Statistical Inference for Imaging and Disease Core Publications

2015
Wachinger C, Golland P. Sampling from Determinantal Point Processes for Scalable Manifold Learning. Inf Process Med Imaging. 2015;24 :687-98.Abstract
High computational costs of manifold learning prohibit its application for large datasets. A common strategy to overcome this problem is to perform dimensionality reduction on selected landmarks and to successively embed the entire dataset with the Nyström method. The two main challenges that arise are: (i) the landmarks selected in non-Euclidean geometries must result in a low reconstruction error, (ii) the graph constructed from sparsely sampled landmarks must approximate the manifold well. We propose to sample the landmarks from determinantal distributions on non-Euclidean spaces. Since current determinantal sampling algorithms have the same complexity as those for manifold learning, we present an efficient approximation with linear complexity. Further, we recover the local geometry after the sparsification by assigning each landmark a local covariance matrix, estimated from the original point set. The resulting neighborhood selection .based on the Bhattacharyya distance improves the embedding of sparsely sampled manifolds. Our experiments show a significant performance improvement compared to state-of-the-art landmark selection techniques on synthetic and medical data.
Chen GH, Shah D, Golland P. A Latent Source Model for Patch-Based Image Segmentation. Med Image Comput Comput Assist Interv. 2015;9351 :140-8.Abstract

Despite the popularity and empirical success of patch-based nearest-neighbor and weighted majority voting approaches to medical image segmentation, there has been no theoretical development on when, why, and how well these nonparametric methods work. We bridge this gap by providing a theoretical performance guarantee for nearest-neighbor and weighted majority voting segmentation under a new probabilistic model for patch-based image segmentation. Our analysis relies on a new local property for how similar nearby patches are, and fuses existing lines of work on modeling natural imagery patches and theory for nonparametric classification. We use the model to derive a new patch-based segmentation algorithm that iterates between inferring local label patches and merging these local segmentations to produce a globally consistent image segmentation. Many existing patch-based algorithms arise as special cases of the new algorithm.

Langs G, Golland P, Ghosh SS. Predicting Activation Across Individuals with Resting-State Functional Connectivity Based Multi-Atlas Label Fusion. Med Image Comput Comput Assist Interv. 2015;9350 :313-20.Abstract

The alignment of brain imaging data for functional neuroimaging studies is challenging due to the discrepancy between correspondence of morphology, and equivalence of functional role. In this paper we map functional activation areas across individuals by a multi-atlas label fusion algorithm in a functional space. We learn the manifold of resting-state fMRI signals in each individual, and perform manifold alignment in an embedding space. We then transfer activation predictions from a source population to a target subject via multi-atlas label fusion. The cost function is derived from the aligned manifolds, so that the resulting correspondences are derived based on the similarity of intrinsic connectivity architecture. Experiments show that the resulting label fusion predicts activation evoked by various experiment conditions with higher accuracy than relying on morphological alignment. Interestingly, the distribution of this gain is distributed heterogeneously across the cortex, and across tasks. This offers insights into the relationship between intrinsic connectivity, morphology and task activation. Practically, the mechanism can serve as prior, and provides an avenue to infer task-related activation in individuals for whom only resting data is available.

Wachinger C, Toews M, Langs G, Wells III WM, Golland P. Keypoint Transfer Segmentation. Inf Process Med Imaging. 2015;24 :233-45.Abstract

We present an image segmentation method that transfers label maps of entire organs from the training images to the novel image to be segmented. The transfer is based on sparse correspondences between keypoints that represent automatically identified distinctive image locations. Our segmentation algorithm consists of three steps: (i) keypoint matching, (ii) voting-based keypoint labeling, and (iii) keypoint-based probabilistic transfer of organ label maps. We introduce generative models for the inference of keypoint labels and for image segmentation, where keypoint matches are treated as a latent random variable and are marginalized out as part of the algorithm. We report segmentation results for abdominal organs in whole-body CT and in contrast-enhanced CT images. The accuracy of our method compares favorably to common multi-atlas segmentation while offering a speed-up of about three orders of magnitude. Furthermore, keypoint transfer requires no training phase or registration to an atlas. The algorithm's robustness enables the segmentation of scans with highly variable field-of-view.

