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Hesterman, J.

Publications and source records attributed to Hesterman, J..

2 recordsLinked to original sources

Application of Aligned-UMAP to longitudinal biomedical studies

Longitudinal multi-dimensional biological datasets are ubiquitous and highly abundant. These datasets are essential to understanding disease progression, identifying subtypes, and drug discovery. Discovering meaningful patterns or disease pathophysiologies in these datasets is challenging due to their high dimensionality, making it difficult to visualize hidden patterns. Several methods have been developed for dimensionality reduction, but they are limited to cross-sectional datasets. Recently proposed Aligned-UMAP, an extension of the UMAP algorithm, can visualize high-dimensional longitudinal datasets. In this work, we applied Aligned-UMAP on a broad spectrum of clinical, imaging, proteomics, and single-cell datasets. Aligned-UMAP reveals time-dependent hidden patterns when color-coded with the metadata. We found that the algorithm parameters also play a crucial role and must be tuned carefully to utilize the algorithms potential fully. Altogether, based on its ease of use and our evaluation of its performance on different modalities, we anticipate that Aligned-UMAP will be a valuable tool for the biomedical community. We also believe our benchmarking study becomes more important as more and more high-dimensional longitudinal data in biomedical research becomes available. Highlights- explored the utility of Aligned-UMAP in longitudinal biomedical datasets - offer insights on optimal uses for the technique - provide recommendations for best practices In BriefHigh-dimensional longitudinal data is prevalent yet understudied in biological literature. High-dimensional data analysis starts with projecting the data to low dimensions to visualize and understand the underlying data structure. Though few methods are available for visualizing high dimensional longitudinal data, they are not studied extensively in real-world biological datasets. A recently developed nonlinear dimensionality reduction technique, Aligned-UMAP, analyzes sequential data. Here, we give an overview of applications of Aligned-UMAP on various biomedical datasets. We further provide recommendations for best practices and offer insights on optimal uses for the technique.

bioinformatics↗

Convective forces increase rostral delivery of intrathecal antisense oligonucleotides in the cynomolgus monkey nervous system

BackgroundThe intrathecal (IT) dosing route introduces drugs directly into the CSF to bypass the blood-brain barrier and gain direct access to the CNS. We evaluated the use of convective forces acting on the cerebrospinal fluid as a means for increasing rostral delivery of IT dosed radioactive tracer molecules and antisense oligonucleotides (ASO) in the monkey CNS. We also measured the cerebral spinal fluid (CSF) volume in a group of cynomolgus monkeys. MethodsThere are three studies presented, in each of which cynomolgus monkeys were injected into the IT space with radioactive tracer molecules and/or ASO by lumbar puncture in either a low or high volume. The first study used the radioactive tracer 64Cu-DOTA and PET imaging to evaluate the effect of the convective forces. The second study combined the injection of the radioactive tracer 99mTc-DTPA and ASO, then used SPECT imaging and ex vivo tissue analysis of the effects of convective forces to bridge between the tracer and the ASO distributions. The third experiment evaluated the effects of different injection volumes on the distribution of an ASO. In the course of performing these studies we also measured the CSF volume in the subject monkeys by Magnetic Resonance Imaging. ResultsIt was consistently found that larger bolus dose volumes produced greater rostral distribution along the neuraxis. Thoracic percussive treatment also increased rostral distribution of low volume injections. There was little added benefit on distribution by combining the thoracic percussive treatment with the high-volume injection. The CSF volume of the monkeys was found to be 11.9 {+/-} 1.6 cm3. ConclusionsThese results indicate that increasing convective forces after IT injection increases distribution of molecules up the neuraxis. In particular, the use of high IT injection volumes will be useful to increase rostral CNS distribution of therapeutic ASOs for CNS diseases in the clinic.

neuroscience↗