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The phenotyping group develops imaging techniques to investigate the anatomical, structural and functional contributions of genes to human diseases and development using genetically modified mice. These techniques are becoming increasingly crucial due to a worldwide initiative to knock out every gene in the mouse genome, which will result in an estimated 21,000 mutant mice that will be available by 2012.
The inherent non-invasive and three-dimensional nature of magnetic resonance imaging (MRI) makes it an ideal platform for phenotyping studies in the adult and embryo mouse. Our goal is to establish a phenotyping process that enables high-throughput screening and automated analysis of genetically modified mice using high-resolution MR images.
We have developed an optimised preparation and scanning protocol for MR imaging of the mouse embryo at an isotropic resolution of ~18µm. This has enabled us to identify cardiac and neurological phenotypic characteristics in Chd7 and Hesx1 mutant mouse embryos (references 1 and 2 in Related Publications).
We are able to scan up to 40 embryos (≥ 15.5 days post coitum) in a single scan, resulting in an MR data set that allows the entire cohort to be visualised on a slice-by-slice basis.
Methods of analysis
The following work has been carried out as a joint collaboration between the UCL Centre for Advanced Biomedical Imaging and the UCL Centre for Medical Image Computing (CMIC) and provides examples of the type of analysis that can be performed on genetically modified embryo and adult mice.
- Atlas generation: MR atlases are the cornerstone of advanced computational techniques. These may be generated by combining individual MR images using registration techniques, to provide enhanced signal-to-noise ratio and visualisation of anatomical detail. We have developed an embryo atlas using MR images to enable automatic, high-throughput methods, which is freely available upon request.
- Tensor-based morphometry: Tensor-based morphometry is a fully automated technique that enables unbiased and unsupervised detection of local, volumetric differences in a population on a voxel-wise basis, which are not visible to the human eye.
- Segmentation propagation: Segmentation propagation is a semi-automated technique that enables rapid acquisition of volumetric data in a population. This technique calculates a variety of volumes, including the heart, whole brain, olfactory bulb, pituitary gland and mesencephalic vesicle.
These segmented volumes may be propagated to any embryo MR dataset that has been registered to our embryo atlas, automatically generating volumetric data. If you are interested in applying segmentation propagation in this way, please contact Francesca Norris with your name and institution and we will provide you with the embryo atlas and segmented volumes in NIfTY format. If this data is used in a publication, we request that the following citation is referenced and that acknowledgements are provided to Jon O. Cleary, Francesca C. Norris and Mark F. Lythgoe at the UCL Centre for Advanced Biomedical Imaging, and Marc Modat and Sebastien Ourselin at the UCL Centre for Medical Image Computing.
Cleary JO, Modat M, Norris FC, Price AN, Jayakody SA, Martinez-Barbera JP, Greene ND, Hawkes DJ, Ordidge RJ, Scambler PJ, Ourselin S, Lythgoe MF. Magnetic resonance virtual histology for embryos: 3D atlases for automated high-throughput phenotyping. Neuroimage 2010. EPub ahead of print.PDF
- Cleary JO, Price AN, Thomas DL, Scambler PJ, Kyriakopoulou V, McCue K, Schneider JE, Ordidge RJ, Lythgoe MF. Cardiac phenotyping in ex vivo murine embryos using µMRI. NMR Biomed 2009; 22: 857-866.PDF
- Modat M, Ridgway GR, Taylor ZA, Lehmann M, Barnes J, Hawkes DJ, Fox NC, Ourselin S. Fast free-form deformation using graphics processing units. Comput Methods Programs Biomed 2010; 98:278-84.
- Thayyil S, Cleary JO, Sebire NJ, Scott RJ, Chong K, Gunny R, Owens CM, Olsen OE, Offiah AC, Parks HG, Chitty LS, Price AN, Yousry TA, Robertson NJ, Lythgoe MF, Taylor AM. Post-mortem examination of human fetuses: a comparison of whole-body high-field MRI at 9·4 T with conventional MRI and invasive autopsy. Lancet. 2009; 374: 467–475.PDF
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