Development of the CHARIOT Research Register for the Prevention of Alzheimer’s Dementia and Other Late Onset Neurodegenerative Diseases

Identifying cognitively healthy people at high risk of developing dementia is an ever-increasing focus. These individuals are essential for inclusion in observational studies into the natural history of the prodromal and early disease stages and for interventional studies aimed at prevention or disease modification. The success of this research is dependent on having access to a well characterised, representative and sufficiently large population of individuals. Access to such a population remains challenging as clinical research has, historically, focussed on patients with dementia referred to secondary and tertiary services. The primary care system in the United Kingdom allows access to a true prodromal population prior to symptoms emerging and specialist referral. We report the development and recruitment rates of the CHARIOT register, a primary care-based recruitment register for research into the prevention of dementia. The CHARIOT register was designed specifically to support recruitment into observational natural history studies of pre-symptomatic or prodromal dementia stages, and primary or secondary prevention pharmaceutical trials or other prevention strategies for dementia and other cognitive problems associated with ageing.Participants were recruited through searches of general practice lists across the west and central London regions. Invitations were posted to individuals aged between 60 and 85 years, without a diagnosis of dementia. Upon consent, a minimum data set of demographic and contact details was extracted from the patient's electronic health record.To date, 123 surgeries participated in the register, recruiting a total of 24,509 participants-a response rate of 22.3%. The age, gender and ethnicity profiles of participants closely match that of the overall eligible population. Higher response rates tended to be associated with larger practices (r = 0.34), practices with a larger older population (r = 0.27), less socioeconomically disadvantaged practices (r = 0.68), and practices with a higher proportion of White patients (r = 0.82).Response rates are comparable to other registers reported in the literature, and indicate good interest and support for a research register and for participation in research for the prevention of age-related neurodegenerative diseases and dementia. We consider that the simplicity of the approach means that this system is easily scalable and replicable across the UK and internationally

Alzheimers Disease Diagnosis by Deep Learning Using MRI-Based Approaches

The most frequent kind of dementia of the nervous system, Alzheimer's disease, weakens several brain processes (such as memory) and eventually results in death. The clinical study uses magnetic resonance imaging to diagnose AD. Deep learning algorithms are capable of pattern recognition and feature extraction from the inputted raw data. As early diagnosis and stage detection are the most crucial elements in enhancing patient care and treatment outcomes, deep learning algorithms for MRI images have recently allowed for diagnosing a medical condition at the beginning stage and identifying particular symptoms of Alzheimer's disease. As a result, we aimed to analyze five specific studies focused on AD diagnosis using MRI-based deep learning algorithms between 2021 and 2023 in this study. To completely illustrate the differences between these techniques and comprehend how deep learning algorithms function, we attempted to explore selected approaches in depth

Accurate multimodal probabilistic prediction of conversion to Alzheimer's disease in patients with mild cognitive impairment

Accurately identifying the patients that have mild cognitive impairment (MCI) who will go on to develop Alzheimer's disease (AD) will become essential as new treatments will require identification of AD patients at earlier stages in the disease process. Most previous work in this area has centred around the same automated techniques used to diagnose AD patients from healthy controls, by coupling high dimensional brain image data or other relevant biomarker data to modern machine learning techniques. Such studies can now distinguish between AD patients and controls as accurately as an experienced clinician. Models trained on patients with AD and control subjects can also distinguish between MCI patients that will convert to AD within a given timeframe (MCI-c) and those that remain stable (MCI-s), although differences between these groups are smaller and thus, the corresponding accuracy is lower. The most common type of classifier used in these studies is the support vector machine, which gives categorical class decisions. In this paper, we introduce Gaussian process (GP) classification to the problem. This fully Bayesian method produces naturally probabilistic predictions, which we show correlate well with the actual chances of converting to AD within 3 years in a population of 96 MCI-s and 47 MCI-c subjects. Furthermore, we show that GPs can integrate multimodal data (in this study volumetric MRI, FDG-PET, cerebrospinal fluid, and APOE genotype with the classification process through the use of a mixed kernel). The GP approach aids combination of different data sources by learning parameters automatically from training data via type-II maximum likelihood, which we compare to a more conventional method based on cross validation and an SVM classifier. When the resulting probabilities from the GP are dichotomised to produce a binary classification, the results for predicting MCI conversion based on the combination of all three types of data show a balanced accuracy of 74%. This is a substantially higher accuracy than could be obtained using any individual modality or using a multikernel SVM, and is competitive with the highest accuracy yet achieved for predicting conversion within three years on the widely used ADNI dataset

Data fusion of complementary information from parietal and occipital event related potentials for early diagnosis of Alzheimer\u27s disease

