Developing an automated skeletal phenotyping pipeline to leverage biobank-level medical imaging databases.

OBJECTIVES: Collecting skeletal measurements from medical imaging databases remains a tedious task, limiting the research utility of biobank-level data. Here we present an automated phenotyping pipeline for obtaining skeletal measurements from DXA scans and compare its performance to manually collected measurements. MATERIALS AND METHODS: A pipeline that extends the Advanced Normalization Tools (ANTs) framework was developed on 341 whole-body DXA scans of UK Biobank South Asian participants. A set of 10 measurements throughout the skeleton was automatically obtained via this process, and the performance of the method was tested on 20 additional DXA images by calculating percent error and concordance correlation coefficients (CCC) for manual and automated measurements. Stature was then regressed on the automated femoral and tibia lengths and compared to published stature regressions to further assess the reliability of the automated measurements. RESULTS: Based on percent error and CCC, the performance of the automated measurements falls into three categories: poor (sacral and acetabular breadths), variable (trunk length, upper thoracic breadth, and innominate height), and high (maximum pelvic aperture breadth, bi-iliac breadth, femoral maximum length, and tibia length). Stature regression plots indicate that the automated measurements reflect realistic body proportions and appear consistent with published data reflecting these relationships in South Asian populations. DISCUSSION: Based on the performance of this pipeline, a subset of measurements can be reliably extracted from DXA scans, greatly expanding the utility of biobank-level data for biological anthropologists and medical researchers.

Evaluation of a new method of fossil retrodeformation by algorithmic symmetrization: crania of papionins (Primates, Cercopithecidae) as a test case.

Diagenetic distortion can be a major obstacle to collecting quantitative shape data on paleontological specimens, especially for three-dimensional geometric morphometric analysis. Here we utilize the recently-published algorithmic symmetrization method of fossil reconstruction and compare it to the more traditional reflection & averaging approach. In order to have an objective test of this method, five casts of a female cranium of Papio hamadryas kindae were manually deformed while the plaster hardened. These were subsequently "retrodeformed" using both algorithmic symmetrization and reflection & averaging and then compared to the original, undeformed specimen. We found that in all cases, algorithmic retrodeformation improved the shape of the deformed cranium and in four out of five cases, the algorithmically symmetrized crania were more similar in shape to the original crania than the reflected & averaged reconstructions. In three out of five cases, the difference between the algorithmically symmetrized crania and the original cranium could be contained within the magnitude of variation among individuals in a single subspecies of Papio. Instances of asymmetric distortion, such as breakage on one side, or bending in the axis of symmetry, were well handled, whereas symmetrical distortion remained uncorrected. This technique was further tested on a naturally deformed and fossilized cranium of Paradolichopithecus arvernensis. Results, based on a principal components analysis and Procrustes distances, showed that the algorithmically symmetrized Paradolichopithecus cranium was more similar to other, less-deformed crania from the same species than was the original. These results illustrate the efficacy of this method of retrodeformation by algorithmic symmetrization for the correction of asymmetrical distortion in fossils. Symmetrical distortion remains a problem for all currently developed methods of retrodeformation.

Globally optimal cortical surface matching with exact landmark correspondence.

We present a method for establishing correspondences between human cortical surfaces that exactly matches the positions of given point landmarks, while attaining the global minimum of an objective function that quantifies how far the mapping deviates from conformality. On each surface, a conformal transformation is applied to the Euclidean distance metric, resulting in a hyperbolic metric with isolated cone point singularities at the landmarks. Equivalently, each surface is mapped to a hyperbolic orbifold: a pillow-like surface with each point landmark corresponding to a pillow corner. An initial surface-to-surface mapping exactly aligns the landmarks, and gradient descent is used to find the single, global minimum of the Dirichlet energy of the remainder of the mapping. Using a population of real MRI-based cortical surfaces with manually labeled sulcus endpoints as landmarks, we evaluate the approach by how much it distorts surfaces and by its biological plausibility: how well it aligns previously-unseen anatomical landmarks and by how well it promotes expected associations between cortical thickness and age. We show that, compared to a painstakingly-tuned approach that balances a tradeoff between minimizing landmark mismatch and Dirichlet energy, our method has similar biological plausibility, superior surface distortion, a better theoretical foundation, and fewer arbitrary parameters to tune. We also compare to conformal mapper in the spherical domain to show that sacrificing exact conformality of the mapping does not cause noticeable reductions in biological plausibility.

