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Palmer, L. J.

Publications and source records attributed to Palmer, L. J..

3 recordsLinked to original sources

Deep-diffeomorphic networks for conditional brain templates

Deformable brain templates are an important tool in many neuroimaging analyses. Conditional templates (e.g., age-specific templates) have advantages over single population templates by enabling improved registration accuracy and capturing common processes in brain development and degeneration. Conventional methods require large, evenly-spread cohorts to develop conditional templates, limiting their ability to create templates that could reflect richer combinations of clinical and demographic variables. More recent deep-learning methods, which can infer relationships in very high dimensional spaces, open up the possibility of producing conditional templates that are jointly optimised for these richer sets of conditioning parameters. We have built on recent deep-learning template generation approaches using a diffeomorphic (topology-preserving) framework to create a purely geometric method of conditional template construction that learns diffeomorphisms between: (i) a global or group template and conditional templates, and (ii) conditional templates and individual brain scans. We evaluated our method, as well as other recent deep-learning approaches, on a dataset of cognitively normal (CN) participants from the Alzheimers Disease Neuroimaging Initiative (ADNI), using age as the conditioning parameter of interest. We assessed the effectiveness of these networks at capturing age-dependent anatomical differences. Our results demonstrate that while the assessed deep-learning methods have a number of strengths, they require further refinement to capture morphological changes in ageing brains with an acceptable degree of accuracy. The volumetric output of our method, and other recent deep-learning approaches, across four brain structures (grey matter, white matter, the lateral ventricles and the hippocampus), was measured and showed that although each of the methods captured some changes well, each method was unable to accurately track changes in all of the volumes. However, as our method is purely geometric it was able to produce T1-weighted conditional templates with high spatial fidelity and with consistent topology as age varies, making these conditional templates advantageous for spatial registrations. The use of diffeomorphisms in these deep-learning methods represents an important strength of these approaches, as they can produce conditional templates that can be explicitly linked, geometrically, across age as well as to fixed, unconditional templates or brain atlases. The use of deep-learning in conditional template generation provides a framework for creating templates for more complex sets of conditioning parameters, such as pathologies and demographic variables, in order to facilitate a broader application of conditional brain templates in neuroimaging studies. This can aid researchers and clinicians in their understanding of how brain structure changes over time, and under various interventions, with the ultimate goal of improving the calibration of treatments and interventions in personalised medicine. The code to implement our conditional brain template network is available at: github.com/lwhitbread/deep-diff.

neuroscience↗

Leveraging pleiotropy to discover and interpret GWAS results for sleep-associated traits

Genetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations in underpowered validation cohorts and leads to higher interpretability. Here, as an exemplar, we use Obstructive Sleep Apnea (OSA), a common disorder diagnosed using overnight multi-channel physiological testing. We leverage pleiotropy with relevant cellular and cardio-metabolic phenotypes and gene expression traits to map new risk loci in an underpowered OSA GWAS. We identify several pleiotropic loci harboring suggestive associations to OSA and genome-wide significant associations to other traits, and show that their OSA association replicates in independent cohorts of diverse ancestries. By investigating pleiotropic loci, our strategy allows proposing new hypotheses about OSA pathobiology across many physiological layers. For example, we identify and replicate the pleiotropy across the plateletcrit, OSA and an eQTL of DNA primase subunit 1 (PRIM1) in immune cells. We find suggestive links between OSA, a measure of lung function (FEV1/FVC), and an eQTL of matrix metallopeptidase 15 (MMP15) in lung tissue. We also link a previously known genome-wide significant peak for OSA in the hexokinase 1 (HK1) locus to hematocrit and other red blood cell related traits. Thus, the analysis of pleiotropic associations has the potential to assemble diverse phenotypes into a chain of mechanistic hypotheses that provide insight into the pathogenesis of complex human diseases. Author SummaryLarge genetic studies with hundreds of thousands of patients have been successful at finding genetic variants that associate with disease traits in humans. However, smaller-scale studies can often have inadequate power to discover new genetic associations. Here, we use a small genetic study of Obstructive Sleep Apnea (OSA), to introduce a strategy that both helps find genetic associations and proposes biological hypotheses for the mechanisms behind those associations. To achieve this, we use large genetic studies carried out on traits that are related to OSA, and look for genetic variants that affect both OSA in our small study and the trait in question in the large study. By linking two or more traits at select loci, we were able to, among other results, find a locus that affects the expression of a gene in immune cells (DNA primase subunit 1), a marker of thrombotic and inflammatory processes (plateletcrit) and OSA. This results in a novel genetic association to OSA and a corresponding biological hypothesis behind its effect on OSA.

genetics↗

Whole-Genome Association Analyses of Sleep-disordered Breathing Phenotypes in the NHLBI TOPMed Program

Sleep-disordered breathing (SDB) is a common disorder associated with significant morbidity. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program we report the first whole-genome sequence analysis of SDB. We identified 4 rare gene-based associations with SDB traits in 7,988 individuals of diverse ancestry and 4 replicated common variant associations with inclusion of additional samples (n=13,257). We identified a multi-ethnic set-based rare-variant association (p = 3.48 x 10-8) on chromosome X with ARMCX3. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Results highlighted associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis and HIF1A-mediated hypoxic response.

genetics↗