Bridge Simulation and Metric Estimation on Landmark Manifolds

We present an inference algorithm and connected Monte Carlo based estimation procedures for metric estimation from landmark configurations distributed according to the transition distribution of a Riemannian Brownian motion arising from the Large Deformation Diffeomorphic Metric Mapping (LDDMM) metric. The distribution possesses properties similar to the regular Euclidean normal distribution but its transition density is governed by a high-dimensional PDE with no closed-form solution in the nonlinear case. We show how the density can be numerically approximated by Monte Carlo sampling of conditioned Brownian bridges, and we use this to estimate parameters of the LDDMM kernel and thus the metric structure by maximum likelihood

Personalized prediction of progression in pre-dementia patients based on individual biomarker profile: A development and validation study

INTRODUCTION: The prognosis of patients at the pre-dementia stage is difficult to define. The aim of this study is to develop and validate a biomarker-based continuous model for predicting the individual cognitive level at any future moment. In addition to personalized prognosis, such a model could reduce trial sample size requirements by allowing inclusion of a homogenous patient population. METHODS: Disease-progression modeling of longitudinal cognitive scores of pre-dementia patients (baseline Clinical Dementia Rating </= 0.5) was used to derive a biomarker profile that was predictive of patient's cognitive progression along the dementia continuum. The biomarker profile model was developed and validated in the MEMENTO cohort and externally validated in the Alzheimer's Disease Neuroimaging Initiative. RESULTS: Of nine candidate biomarkers in the development analysis, three cerebrospinal fluid and two magnetic resonance imaging measures were selected to form the final biomarker profile. The model-based prognosis of individual future cognitive deficit was shown to significantly improve when incorporating biomarker information on top of cognition and demographic data. In trial power calculations, adjusting the primary analysis for the baseline biomarker profile reduced sample size requirements by approximately 10%. Compared to conventional cognitive cut-offs, inclusion criteria based on biomarker-profile cut-offs resulted in up to 28% reduced sample size requirements due to increased homogeneity in progression patterns. DISCUSSION: The biomarker profile allows prediction of personalized trajectories of future cognitive progression. This enables accurate personalized prognosis in clinical care and better selection of patient populations for clinical trials. A web-based application for prediction of patients' future cognitive progression is available online