Menze BH, Jakab A, Bauer S, Kalpathy-Cramer J, Farahani K, et al. The Multimodal Brain Tumor Image Segmentation Benchmark (BRATS). IEEE Trans Med Imaging. 2015;34 (10) :1993-2024.Abstract

In this paper we report the set-up and results of the Multimodal Brain Tumor Image Segmentation Benchmark (BRATS) organized in conjunction with the MICCAI 2012 and 2013 conferences. Twenty state-of-the-art tumor segmentation algorithms were applied to a set of 65 multi-contrast MR scans of low- and high-grade glioma patients-manually annotated by up to four raters-and to 65 comparable scans generated using tumor image simulation software. Quantitative evaluations revealed considerable disagreement between the human raters in segmenting various tumor sub-regions (Dice scores in the range 74%-85%), illustrating the difficulty of this task. We found that different algorithms worked best for different sub-regions (reaching performance comparable to human inter-rater variability), but that no single algorithm ranked in the top for all sub-regions simultaneously. Fusing several good algorithms using a hierarchical majority vote yielded segmentations that consistently ranked above all individual algorithms, indicating remaining opportunities for further methodological improvements. The BRATS image data and manual annotations continue to be publicly available through an online evaluation system as an ongoing benchmarking resource.

Dalca AV, Sridharan R, Sabuncu MR, Golland P. Predictive Modeling of Anatomy with Genetic and Clinical Data. Med Image Comput Comput Assist Interv. 2015;9351 :519-26.Abstract

We present a semi-parametric generative model for predicting anatomy of a patient in subsequent scans following a single baseline image. Such predictive modeling promises to facilitate novel analyses in both voxel-level studies and longitudinal biomarker evaluation. We capture anatomical change through a combination of population-wide regression and a non-parametric model of the subject's health based on individual genetic and clinical indicators. In contrast to classical correlation and longitudinal analysis, we focus on predicting new observations from a single subject observation. We demonstrate prediction of follow-up anatomical scans in the ADNI cohort, and illustrate a novel analysis approach that compares a patient's scans to the predicted subject-specific healthy anatomical trajectory.

2014
Sridharan R, Dalca AV, Golland P. An Interactive Visualization Tool for Nipype Medical Image Computing Pipelines. Int Conf Med Image Comput Comput Assist Interv. Workshop on Interactive Medical Image Computing. 2014;17.
Dalca AV, Sridharan R, Rost NS, Golland P. tipiX: Rapid Visualization of Large Image Collections. Int Conf Med Image Comput Comput Assist Interv. Workshop on Interactive Medical Image Computing. 2014;14.
Woolgar A, Golland P, Bode S. Coping With Confounds in Multivoxel Pattern Analysis: What Should We Do About Reaction Time Differences? A Comment On Todd, Nystrom & Cohen 2013. Neuroimage. 2014;98 :506-12.Abstract
Multivoxel pattern analysis (MVPA) is a sensitive and increasingly popular method for examining differences between neural activation patterns that cannot be detected using classical mass-univariate analysis. Recently, Todd et al. ("Confounds in multivariate pattern analysis: Theory and rule representation case study", 2013, NeuroImage 77: 157-165) highlighted a potential problem for these methods: high sensitivity to confounds at the level of individual participants due to the use of directionless summary statistics. Unlike traditional mass-univariate analyses where confounding activation differences in opposite directions tend to approximately average out at group level, group level MVPA results may be driven by any activation differences that can be discriminated in individual participants. In Todd et al.'s empirical data, factoring out differences in reaction time (RT) reduced a classifier's ability to distinguish patterns of activation pertaining to two task rules. This raises two significant questions for the field: to what extent have previous multivoxel discriminations in the literature been driven by RT differences, and by what methods should future studies take RT and other confounds into account? We build on the work of Todd et al. and compare two different approaches to remove the effect of RT in MVPA. We show that in our empirical data, in contrast to that of Todd et al., the effect of RT on rule decoding is negligible, and results were not affected by the specific details of RT modelling. We discuss the meaning of and sensitivity for confounds in traditional and multivoxel approaches to fMRI analysis. We observe that the increased sensitivity of MVPA comes at a price of reduced specificity, meaning that these methods in particular call for careful consideration of what differs between our conditions of interest. We conclude that the additional complexity of the experimental design, analysis and interpretation needed for MVPA is still not a reason to favour a less sensitive approach.
Langs G, Sweet A, Lashkari D, Tie Y, Rigolo L, Golby AJ, Golland P. Decoupling Function and Anatomy in Atlases of Functional Connectivity Patterns: Language Mapping in Tumor Patients. Neuroimage. 2014;103 :462-75.Abstract
In this paper we construct an atlas that summarizes functional connectivity characteristics of a cognitive process from a population of individuals. The atlas encodes functional connectivity structure in a low-dimensional embedding space that is derived from a diffusion process on a graph that represents correlations of fMRI time courses. The functional atlas is decoupled from the anatomical space, and thus can represent functional networks with variable spatial distribution in a population. In practice the atlas is represented by a common prior distribution for the embedded fMRI signals of all subjects. We derive an algorithm for fitting this generative model to the observed data in a population. Our results in a language fMRI study demonstrate that the method identifies coherent and functionally equivalent regions across subjects. The method also successfully maps functional networks from a healthy population used as a training set to individuals whose language networks are affected by tumors.
Dalca AV, Sridharan R, Cloonan L, Fitzpatrick KM, Kanakis A, Furie KL, Rosand J, Wu O, Sabuncu M, Rost NS, et al. Segmentation 0f Cerebrovascular Pathologies in Stroke Patients with Spatial and Shape Priors. Med Image Comput Comput Assist Interv. 2014;17 (Pt 2) :773-80.Abstract
We propose and demonstrate an inference algorithm for the automatic segmentation of cerebrovascular pathologies in clinical MR images of the brain. Identifying and differentiating pathologies is important for understanding the underlying mechanisms and clinical outcomes of cerebral ischemia. Manual delineation of separate pathologies is infeasible in large studies of stroke that include thousands of patients. Unlike normal brain tissues and structures, the location and shape of the lesions vary across patients, presenting serious challenges for prior-driven segmentation. Our generative model captures spatial patterns and intensity properties associated with different cerebrovascular pathologies in stroke patients. We demonstrate the resulting segmentation algorithm on clinical images of a stroke patient cohort.
Batmanghelich KN, Cho M, Jose RS, Golland P. Spherical Topic Models for Imaging Phenotype Discovery in Genetic Studies. Bayesian Graph Models Biomed Imaging. 2014;8677 :107-17.Abstract
In this paper, we use Spherical Topic Models to discover the latent structure of lung disease. This method can be widely employed when a measurement for each subject is provided as a normalized histogram of relevant features. In this paper, the resulting descriptors are used as phenotypes to identify genetic markers associated with the Chronic Obstructive Pulmonary Disease (COPD). Features extracted from images capture the heterogeneity of the disease and therefore promise to improve detection of relevant genetic variants in Genome Wide Association Studies (GWAS). Our generative model is based on normalized histograms of image intensity of each subject and it can be readily extended to other forms of features as long as they are provided as normalized histograms. The resulting algorithm represents the intensity distribution as a combination of meaningful latent factors and mixing co-efficients that can be used for genetic association analysis. This approach is motivated by a clinical hypothesis that COPD symptoms are caused by multiple coexisting disease processes. Our experiments show that the new features enhance the previously detected signal on chromosome 15 with respect to standard respiratory and imaging measurements.
Wachinger C, Golland P. Atlas-based Under-segmentation. Med Image Comput Comput Assist Interv. 2014;17 (Pt 1) :315-22.Abstract

