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Predicting the course of Alzheimer's progression.
Alzheimer's disease is the most common neurodegenerative disease and is characterized by the accumulation of amyloid-beta peptides leading to the formation of plaques and tau protein tangles in brain. These neuropathological features precede cognitive impairment and Alzheimer's dementia by many years. To better understand and predict the course of disease from early-stage asymptomatic to late-stage dementia, it is critical to study the patterns of progression of multiple markers. In particular, we aim to predict the likely future course of progression for individuals given only a single observation of their markers. Improved individual-level prediction may lead to improved clinical care and clinical trials. We propose a two-stage approach to modeling and predicting measures of cognition, function, brain imaging, fluid biomarkers, and diagnosis of individuals using multiple domains simultaneously. In the first stage, joint (or multivariate) mixed-effects models are used to simultaneously model multiple markers over time. In the second stage, random forests are used to predict categorical diagnoses (cognitively normal, mild cognitive impairment, or dementia) from predictions of continuous markers based on the first-stage model. The combination of the two models allows one to leverage their key strengths in order to obtain improved accuracy. We characterize the predictive accuracy of this two-stage approach using data from the Alzheimer's Disease Neuroimaging Initiative. The two-stage approach using a single joint mixed-effects model for all continuous outcomes yields better diagnostic classification accuracy compared to using separate univariate mixed-effects models for each of the continuous outcomes. Overall prediction accuracy above 80% was achieved over a period of 2.5 years. The results further indicate that overall accuracy is improved when markers from multiple assessment domains, such as cognition, function, and brain imaging, are used in the prediction algorithm as compared to the use of markers from a single domain only
Deep learning methods to predict amyotrophic lateral sclerosis disease progression
Amyotrophic lateral sclerosis (ALS) is a highly complex and heterogeneous neurodegenerative disease that affects motor neurons. Since life expectancy is relatively low, it is essential to promptly understand the course of the disease to better target the patient’s treatment. Predictive models for disease progression are thus of great interest. One of the most extensive and well-studied open-access data resources for ALS is the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) repository. In 2015, the DREAM-Phil Bowen ALS Prediction Prize4Life Challenge was held on PRO-ACT data, where competitors were asked to develop machine learning algorithms to predict disease progression measured through the slope of the ALSFRS score between 3 and 12 months. However, although it has already been successfully applied in several studies on ALS patients, to the best of our knowledge deep learning approaches still remain unexplored on the ALSFRS slope prediction in PRO-ACT cohort. Here, we investigate how deep learning models perform in predicting ALS progression using the PRO-ACT data. We developed three models based on different architectures that showed comparable or better performance with respect to the state-of-the-art models, thus representing a valid alternative to predict ALS disease progression
Forecasting the Progression of Alzheimer's Disease Using Neural Networks and a Novel Pre-Processing Algorithm
Alzheimer's disease (AD) is the most common neurodegenerative disease in
older people. Despite considerable efforts to find a cure for AD, there is a
99.6% failure rate of clinical trials for AD drugs, likely because AD patients
cannot easily be identified at early stages. This project investigated machine
learning approaches to predict the clinical state of patients in future years
to benefit AD research. Clinical data from 1737 patients was obtained from the
Alzheimer's Disease Neuroimaging Initiative (ADNI) database and was processed
using the "All-Pairs" technique, a novel methodology created for this project
involving the comparison of all possible pairs of temporal data points for each
patient. This data was then used to train various machine learning models.
Models were evaluated using 7-fold cross-validation on the training dataset and
confirmed using data from a separate testing dataset (110 patients). A neural
network model was effective (mAUC = 0.866) at predicting the progression of AD
on a month-by-month basis, both in patients who were initially cognitively
normal and in patients suffering from mild cognitive impairment. Such a model
could be used to identify patients at early stages of AD and who are therefore
good candidates for clinical trials for AD therapeutics.Comment: 10 pages; updated acknowledgement
Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria
Background:
The urinary proteomic classifier CKD273 has shown promise for prediction of progressive diabetic nephropathy (DN). Whether it is also a determinant of mortality and cardiovascular disease in patients with microalbuminuria (MA) is unknown.
Methods:
Urine samples were obtained from 155 patients with type 2 diabetes and confirmed microalbuminuria. Proteomic analysis was undertaken using capillary electrophoresis coupled to mass spectrometry to determine the CKD273 classifier score. A previously defined CKD273 threshold of 0.343 for identification of DN was used to categorise the cohort in Kaplan–Meier and Cox regression models with all-cause mortality as the primary endpoint. Outcomes were traced through national health registers after 6 years.
Results:
CKD273 correlated with urine albumin excretion rate (UAER) (r = 0.481, p = <0.001), age (r = 0.238, p = 0.003), coronary artery calcium (CAC) score (r = 0.236, p = 0.003), N-terminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.190, p = 0.018) and estimated glomerular filtration rate (eGFR) (r = 0.265, p = 0.001). On multivariate analysis only UAER (β = 0.402, p < 0.001) and eGFR (β = − 0.184, p = 0.039) were statistically significant determinants of CKD273. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank [Mantel-Cox] p = 0.004), and retained significance (p = 0.048) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model.