Surface-histogram: a new shape descriptor for protein-protein docking.

Determining the structure of protein-protein complexes remains a difficult and lengthy process, either by NMR or by X-ray crystallography. Several computational methods based on docking have been developed to support and even serve as possible alternatives to these experimental methods. In this article, we introduce a new protein-protein docking algorithm, shDock, based on shape complementarity. We characterize the local geometry on each protein surface with a new shape descriptor, the surface-histogram. We measure the complementarity between two surface-histograms, one on each protein, using a modified Manhattan distance. When a match is found between two local protein surfaces, a model is generated for the protein complex, which is then scored by checking for collision between the two proteins. We have tested our algorithm on Version 3 of the ZDOCK protein-protein docking benchmark. We found that for 110 out of the 124 test cases of bound docking in the benchmark, our algorithm was able to generate a model in the top 3600 candidates for the protein complex within an root-mean-square deviation of 2.5 Å from its native structure. For unbound docking predictions, we found a model within 2.5 Å in the top 3600 models in 54 out of 124 test cases. A comparison with other shape-based docking algorithms demonstrates that our approach gives significantly improved performance for both bound and unbound docking test cases.

Sampling the conformation of protein surface residues for flexible protein docking.

BACKGROUND: The problem of determining the physical conformation of a protein dimer, given the structures of the two interacting proteins in their unbound state, is a difficult one. The location of the docking interface is determined largely by geometric complementarity, but finding complementary geometry is complicated by the flexibility of the backbone and side-chains of both proteins. We seek to generate candidates for docking that approximate the bound state well, even in cases where there is backbone and/or side-chain difference from unbound to bound states. RESULTS: We divide the surfaces of each protein into local patches and describe the effect of side-chain flexibility on each patch by sampling the space of conformations of its side-chains. Likely positions of individual side-chains are given by a rotamer library; this library is used to derive a sample of possible mutual conformations within the patch. We enforce broad coverage of torsion space. We control the size of the sample by using energy criteria to eliminate unlikely configurations, and by clustering similar configurations, resulting in 50 candidates for a patch, a manageable number for docking. CONCLUSIONS: Using a database of protein dimers for which the bound and unbound structures of the monomers are known, we show that from the unbound patch we are able to generate candidates for docking that approximate the bound structure. In patches where backbone change is small (within 1 Å RMSD of bound), we are able to account for flexibility and generate candidates that are good approximations of the bound state (82% are within 1 Å and 98% are within 1.4 Å RMSD of the bound conformation). We also find that even in cases of moderate backbone flexibility our candidates are able to capture some of the overall shape change. Overall, in 650 of 700 test patches we produce a candidate that is either within 1 Å RMSD of the bound conformation or is closer to the bound state than the unbound is.

Exploration of shape variation using localized components analysis.

Localized Components Analysis (LoCA) is a new method for describing surface shape variation in an ensemble of objects using a linear subspace of spatially localized shape components. In contrast to earlier methods, LoCA optimizes explicitly for localized components and allows a flexible trade-off between localized and concise representations, and the formulation of locality is flexible enough to incorporate properties such as symmetry. This paper demonstrates that LoCA can provide intuitive presentations of shape differences associated with sex, disease state, and species in a broad range of biomedical specimens, including human brain regions and monkey crania.

