Armin Schwartzman, Ph.D. - US grants

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is an added subproject to Imaging Core, Project 1 Overall Goal: Currently, most brain image analyses, particularly in the study of neurodegenerative diseases concentrate on a single imaging modality, e.g. structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), perfusion MRI, positron emission tomography (PET), functional MRI. Different imaging modalities provide complementary, but not necessarily independent, information about the brain. New insights may be obtained by performing an integrated analysis of several modalities simultaneously. Such analysis not only enables the discovery of relationships between the modalities, but also allows the discovery of neurodegenerative effects in either one or perhaps several modalities simultaneously.The goal of this project is to develop a general statistical methodology that can be used to analyze several imaging modalities simultaneously in order to increase the statistical power of finding localized characteristics of disease, as well as revealing relationships between the modalities and between different locations in the brain. For this purpose, we assume that the imaging data is given as a set of co-registered scalar images from a number of subjects and corresponding to various imaging modalities. These images may be, among others, volume expansion/contraction obtained from TBM applied to sMRI, blood flow measurements obtained from perfusion MRI, and scalar summaries such as fractional anisotropy obtained from DTI. The specific aims of this subproject are the following. Aim 1: Develop a multivariate statistical methodology for testing the effect of disease status on multimodality imaging simultaneously at each voxel. This includes: a) Comparison of univariate and multivariate regression approaches b) Performance evaluation via simulations Aim 2: Develop a multivariate statistical methodology for testing the effect of disease status of multimodality imaging simultaneously at different voxels. This includes: a) Comparison of cross-correlation analysis and canonical correlation analysis b) Performance evaluation via simulations Aim 3: Implementation of the above methods in the R software and apply them to the ADNI data base.

DESCRIPTION (provided by applicant): Large-scale multiple testing has become ubiquitous in the search for disease and health risk markers using high-throughput technologies. While statistical methods for multiple testing often assume independence between the tests, many real situations exhibit dependence and an underlying structure. Examples of spatial structure are one-dimensional (1D) in the case of proteomic data; 2D in the case of environmental data; and 3D in the case of brain imaging data. Ignoring correlation in the analysis may lead to a different set and ordering of discovered features, resulting in increased error rates and potential missing of important features. There is a need to characterize the effect of correlation in multiple testing and incorporate it into the analysis. The goal of this proposal is to develop multiple testing methods that incorporate the correlation in the data in order to increase statistical power, control error rates and obtain appropriately interpretable results. This is done in two different ways. (1) In Aims 1 and 2, we assume a spatial structure and stationary ergodic correlation, where the signal of interest consists of a relatively small number of unimodal peaks. We use random field theory to compute p-values for testing the heights of local maxima of the observed data after smoothing. We develop these methods in complexity from 1D to 3D domains, and from peaks of equal width to peaks of unequal width. We then adapt and apply these methods to various types of data obtained from high-throughput technologies, specifically: mass- spectrometry data for identifying protein biomarkers of cancer; climate model output data for identification of geographical regions at risk for heat stress as a result of climate change; and brain imaging data for identification of anatomical regions involved in abnormal cognitive development. (2) In Aim 3, we assume a general correlation structure, not necessarily stationary or ergodic, and propose a conditional marginal analysis, where correlation is incorporated through conditioning on the observed marginal distribution of likely null cases. Although not exclusively, emphasis throughout is placed on false discovery rate inference. This proposal provides a unified view of signal detection for random fields that applies broadly to a large class of problems ranging from proteomics to medical imaging to environmental monitoring. From a statistical point of view, it provides a new answer to the problem of controlling FDR in random fields. By taking advantage of the dependence structure, the methods developed in this proposal offer higher statistical power in the search for markers, so that a smaller number of false markers will be tested in follow-up studies. PUBLIC HEALTH RELEVANCE: This proposal provides a unified view of feature detection in high-throughput data that applies to a large class of problems ranging from cancer proteomics to medical imaging to environmental monitoring. By taking advantage of the dependence structure, the methods developed in this proposal offer higher statistical power in the search for markers, facilitating the discovery of new true markers and reducing the number of false markers to be tested in follow-up studies.

