Dealing with dimensionality: the application of machine learning to multi-omics data.

MOTIVATION: Machine learning (ML) methods are motivated by the need to automate information extraction from large datasets in order to support human users in data-driven tasks. This is an attractive approach for integrative joint analysis of vast amounts of omics data produced in next generation sequencing and other -omics assays. A systematic assessment of the current literature can help to identify key trends and potential gaps in methodology and applications. We surveyed the literature on ML multi-omic data integration and quantitatively explored the goals, techniques and data involved in this field. We were particularly interested in examining how researchers use ML to deal with the volume and complexity of these datasets. RESULTS: Our main finding is that the methods used are those that address the challenges of datasets with few samples and many features. Dimensionality reduction methods are used to reduce the feature count alongside models that can also appropriately handle relatively few samples. Popular techniques include autoencoders, random forests and support vector machines. We also found that the field is heavily influenced by the use of The Cancer Genome Atlas dataset, which is accessible and contains many diverse experiments. AVAILABILITY AND IMPLEMENTATION: All data and processing scripts are available at this GitLab repository: https://gitlab.com/polavieja_lab/ml_multi-omics_review/ or in Zenodo: https://doi.org/10.5281/zenodo.7361807. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The first UK national blepharospasm patient and public involvement day; identifying priorities.

PURPOSE: We describe the planning and outcomes of the first 'Blepharospasm Day' in the UK. Blepharospasm is a distressing condition for patients and carers. Our 'patient and public involvement' event aimed to: cultivate a more informed patient group via active dialogue, help clinicians more effectively prioritise research and to facilitate peer-to-peer support for affected patients and public. DESIGN: A national one-day event was organised by the oculoplastics department at Moorfields Eye Hospital. The event was divided into informative lectures delivered by professionals and a patient panel, during which patients shared their experiences and expectations. METHODS: Data were collected from a variety of sources including: an interactive voting "LiveWall" poster, a pre-event questionnaire; "living with Blepharospasm", transcripts from patient panel discussions; and a feedback questionnaire. RESULTS: The event was well-received with 100% of respondents rating it good or excellent. Four research themes were identified: "aetiology", "alternative treatments", "faster, more accurate diagnosis", and "symptom control". Delegates' self-reported knowledge of blepharospasm increased significantly after the event. Limitations of the BdSI severity-assessment tool were noted with 22% of respondents failing to utilise it appropriately. CONCLUSION: Through our innovative "Blepharospasm Day", patient's priorities for research were identified, delegates understanding of blepharospasm increased and an independent blepharospasm patients-representatives' group was established; a first in the UK. Furthermore, short-fallings identified in the BdSI tool highlight the need for better severity-assessment tools. We demonstrate the benefits of the 'patient and public involvement' approach in the management of complex conditions such as blepharospasm. ABBREVIATIONS: PPI: Patient and public involvement; SLV-PSP: sight loss and vision sector - priority setting partnership; BRC: Biomedical Research Centre; NIHR: National Institute for Health Research; BsDI: Blepharospasm Disability Index.

Case report: Diffuse hyperplastic perilobar nephroblastomatosis complicated by a unilateral Wilms tumour: diagnosis, treatment and follow-up.

BACKGROUND: Nephroblastomatosis is an uncommon pathologic process characterized by the presence of persistent embryonic nephrogenic rests. Progression to Wilms tumour occurs in an estimated 35% of patients. Cure rates are based on histologic findings and disease stage and have improved from 10% in the 1920s to over 90% today. CASE PRESENTATION: We report a case of a 9-month-old female presenting with a 2-month history of abdominal distension. Ultrasonographic and computed tomographic assessments demonstrated features consistent with bilateral, diffuse, hyperplastic perilobar nephroblastomatosis (DHPLNB) for which she underwent chemotherapy. Magnetic resonance imaging 6 weeks following commencement of chemotherapy revealed a mass concerning for unilateral Wilms tumor for which she underwent partial nephrectomy. Pathology confirmed DHPLNB with a unilateral Wilms tumor. CONCLUSION: 3.5 year radiographic follow up demonstrates complete recovery. To our knowledge, there are no similar cases with imaging depiction recently published. With potential for malignant transformation into Wilms tumour and low survival rate for late diagnosed Wilms tumors, it is important to recognize nephroblastomatosis early, both clinically and radiographically to improve overall patient prognosis.

Morel-Lavallee lesion in pediatric trauma.

Morel-Lavallee lesions (MLL) are closed degloving injuries that have been rarely described in the pediatric literature. These internal degloving injuries can have serious complications and long-term morbidity. Early diagnosis and intervention is imperative. We present the case of a 20-month-old with MLL of the thigh.

Pediatric metanephric adenoma: case report and review of the literature.

Metanephric adenomas are rare benign renal neoplasms, uncommonly seen in the pediatric population. They are typically detected incidentally on imaging studies performed for unrelated clinical presentations. Preoperatively, the imaging appearance of this tumor overlaps with the appearance of more common and more aggressive renal neoplasms such as Wilms' tumor or renal cell carcinoma. We present a case of a pathologically proven metanephric adenoma, monitored preoperatively for approximately 5 years, prior to definitive nephrectomy. As the majority of solid renal masses are resected soon after they are detected, to the best of our knowledge, this case is the first to demonstrate the natural in vivo progression of a pathologically proven metanephric adenoma.

