The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality. Recent enhancements include statistical, visualization, and deep learning capabilities through interfacing with both the R statistical project (ANTsR) and Python (ANTsPy). Additionally, the corresponding deep learning extensions ANTsRNet and ANTsPyNet (built on the popular TensorFlow/Keras libraries) contain several popular network architectures and trained models for specific applications. One such comprehensive application is a deep learning analog for generating cortical thickness data from structural T1-weighted brain MRI, both cross-sectionally and longitudinally. These pipelines significantly improve computational efficiency and provide comparable-to-superior accuracy over multiple criteria relative to the existing ANTs workflows and simultaneously illustrate the importance of the comprehensive ANTsX approach as a framework for medical image analysis.

Calculation of the log-likelihood stands as the computational bottleneck for many statistical phylogenetic algorithms. Even worse is its gradient evaluation, often used to target regions of high probability. Order 𝒪 (N)-dimensional gradient calculations based on the standard pruning algorithm require 𝒪 (N) operations where N is the number of sampled molecular sequences. With the advent of high-throughput sequencing, recent phylogenetic studies have analyzed hundreds to thousands of sequences, with an apparent trend towards even larger data sets as a result of advancing technology. Such large-scale analyses challenge phylogenetic reconstruction by requiring inference on larger sets of process parameters to model the increasing data heterogeneity. To make these analyses tractable, we present a linear-time algorithm for 𝒪 (N)-dimensional gradient evaluation and apply it to general continuous-time Markov processes of sequence substitution on a phylogenetic tree without a need to assume either stationarity or reversibility. We apply this approach to learn the branch-specific evolutionary rates of three pathogenic viruses: West Nile virus, Dengue virus and Lassa virus. Our proposed algorithm significantly improves inference efficiency with a 126- to 234-fold increase in maximum-likelihood optimization and a 16- to 33-fold computational performance increase in a Bayesian framework.

Longitudinal studies of development and disease in the human brain have motivated the acquisition of large neuroimaging data sets and the concomitant development of robust methodological and statistical tools for quantifying neurostructural changes. Longitudinal-specific strategies for acquisition and processing have potentially significant benefits including more consistent estimates of intra-subject measurements while retaining predictive power. Using the first phase of the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) data, comprising over 600 subjects with multiple time points from baseline to 36 months, we evaluate the utility of longitudinal FreeSurfer and Advanced Normalization Tools (ANTs) surrogate thickness values in the context of a linear mixed-effects (LME) modeling strategy. Specifically, we estimate the residual variability and between-subject variability associated with each processing stream as it is known from the statistical literature that minimizing the former while simultaneously maximizing the latter leads to greater scientific interpretability in terms of tighter confidence intervals in calculated mean trends, smaller prediction intervals, and narrower confidence intervals for determining cross-sectional effects. This strategy is evaluated over the entire cortex, as defined by the Desikan-Killiany-Tourville labeling protocol, where comparisons are made with the cross-sectional and longitudinal FreeSurfer processing streams. Subsequent linear mixed effects modeling for identifying diagnostic groupings within the ADNI cohort is provided as supporting evidence for the utility of the proposed ANTs longitudinal framework which provides unbiased structural neuroimage processing and competitive to superior power for longitudinal structural change detection.

Introduction Loss of entorhinal cortex (EC) layer II neurons represents the earliest Alzheimer's disease (AD) lesion in the brain. Research suggests differing functional roles between two EC subregions, the anterolateral EC (aLEC) and the posteromedial EC (pMEC). Methods We use joint label fusion to obtain aLEC and pMEC cortical thickness measurements from serial magnetic resonance imaging scans of 775 ADNI‐1 participants (219 healthy; 380 mild cognitive impairment; 176 AD) and use linear mixed‐effects models to analyze longitudinal associations among cortical thickness, disease status, and cognitive measures. Results Group status is reliably predicted by aLEC thickness, which also exhibits greater associations with cognitive outcomes than does pMEC thickness. Change in aLEC thickness is also associated with cerebrospinal fluid amyloid and tau levels. Discussion Thinning of aLEC is a sensitive structural biomarker that changes over short durations in the course of AD and tracks disease severity—it is a strong candidate biomarker for detection of early AD.

Longitudinal studies of development and disease in the human brain have motivated the acquisition of large neuroimaging data sets and the concomitant development of robust methodological and statistical tools for quantifying neurostructural changes. Longitudinal-specific strategies for acquisition and processing have potentially significant benefits including more consistent estimates of intra-subject measurements while retaining predictive power. In this work, we introduce the opensource Advanced Normalization Tools (ANTs) cortical thickness longitudinal processing pipeline and its application on the first phase of the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) comprising over 600 subjects with multiple time points from baseline to 36 months. We demonstrate in these data that the single-subject template construction and native subject-space processing advantageously localizes data transformations and mitigates interpolation artifacts which results in a simultaneous minimization of within-subject variability and maximization of between-subject variability immediately estimable from a longitudinal mixed-effects modeling strategy. It is further shown that optimizing these dual criteria leads to greater scientific interpretability in terms of tighter confidence intervals in calculated mean trends, smaller prediction intervals, and narrower confidence intervals for determining cross-sectional effects. These concepts are first illustrated and explored in the entorhinal cortex. This evaluation strategy is then extended to the entire cortex, as defined by the Desikan-Killiany-Tourville labeling protocol, where comparisons are made with the popular crosssectional and longitudinal FreeSurfer processing streams.