Spatially localized hippocampal shape analysis in late-life cognitive decline.

We present a method for generating data-driven, concise, and spatially localized parameterizations of hippocampal (HP) shape, and use the method to analyze HP atrophy in late-life cognitive decline. The method optimizes a set of shape basis vectors (shape components) that strike a balance between spatial locality and compact representation of population shape characteristics. The method can be used for exploratory analysis of localized shape deformations in any population of HP on which point-to-point correspondence mappings have been established via anatomical landmarking or high-dimensional warping. Experiments combine the method with an automated HP to HP mapping method to analyze tracings of 101 elderly subjects with normal cognition, mild cognitive impairment, and Alzheimer's Disease (AD) from an AD Center population. Results suggest that shape components corresponding to atrophy to the CA1 and subiculum HP fields--where early AD pathology is located--correlate strongly with robust measures of the cognitive dysfunction that is typical of early AD. Furthermore, the energy function minimized by the shape component optimization technique is shown to be smooth with few local minima, suggesting that the method may be relatively easy to apply in practice.

Localized measures of callosal atrophy are associated with late-life hypertension: AGES-Reykjavik Study.

Hypertension is highly prevalent in elderly individuals and may be associated with cognitive decline, but the mechanisms by which hypertension may impact brain structure, and thereby modulate the time course of late-life cognitive performance, are not well understood. Therefore we used Localized Components Analysis, a novel computational method, to measure spatially-localized patterns of corpus callosum (CC) atrophy in 28 right-handed female subjects aged 75-79 years in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), a large-scale epidemiological study of aging. Localized callosal atrophy in the posterior midbody and splenium was significantly associated with systolic blood pressure in linear statistical models that controlled for age, while associations between blood pressure and anterior CC atrophy measures were not statistically significant. Additionally, overall measures of global CC atrophy were not significantly associated with blood pressure. The posterior CC may be differentially vulnerable to hypertension-associated atrophy, possibly due to its relatively tenuous vascularization.

Localized components analysis.

We introduce Localized Components Analysis (LoCA) for describing surface shape variation in an ensemble of biomedical objects using a linear subspace of spatially localized shape components. In contrast to earlier methods, LoCA optimizes explicitly for localized components and allows a flexible trade-off between localized and concise representations. Experiments comparing LoCA to a variety of competing shape representation methods on 2D and 3D shape ensembles establish the superior ability of LoCA to modulate the locality-conciseness tradeoff and generate shape components corresponding to intuitive modes of shape variation. Our formulation of locality in terms of compatibility between pairs of surface points is shown to be flexible enough to enable spatially-localized shape descriptions with attractive higher-order properties such as spatial symmetry.

TreeQ-VISTA: an interactive tree visualization tool with functional annotation query capabilities.

UNLABELLED: We describe a general multiplatform exploratory tool called TreeQ-Vista, designed for presenting functional annotations in a phylogenetic context. Traits, such as phenotypic and genomic properties, are interactively queried from a user-provided relational database with a user-friendly interface which provides a set of tools for users with or without SQL knowledge. The query results are projected onto a phylogenetic tree and can be displayed in multiple color groups. A rich set of browsing, grouping and query tools are provided to facilitate trait exploration, comparison and analysis. AVAILABILITY: The program, detailed tutorial and examples are available online (http:/genome.lbl.gov/vista/TreeQVista).

Approximating subtree distances between phylogenies.

We give a 5-approximation algorithm to the rooted Subtree-Prune-and-Regraft (rSPR) distance between two phylogenies, which was recently shown to be NP-complete. This paper presents the first approximation result for this important tree distance. The algorithm follows a standard format for tree distances. The novel ideas are in the analysis. In the analysis, the cost of the algorithm uses a "cascading" scheme that accounts for possible wrong moves. This accounting is missing from previous analysis of tree distance approximation algorithms. Further, we show how all algorithms of this type can be implemented in linear time and give experimental results.