title: A simulation system for biomarker evolution in neurodegenerative disease.
abstract: We present a framework for simulating cross-sectional or longitudinal biomarker data sets from neurodegenerative disease cohorts that reflect the temporal evolution of the disease and population diversity. The simulation system provides a mechanism for evaluating the performance of data-driven models of disease progression, which bring together biomarker measurements from large cross-sectional (or short term longitudinal) cohorts to recover the average population-wide dynamics. We demonstrate the use of the simulation framework in two different ways. First, to evaluate the performance of the Event Based Model (EBM) for recovering biomarker abnormality orderings from cross-sectional datasets. Second, to evaluate the performance of a differential equation model (DEM) for recovering biomarker abnormality trajectories from short-term longitudinal datasets. Results highlight several important considerations when applying data-driven models to sporadic disease datasets as well as key areas for future work. The system reveals several important insights into the behaviour of each model. For example, the EBM is robust to noise on the underlying biomarker trajectory parameters, under-sampling of the underlying disease time course and outliers who follow alternative event sequences. However, the EBM is sensitive to accurate estimation of the distribution of normal and abnormal biomarker measurements. In contrast, we find that the DEM is sensitive to noise on the biomarker trajectory parameters, resulting in an over estimation of the time taken for biomarker trajectories to go from normal to abnormal. This over estimate is approximately twice as long as the actual transition time of the trajectory for the expected noise level in neurodegenerative disease datasets. This simulation framework is equally applicable to a range of other models and longitudinal analysis techniques.
authors.affiliation: Centre for Medical Image Computing, Department of Computer Science, University College London, Gower Street, London, WC1E 6BT, United Kingdom. Electronic address: alexandra.young.11@ucl.ac.uk.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Young
authors.affiliation: Centre for Medical Image Computing, Department of Computer Science, University College London, Gower Street, London, WC1E 6BT, United Kingdom.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Oxtoby
authors.affiliation: Centre for Medical Image Computing, Department of Computer Science, University College London, Gower Street, London, WC1E 6BT, United Kingdom.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Ourselin
authors.affiliation: Dementia Research Centre, Institute of Neurology, University College London, 8-11 Queen Square, London, WC1N 3AR, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schott
authors.affiliation: Centre for Medical Image Computing, Department of Computer Science, University College London, Gower Street, London, WC1E 6BT, United Kingdom.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Alexander
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003198:Computer Simulation; D018450:Disease Progression; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D008137:Longitudinal Studies; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D015415:Biomarkers; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18
keywords: Alzheimer's disease; Biomarker evolution; Differential equation model; Event-based model; Simulation system