DESCRIPTION (provided by applicant): The aggressiveness of brain cancer requires quantitative evaluation tools that can detect response to therapy early in order to guide treatment. Quantitative FDG-PET imaging has been used extensively, both within clinical trials at the Dana-Farber Cancer Institute (DFCI) and elsewhere, to evaluate the response of novel cancer therapies between a baseline (pre-treatment) and a follow-up (post-treatment) scan. The standard analysis approach, involving manual delineation of regions of interest, is robust but limited in scope, time-consuming, and subjective. In the context of neuroimaging, we propose to develop more objective methods that can indicate changes anywhere in the brain and correct for the confounding induced by global and regional changes in normal brain metabolism. This is achieved by a voxelwise comparison between the pre-treatment and post-treatment 3D scans, preceded by spatial registration, segmentation and background adjustment, and followed by significance thresholding. Summary measures of the generated voxelwise change maps are evaluated as predictors of survival in clinical trials. The methods in this proposal will provide a better tool for radiological assessment of patient progression or response and a better standard for evaluation of therapy in clinical trials. Capitalizing on complimentary expertise and interests in image analysis, this unique collaboration between the departments of Imaging and Biostatistics at DFCI holds the promise of developing fundamental methodologies that can immediately be evaluated and utilized in previous and future clinical trials. PUBLIC HEALTH RELEVANCE: The methods in this proposal will provide a better tool for radiological assessment of patient progression or response to treatment in brain cancer and a better standard for evaluation of therapy in clinical trials.

From biomedical to environmental research, a central problem in image analysis is to recognize and locate important effects. An archetypal example is image analysis of the 3D brain volume or the 2D cortical surface, using both anatomical and functional imaging. Examples also abound in 1D functional data (EEG patterns or anatomical neural fibers), 2D images (microscopy) and 2D spatial data (climate maps). These problems share a common data structure in which smooth functions or images are observed repeatedly and aligned on a fine grid. The goal of localization is to identify regions where the signal is strong or where differences exist between conditions or groups of subjects. While there is a rich collection of tools to analyze imaging data, the focus has been mainly on significance testing and controlling error rates under the null hypothesis and has been limited by practical but unrealistic assumptions about the noise field, compromising error control and statistical power. On the other hand, the functional data analysis approach rightly works under the non-zero mean model but ignores the analytical power of smooth random field theory, which has been so successful in image analysis and could enable similar gains for functional data. The main goal of this proposal is to develop new spatial inference methods that directly address the estimation of non-sparse signals and quantification of their spatial uncertainty, in order to increase statistical power, control error rates and obtain appropriately interpretable results. In the previous cycle of this grant, we established methodology for formal error control in peak detection. This renewal develops location uncertainty and detection power for peaks (Aim 1), and moves further to develop confidence bands and spatial confidence regions for the entire signal (Aim 2) and for excursion sets where the signal exceeds a threshold (Aim 3). Methods are proposed to target both the mean (effect magnitude) and the signal-to-noise ratio (standardized mean or effect size), allowing interpretable inference in the presence of spatially non- constant variance, characteristic of neuroimaging data. The proposal offers clear definitions of spatial inference, and supports the methodology with smooth Gaussian random field theory, forgoing the stationarity and zero-mean assumptions. These methods are rigorously validated and used to map the cognitive effects of addictive substance use in the large NIH-funded Adolescent Brain Cognitive Development (ABCD) study. This proposal uniquely brings together ideas from image and functional data analysis to provide more accurate and interpretable spatial localization of important effects in smooth signals and images. The methods developed in this proposal offer more accurate mapping of the brain and other domains, and higher statistical power to identify locations where important effects occur, enhancing scientific understanding and guiding better targeted follow-up studies.