Conclusion:
A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the urinary proteomic classifier CKD273 is associated with mortality in individuals with type 2 diabetes and MA even when adjusted for other established cardiovascular and renal biomarkers
Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria
Background:
The urinary proteomic classifier CKD273 has shown promise for prediction of progressive diabetic nephropathy (DN). Whether it is also a determinant of mortality and cardiovascular disease in patients with microalbuminuria (MA) is unknown.
Methods:
Urine samples were obtained from 155 patients with type 2 diabetes and confirmed microalbuminuria. Proteomic analysis was undertaken using capillary electrophoresis coupled to mass spectrometry to determine the CKD273 classifier score. A previously defined CKD273 threshold of 0.343 for identification of DN was used to categorise the cohort in Kaplan–Meier and Cox regression models with all-cause mortality as the primary endpoint. Outcomes were traced through national health registers after 6 years.
Results:
CKD273 correlated with urine albumin excretion rate (UAER) (r = 0.481, p = <0.001), age (r = 0.238, p = 0.003), coronary artery calcium (CAC) score (r = 0.236, p = 0.003), N-terminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.190, p = 0.018) and estimated glomerular filtration rate (eGFR) (r = 0.265, p = 0.001). On multivariate analysis only UAER (β = 0.402, p < 0.001) and eGFR (β = − 0.184, p = 0.039) were statistically significant determinants of CKD273. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank [Mantel-Cox] p = 0.004), and retained significance (p = 0.048) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model.
Conclusion:
A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the urinary proteomic classifier CKD273 is associated with mortality in individuals with type 2 diabetes and MA even when adjusted for other established cardiovascular and renal biomarkers
Tensor Networks for Dimensionality Reduction and Large-Scale Optimizations. Part 2 Applications and Future Perspectives
Part 2 of this monograph builds on the introduction to tensor networks and
their operations presented in Part 1. It focuses on tensor network models for
super-compressed higher-order representation of data/parameters and related
cost functions, while providing an outline of their applications in machine
learning and data analytics. A particular emphasis is on the tensor train (TT)
and Hierarchical Tucker (HT) decompositions, and their physically meaningful
interpretations which reflect the scalability of the tensor network approach.
Through a graphical approach, we also elucidate how, by virtue of the
underlying low-rank tensor approximations and sophisticated contractions of
core tensors, tensor networks have the ability to perform distributed
computations on otherwise prohibitively large volumes of data/parameters,
thereby alleviating or even eliminating the curse of dimensionality. The
usefulness of this concept is illustrated over a number of applied areas,
including generalized regression and classification (support tensor machines,
canonical correlation analysis, higher order partial least squares),
generalized eigenvalue decomposition, Riemannian optimization, and in the
optimization of deep neural networks. Part 1 and Part 2 of this work can be
used either as stand-alone separate texts, or indeed as a conjoint
comprehensive review of the exciting field of low-rank tensor networks and
tensor decompositions.Comment: 232 page
Tensor Networks for Dimensionality Reduction and Large-Scale Optimizations. Part 2 Applications and Future Perspectives
Part 2 of this monograph builds on the introduction to tensor networks and
their operations presented in Part 1. It focuses on tensor network models for
super-compressed higher-order representation of data/parameters and related
cost functions, while providing an outline of their applications in machine
learning and data analytics. A particular emphasis is on the tensor train (TT)
and Hierarchical Tucker (HT) decompositions, and their physically meaningful
interpretations which reflect the scalability of the tensor network approach.
Through a graphical approach, we also elucidate how, by virtue of the
underlying low-rank tensor approximations and sophisticated contractions of
core tensors, tensor networks have the ability to perform distributed
computations on otherwise prohibitively large volumes of data/parameters,
thereby alleviating or even eliminating the curse of dimensionality. The
usefulness of this concept is illustrated over a number of applied areas,
including generalized regression and classification (support tensor machines,
canonical correlation analysis, higher order partial least squares),
generalized eigenvalue decomposition, Riemannian optimization, and in the
optimization of deep neural networks. Part 1 and Part 2 of this work can be
used either as stand-alone separate texts, or indeed as a conjoint
comprehensive review of the exciting field of low-rank tensor networks and
tensor decompositions.Comment: 232 page
Model-based Recursive Partitioning for Subgroup Analyses
The identification of patient subgroups with differential treatment effects
is the first step towards individualised treatments. A current draft guideline
by the EMA discusses potentials and problems in subgroup analyses and
formulated challenges to the development of appropriate statistical procedures
for the data-driven identification of patient subgroups. We introduce
model-based recursive partitioning as a procedure for the automated detection
of patient subgroups that are identifiable by predictive factors. The method
starts with a model for the overall treatment effect as defined for the primary
analysis in the study protocol and uses measures for detecting parameter
instabilities in this treatment effect. The procedure produces a segmented
model with differential treatment parameters corresponding to each patient
subgroup. The subgroups are linked to predictive factors by means of a decision
tree. The method is applied to the search for subgroups of patients suffering
from amyotrophic lateral sclerosis that differ with respect to their Riluzole
treatment effect, the only currently approved drug for this disease.Comment: 26 pages, 6 figure
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