The number of the elderly population affected by Alzheimer\u27s disease is rapidly rising. The need to find an accurate, inexpensive, and non-intrusive procedure that can be made available to community healthcare providers for the early diagnosis of Alzheimer\u27s disease is becoming an increasingly urgent public health concern. Several recent studies have looked at analyzing electroencephalogram signals through the use of many signal processing techniques. While their methods show great promise, the final outcome of these studies has been largely inconclusive. The inherent difficulty of the problem may be the cause of this outcome, but most likely it is due to the inefficient use of the available information, as many of these studies have used only a single EEG source for the analysis. In this contribution, data from the event related potentials of 19 available electrodes of the EEG are analyzed. These signals are decomposed into different frequency bands using multiresolution wavelet analysis. Two data fusion approaches are then investigated: i.) concatenating features before presenting them to a classification algorithm with the expectation of creating a more informative feature space, and ii.) generating multiple classifiers each trained with a different combination of features obtained from various stimuli, electrode, and frequency bands. The classifiers are then combined through the weighted majority vote, product and sum rule combination schemes. The results indicate that a correct diagnosis performance of over 80% can be obtained by combining data primarily from parietal and occipital lobe electrodes. The performance significantly exceeds that reported from community clinic physicians, despite their access to the outcomes of longitudinal monitoring of the patients

Supervised machine learning in psychiatry:towards application in clinical practice

In recent years, the field of machine learning (often named with the more general term artificial intelligence) has literally exploded and its application has been proposed in basically all fields, including psychiatry and mental health. This has been motivated by the promise of using machine learning to develop new clinical tools that could help perform personalized predictions and recommendations, ultimately improving the results achievable in the psychiatric clinical practice that still faces only a limited success in the fight against mental diseases. However, despite this huge interest, there is still a substantial lack of tools in psychiatry that are based on machine learning algorithms. Massimiliano Grassi, in his Ph.D. thesis, investigates the challenges of translating machine learning algorithms into clinical practice and proposes innovative solutions to these challenges. The thesis presents the development and validation of new algorithms for the prediction of the onset of Alzheimer’s disease, the remission of obsessive-compulsive disorder, and the automatization of sleep staging in polysomnography, a method to diagnose sleep disorders. The results from these studies demonstrate that the use of machine learning in psychiatric clinical practice is not just a promise, and it is possible to develop machine learning algorithms that achieve clinically relevant performance even if based solely on information that can be easily accessible in the daily clinical routine

Unsupervised learning methods for identifying and evaluating disease clusters in electronic health records

Introduction Clustering algorithms are a class of algorithms that can discover groups of observations in complex data and are often used to identify subtypes of heterogeneous diseases in electronic health records (EHR). Evaluating clustering experiments for biological and clinical significance is a vital but challenging task due to the lack of consensus on best practices. As a result, the translation of findings from clustering experiments to clinical practice is limited. Aim The aim of this thesis was to investigate and evaluate approaches that enable the evaluation of clustering experiments using EHR. Methods We conducted a scoping review of clustering studies in EHR to identify common evaluation approaches. We systematically investigated the performance of the identified approaches using a cohort of Alzheimer's Disease (AD) patients as an exemplar comparing four different clustering methods (K-means, Kernel K-means, Affinity Propagation and Latent Class Analysis.). Using the same population, we developed and evaluated a method (MCHAMMER) that tested whether clusterable structures exist in EHR. To develop this method we tested several cluster validation indexes and methods of generating null data to see which are the best at discovering clusters. In order to enable the robust benchmarking of evaluation approaches, we created a tool that generated synthetic EHR data that contain known cluster labels across a range of clustering scenarios. Results Across 67 EHR clustering studies, the most popular internal evaluation metric was comparing cluster results across multiple algorithms (30% of studies). We examined this approach conducting a clustering experiment on AD patients using a population of 10,065 AD patients and 21 demographic, symptom and comorbidity features. K-means found 5 clusters, Kernel K means found 2 clusters, Affinity propagation found 5 and latent class analysis found 6. K-means 4 was found to have the best clustering solution with the highest silhouette score (0.19) and was more predictive of outcomes. The five clusters found were: typical AD (n=2026), non-typical AD (n=1640), cardiovascular disease cluster (n=686), a cancer cluster (n=1710) and a cluster of mental health issues, smoking and early disease onset (n=1528), which has been found in previous research as well as in the results of other clustering methods. We created a synthetic data generation tool which allows for the generation of realistic EHR clusters that can vary in separation and number of noise variables to alter the difficulty of the clustering problem. We found that decreasing cluster separation did increase cluster difficulty significantly whereas noise variables increased cluster difficulty but not significantly. To develop the tool to assess clusters existence we tested different methods of null dataset generation and cluster validation indices, the best performing null dataset method was the min max method and the best performing indices we Calinksi Harabasz index which had an accuracy of 94%, Davies Bouldin index (97%) silhouette score ( 93%) and BWC index (90%). We further found that when clusters were identified using the Calinski Harabasz index they were more likely to have significantly different outcomes between clusters. Lastly we repeated the initial clustering experiment, comparing 10 different pre-processing methods. The three best performing methods were RBF kernel (2 clusters), MCA (4 clusters) and MCA and PCA (6 clusters). The MCA approach gave the best results highest silhouette score (0.23) and meaningful clusters, producing 4 clusters; heart and circulatory( n=1379), early onset mental health (n=1761), male cluster with memory loss (n = 1823), female with more problem (n=2244). Conclusion We have developed and tested a series of methods and tools to enable the evaluation of EHR clustering experiments. We developed and proposed a novel cluster evaluation metric and provided a tool for benchmarking evaluation approaches in synthetic but realistic EHR

