Joint Modeling of Biomarker Cascades Along An Unobserved Disease Progression with Differentiate Covariate Effects: An Application in Alzheimer's Disease
Alzheimer's Disease (AD) research has shifted to focus on biomarker trajectories and their potential use in understanding the underlying AD-related pathological process. A conceptual framework was proposed in modern AD research that hypothesized biomarker cascades as a result of underlying AD pathology. In this paper, we leveraged this idea to jointly model AD biomarker trajectories as a function of the latent AD disease progression with individual and covariate effects in the latent disease progression model and the biomarker cascade. We tailored our methods to address a number of real-data challenges that are often present in AD studies. Simulation studies were performed to investigate the proposed approach under various realistic but less-than-ideal situations. Finally, we illustrated the methods using real data from the BIOCARD and the ADNI studies. The analyses investigated cascading patterns of AD biomarkers in these datasets and presented prediction results for individual-level profiles over time. These findings highlight the potential of the conceptual biomarker cascade framework to be leveraged for diagnosis and monitoring.
There is no gold standard for the diagnosis of Alzheimer's disease (AD), except from autopsies. Unsupervised learning can provide insight into the pathophysiology of AD. A mixture of regressions can simultaneously identify clusters from multiple biomarkers while accounting for within-cluster demographic effects. Cerebrospinal fluid (CSF) biomarkers for AD have detection limits, which create additional challenges. We apply a mixture of regressions with a multivariate truncated Gaussian distribution (also called a censored multivariate Gaussian mixture of regressions or a mixture of multivariate…
Background: The concept of combinatorial biomarkers was conceived around 2010: it was noticed that simple biomarkers are often inadequate for recognizing and characterizing complex diseases. Methods: Here we present an algorithmic search method for complex biomarkers which may predict or indicate Alzheimer's disease (AD) and other kinds of dementia. We applied data mining techniques that are capable to uncover implication-like logical schemes with detailed quality scoring. Our program SCARF is capable of finding multi-factor relevant association rules automatically. The new SCARF program was a…
Deep Learning Approaches with Explainable AI for Differentiating Alzheimer Disease and Mild Cognitive Impairment
School of Mathematical and Natural Sciences（数学与自然科学学院）；Arizona State University（亚利桑那州立大学）；Department of Mathematics（数学系）；Florida Gulf Coast University（佛罗里达海岸大学）；Department of Public Health（公共卫生系）；Julia Jones Matthews School of Population and Public Health（朱莉亚·琼斯·马修斯人口与公共卫生学院）；Texas Tech University Health Sciences Center（德克萨斯农工大学健康科学中心）
Biomediq A/S（Biomediq公司）；Cerebriu A/S（Cerebriu公司）；University of Copenhagen（哥本哈根大学）；University College London（伦敦大学学院）；King’s College London（伦敦国王学院）
Quantitative characterization of disease progression using longitudinal data can provide long-term predictions for the pathological stages of individuals. This work studies the robust modeling of Alzheimer's disease progression using parametric methods. The proposed method linearly maps the individual's age to a disease progression score (DPS) and jointly fits constrained generalized logistic functions to the longitudinal dynamics of biomarkers as functions of the DPS using M-estimation. Robustness of the estimates is quantified using bootstrapping via Monte Carlo resampling, and the estimated…
Forecasting Medium-Horizon Alzheimer's Disease Progression: Residual Gap-Aware Transformers for 24-Month CDR-SB Change from ADNI Clinical and Biomarker Histories
Department of Mathematical Sciences, University of Texas at Dallas（德克萨斯大学达拉斯分校数学科学系）；Department of Plant Science and Landscape Architecture, University of Connecticut（康奈尔大学植物科学与景观建筑系）；Naveen Jindal School of Management, University of Texas at Dallas（德克萨斯大学达拉斯分校纳文·金达管理学院）；Zhejiang Provincial People’s Hospital（浙江省人民医院）
Studying the relationship between neuroanatomy and cognitive decline due to Alzheimer's has been a major research focus in the last decade. However, to infer cause-effect relationships rather than simple associations from observational data, we need to (i) express the causal relationships leading to cognitive decline in a graphical model, and (ii) ensure the causal effect of interest is identifiable from the collected data. We derive a causal graph from the current clinical knowledge on cause and effect in the Alzheimer's disease continuum, and show that identifiability of the causal effect re…
Pre-symptomatic (or Preclinical) Alzheimer's Disease is defined by biomarker evidence of fibrillar amyloid beta pathology in the absence of clinical symptoms. Clinical trials in this early phase of disease are challenging due to the slow rate of disease progression as measured by periodic cognitive performance tests or by transition to a diagnosis of Mild Cognitive Impairment. In a multisite study, experts provide diagnoses by central chart review without the benefit of in-person assessment. We use a simulation study to demonstrate that models of repeated cognitive assessments detect treatment…
Alzheimer's disease (AD) is characterized by complex and largely unknown progression dynamics affecting the brain's morphology. Although the disease evolution spans decades, to date we cannot rely on long-term data to model the pathological progression, since most of the available measures are on a short-term scale. It is therefore difficult to understand and quantify the temporal progression patterns affecting the brain regions across the AD evolution. In this work, we tackle this problem by presenting a generative model based on probabilistic matrix factorization across temporal and spatial …
Introduction: Identification of blood-based metabolic changes might provide early and easy-to-obtain biomarkers. Methods: We included 127 AD patients and 121 controls with CSF-biomarker-confirmed diagnosis (cut-off tau/A$β_{42}$: 0.52). Mass spectrometry platforms determined the concentrations of 53 amine, 22 organic acid, 120 lipid, and 40 oxidative stress compounds. Multiple signatures were assessed: differential expression (nested linear models), classification (logistic regression), and regulatory (network extraction). Results: Twenty-six metabolites were differentially expressed. Metaboli…
Multiple indications of disease progression found in a cancer patient by loco-regional relapse, distant metastasis and death. Early identification of these indications is necessary to change the treatment strategy. Biomarkers play an essential role in this aspect. The survival chance of a patient is dependent on the biomarker, and the treatment strategy also differs accordingly, e.g., the survival prediction of breast cancer patients diagnosed with HER2 positive status is different from the same with HER2 negative status. This results in a different treatment strategy. So, the heterogeneity of…
Predictive or treatment selection biomarkers are usually evaluated in a subgroup or regression analysis with focus on the treatment-by-marker interaction. Under a potential outcome framework (Huang, Gilbert and Janes [Biometrics 68 (2012) 687-696]), a predictive biomarker is considered a predictor for a desirable treatment benefit (defined by comparing potential outcomes for different treatments) and evaluated using familiar concepts in prediction and classification. However, the desired treatment benefit is unobservable because each patient can receive only one treatment in a typical study. H…
We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linea…
In order to find effective treatments for Alzheimer's disease (AD), we need to identify subjects at risk of AD as early as possible. To this end, recently developed disease progression models can be used to perform early diagnosis, as well as predict the subjects' disease stages and future evolution. However, these models have not yet been applied to rare neurodegenerative diseases, are not suitable to understand the complex dynamics of biomarkers, work only on large multimodal datasets, and their predictive performance has not been objectively validated. In this work I developed novel models …