We study the widespread, but rarely discussed, tendency of atlas-based segmentation to under-segment the organs of interest. Commonly used error measures do not distinguish between under- and over-segmentation, contributing to the problem. We explicitly quantify over- and under-segmentation in several typical examples and present a new hypothesis for the cause. We provide evidence that segmenting only one organ of interest and merging all surrounding structures into one label creates bias towards background in the label estimates suggested by the atlas. We propose a generative model that corrects for this effect by learning the background structures from the data. Inference in the model separates the background into distinct structures and consequently improves the segmentation accuracy. Our experiments demonstrate a clear improvement in several applications.

Wachinger C, Golland P, Reuter M. BrainPrint: Identifying Subjects by Their Brain. Med Image Comput Comput Assist Interv. 2014;17 (Pt 3) :41-8.Abstract

Introducing BrainPrint, a compact and discriminative representation of anatomical structures in the brain. BrainPrint captures shape information of an ensemble of cortical and subcortical structures by solving the 2D and 3D Laplace-Beltrami operator on triangular (boundary) and tetrahedral (volumetric) meshes. We derive a robust classifier for this representation that identifies the subject in a new scan, based on a database of brain scans. In an example dataset containing over 3000 MRI scans, we show that BrainPrint captures unique information about the subject's anatomy and permits to correctly classify a scan with an accuracy of over 99.8%. All processing steps for obtaining the compact representation are fully automated making this processing framework particularly attractive for handling large datasets.

Wachinger C, Golland P, Reuter M, Wells III WM. Gaussian Process Interpolation for Uncertainty Estimation in Image Registration. Med Image Comput Comput Assist Interv. 2014;17 (Pt 1) :267-74.Abstract

Intensity-based image registration requires resampling images on a common grid to evaluate the similarity function. The uncertainty of interpolation varies across the image, depending on the location of resampled points relative to the base grid. We propose to perform Bayesian inference with Gaussian processes, where the covariance matrix of the Gaussian process posterior distribution estimates the uncertainty in interpolation. The Gaussian process replaces a single image with a distribution over images that we integrate into a generative model for registration. Marginalization over resampled images leads to a new similarity measure that includes the uncertainty of the interpolation. We demonstrate that our approach increases the registration accuracy and propose an efficient approximation scheme that enables seamless integration with existing registration methods.

