI could have a greater ability to diagnose cryptic/new species than the Folmers fragment at very short evolutionary distances, such as those observed within clade A. Finally, our new primers simplify the amplification of 860-COI even in non-botryllid ascidians, suggesting their wider usefulness in ascidians.

evolutionary biology↗

bioRxiv2018

The Medical Genome Reference Bank: Whole genomes and phenotype of 2,570 healthy elderly

Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2,570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analysed the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. Individuals in the MGRB had fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK BioBank cohorts, consistent with risk depletion. Pervasive age-related somatic changes were correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing. This research has been conducted using the UK Biobank Resource under Application Number 17984.

genomics↗

bioRxiv2018

The Medical Genome Reference Bank: a whole-genome data resource of 4,000 healthy elderly individuals. Rationale and cohort design

Allele frequency data from human reference populations is of increasing value for filtering and assignment of pathogenicity to genetic variants. Aged and healthy populations are more likely to be selectively depleted of pathogenic alleles, and therefore particularly suitable as a reference populations for the major diseases of clinical and public health importance. However, reference studies of the healthy elderly have remained under-represented in human genetics. We have developed the Medical Genome Reference Bank (MGRB), a large-scale comprehensive whole-genome dataset of confirmed healthy elderly individuals, to provide a publicly accessible resource for health-related research, and for clinical genetics. It also represents a useful resource for studying the genetics of healthy aging. The MGRB comprises 4,000 healthy, older individuals with no reported history of cancer, cardiovascular disease or dementia, recruited from two Australian community-based cohorts. DNA derived from blood samples will be subject to whole genome sequencing. The MGRB will measure genome-wide genetic variation in 4,000 individuals, mostly of European decent, aged 60-95 years (mean age [≥] 75 years). The MGRB has committed to a policy of data sharing, employing a hierarchical data management system to maintain participant privacy and confidentiality, whilst maximizing research and clinical usage of the database. The MGRB will represent a dataset of international significance, broadly accessible to the clinical and genetic research community.

genomics↗