Familial Alzheimer's disease presenilin 1 mutation M146V increases gamma secretase cutting of p75NTR in vitro.

The cholinergic neurons of the basal forebrain are amongst the first to degenerate in Alzheimer's disease. These neurons are unique in the brain, expressing the tyrosine kinase receptor TrkA, together with the common neurotrophin receptor p75NTR; both of which bind nerve growth factor. Activation of the TrkA receptor is important in the maintenance of cell viability, whereas the p75NTR receptor has been implicated in apoptosis. Mutations in the gene for presenilin 1, a multi-transmembrane aspartyl protease, are known to cause familial Alzheimer's disease. This is thought to be due to their effect on gamma-secretase-dependent processing of amyloid precursor protein and subsequent formation of amyloid. Since p75NTR was recently shown to undergo gamma-secretase regulated intramembrane proteolysis, this study examines the effect of familial Alzheimer mutations on processing of p75NTR. PC12 cells were stably transfected with familial mutations M146V, A246E and deltaE9 and wild-type presenilin 1 and were examined here for gamma-secretase-dependent proteolysis of p75NTR. Overexpression of wild-type presenilin 1 did not increase gamma-secretase-mediated cleavage of p75NTR. However, by contrast, the presence of the M146V mutation was shown to significantly increase cleavage of p75NTR compared with the other mutations. Survival of cholinergic neurons will depend on the balance between the receptors TrkA and p75NTR, and their respective signalling pathways. Thus alterations in p75NTR proteolysis may influence this equilibrium. The novel finding that a mutation may increase processing of p75NTR may have implications for the pathogenic outcome in Alzheimer's disease.

Pulmonary distribution, regulation, and functional role of Trk receptors in a murine model of asthma.

BACKGROUND: Neurotrophins have been implicated in the pathogenesis of asthma because of their ability to promote hyperreactivity of sensory neurons and to induce airway inflammation. Hyperreactivity of sensory nerves is one key mechanism of airway hyperreactivity that is defined as an abnormal reactivity of the airways to unspecific stimuli, such as cold air and cigarette smoke. Neurotrophins use a dual-receptor system consisting of Trk receptor tyrosine kinases and the structurally unrelated p75 neurotrophin receptor. OBJECTIVE: The aim of this study was to characterize the distribution, allergen-dependent regulation, and functional relevance of the Trk receptors in allergic asthma. METHODS: BALB/c mice were sensitized to ovalbumin. After provocation with ovalbumin or vehicle aerosol, respectively, Trk receptor expression was analyzed in lung tissue by means of fluorescence microscopy and quantitative RT-PCR. To assess the functional relevance of Trk receptors in asthma, we tested the effects of the intranasally administered pan-Trk receptor decoy REN1826. Allergic airway inflammation was quantified and lung function was measured by using head-out body plethysmography. RESULTS: Trk receptors were expressed in neurons, airway smooth muscle cells, and cells of the inflammatory infiltrate surrounding the bronchi and upregulated after allergen challenge. Local application of REN1826 reduced IL-4 and IL-5 cytokine levels but had no effect on IL-13 levels or the cellular composition of bronchoalveolar lavage fluid cells. Furthermore, REN1826 decreased broncho-obstruction in response to sensory stimuli, indicating a diminished hyperreactivity of sensory nerves, but did not influence airway smooth muscle hyperreactivity in response to methacholine. CONCLUSION: These results emphasize the important role of Trk receptor signaling in the development of asthma. CLINICAL IMPLICATIONS: Our data indicate that blocking of Trk receptor signaling might reduce asthma symptoms.

Measurement of pre- and post-synaptic proteins in cerebral cortex: effects of post-mortem delay.

Assessments of synaptic density in human brain are often based on measurements of synaptic proteins. Little information is available on their post-mortem stability. We have investigated this by ELISAs of the pre-synaptic proteins syntaxin and synaptophysin, and the post-synaptic protein PSD-95, in rat and human cortex. The rat brains were cooled in situ from 37 to 20 or 4 degrees C over 3 h, and then kept at 20 or 4 degrees C for a further 24-72 h, to simulate post-mortem storage at room temperature or in a mortuary refrigerator. Synaptophysin and PSD-95 levels in rat cerebral cortex were not significantly decreased after 72 h of incubation at 20 degrees C. Syntaxin was stable for 24 h but decreased by 39-44% at 48-72 h. Storage at 4 degrees C resulted in a similar reduction of syntaxin levels over 72 h. In human brain tissue from 160 people aged 24-102 years, post-mortem delay had little effect on synaptic protein levels in superior temporal cortex, but was associated with a decline in PSD-95 and syntaxin in mid-frontal cortex after 24 h. The more robust stability of synaptophysin may be related to its multi-transmembrane structure.