2013
Batmanghelich NK, Dalca AV, Sabuncu MR, Polina G, Polina G. Joint Modeling of Imaging and Genetics. Inf Process Med Imaging. 2013;23 :766-77.Abstract
We propose a unified Bayesian framework for detecting genetic variants associated with a disease while exploiting image-based features as an intermediate phenotype. Traditionally, imaging genetics methods comprise two separate steps. First, image features are selected based on their relevance to the disease phenotype. Second, a set of genetic variants are identified to explain the selected features. In contrast, our method performs these tasks simultaneously to ultimately assign probabilistic measures of relevance to both genetic and imaging markers. We derive an efficient approximate inference algorithm that handles high dimensionality of imaging genetic data. We evaluate the algorithm on synthetic data and show that it outperforms traditional models. We also illustrate the application of the method on ADNI data.
Sridharan R, Dalca AV, Fitzpatrick KM, Cloonan L, Kanakis A, Wu O, Furie KL, Rosand J, Rost NS, Golland P. Quantification and Analysis of Large Multimodal Clinical Image Studies: Application to Stroke. Multimodal Brain Image Anal (2013). 2013;8159 :18-30.Abstract
We present an analysis framework for large studies of multimodal clinical quality brain image collections. Processing and analysis of such datasets is challenging due to low resolution, poor contrast, mis-aligned images, and restricted field of view. We adapt existing registration and segmentation methods and build a computational pipeline for spatial normalization and feature extraction. The resulting aligned dataset enables clinically meaningful analysis of spatial distributions of relevant anatomical features and of their evolution with age and disease progression. We demonstrate the approach on a neuroimaging study of stroke with more than 800 patients. We show that by combining data from several modalities, we can automatically segment important biomarkers such as white matter hyperintensity and characterize pathology evolution in this heterogeneous cohort. Specifically, we examine two sub-populations with different dynamics of white matter hyperintensity changes as a function of patients' age. Pipeline and analysis code is available at http://groups.csail.mit.edu/vision/medical-vision/stroke/.
Chen GH, Wachinger C, Golland P. Sparse Projections of Medical Images onto Manifolds. Inf Process Med Imaging. 2013;23 :292-303.Abstract
Manifold learning has been successfully applied to a variety of medical imaging problems. Its use in real-time applications requires fast projection onto the low-dimensional space. To this end, out-of-sample extensions are applied by constructing an interpolation function that maps from the input space to the low-dimensional manifold. Commonly used approaches such as the Nyström extension and kernel ridge regression require using all training points. We propose an interpolation function that only depends on a small subset of the input training data. Consequently, in the testing phase each new point only needs to be compared against a small number of input training data in order to project the point onto the low-dimensional space. We interpret our method as an out-of-sample extension that approximates kernel ridge regression. Our method involves solving a simple convex optimization problem and has the attractive property of guaranteeing an upper bound on the approximation error, which is crucial for medical applications. Tuning this error bound controls the sparsity of the resulting interpolation function. We illustrate our method in two clinical applications that require fast mapping of input images onto a low-dimensional space.
Sweet A, Venkataraman A, Stufflebeam SM, Liu H, Tanaka N, Madsen J, Golland P. Detecting Epileptic Regions Based on Global Brain Connectivity Patterns. Med Image Comput Comput Assist Interv. 2013;16 (Pt 1) :98-105.Abstract
We present a method to detect epileptic regions based on functional connectivity differences between individual epilepsy patients and a healthy population. Our model assumes that the global functional characteristics of these differences are shared across patients, but it allows for the epileptic regions to vary between individuals. We evaluate the detection performance against intracranial EEG observations and compare our approach with two baseline methods that use standard statistics. The baseline techniques are sensitive to the choice of thresholds, whereas our algorithm automatically estimates the appropriate model parameters and compares favorably with the best baseline results. This suggests the promise of our approach for pre-surgical planning in epilepsy.
Wachinger C, Sharp GC, Golland P. Contour-Driven Regression for Label Inference in Atlas-Based Segmentation. Med Image Comput Comput Assist Interv. 2013;16 (Pt 3) :211-8.Abstract
We present a novel method for inferring tissue labels in atlas-based image segmentation using Gaussian process regression. Atlas-based segmentation results in probabilistic label maps that serve as input to our method. We introduce a contour-driven prior distribution over label maps to incorporate image features of the input scan into the label inference problem. The mean function of the Gaussian process posterior distribution yields the MAP estimate of the label map and is used in the subsequent voting. We demonstrate improved segmentation accuracy when our approach is combined with two different patch-based segmentation techniques. We focus on the segmentation of parotid glands in CT scans of patients with head and neck cancer, which is important for radiation therapy planning.

Pages