An Optimized Recursive General Regression Neural Network Oracle for the Prediction and Diagnosis of Diabetes

Diabetes is a serious, chronic disease that has been seeing a rise in the number of cases and prevalence over the past few decades. It can lead to serious complications and can increase the overall risk of dying prematurely. Data-oriented prediction models have become effective tools that help medical decision-making and diagnoses in which the use of machine learning in medicine has increased substantially. This research introduces the Recursive General Regression Neural Network Oracle (R-GRNN Oracle) and is applied on the Pima Indians Diabetes dataset for the prediction and diagnosis of diabetes. The R-GRNN Oracle (Bani-Hani, 2017) is an enhancement to the GRNN Oracle developed by Masters et al. in 1998, in which the recursive model is created of two oracles: one within the other. Several classifiers, along with the R-GRNN Oracle and the GRNN Oracle, are applied to the dataset, they are: Support Vector Machine (SVM), Multilayer Perceptron (MLP), Probabilistic Neural Network (PNN), Gaussian NaEF;ve Bayes (GNB), K-Nearest Neighbor (KNN), and Random Forest (RF). Genetic Algorithm (GA) was used for feature selection as well as the hyperparameter optimization of SVM and MLP, and Grid Search (GS) was used to optimize the hyperparameters of KNN and RF. The performance metrics accuracy, AUC, sensitivity, and specificity were recorded for each classifier. The R-GRNN Oracle was able to achieve the highest accuracy, AUC, and sensitivity (81.14%, 86.03%, and 63.80%, respectively), while the optimized MLP had the highest specificity (89.71%)

Modelling prognostic trajectories in Alzheimer’s disease

Progression to dementia due to Alzheimer’s Disease (AD) is a long and protracted process that involves multiple pathways of disease pathophysiology. Predicting these dynamic changes has major implications for timely and effective clinical management in AD. There are two reasons why at present we lack appropriate tools to make such predictions. First, a key feature of AD is the interactive nature of the relationships between biomarkers, such as accumulation of β-amyloid -a peptide that builds plaques between nerve cells-, tau -a protein found in the axons of nerve cells- and widespread neurodegeneration. Current models fail to capture these relationships because they are unable to successfully reduce the high dimensionality of biomarkers while exploiting informative multivariate relationships. Second, current models focus on simply predicting in a binary manner whether an individual will develop dementia due to AD or not, without informing clinicians about their predicted disease trajectory. This can result in administering inefficient treatment plans and hindering appropriate stratification for clinical trials. In this thesis, we overcome these challenges by using applied machine learning to build predictive models of patient disease trajectories in the earliest stages of AD. Specifically, to exploit the multi-dimensionality of biomarker data, we used a novel feature generation methodology Partial Least Squares regression with recursive feature elimination (PLSr-RFE). This method applies a hybrid-feature selection and feature construction method that captures co-morbidities in cognition and pathophysiology, resulting in an index of Alzheimer’s disease atrophy from structural MRI. We validated our choice of biomarker and the efficacy of our methodology by showing that the learnt pattern of grey matter atrophy is highly predictive of tau accumulation in an independent sample. Next, to go beyond predicting binary outcomes to deriving individualised prognostic scores of cognitive decline due to AD, we used a novel trajectory modelling approach (Generalised Metric Learning Vector Quantization – Scalar projection) that mines multimodal data from large AD research cohorts. Using this approach, we derive individualised prognostic scores of cognitive decline due to AD, revealing interactive cognitive, and biological factors that improve prediction accuracy. Next, we extended our machine learning framework to classify and stage early AD individuals based on future pathological tau accumulation. Our results show that the characteristic spreading pattern of tau in early AD can be predicted by baseline biomarkers, particularly when stratifying groups using multimodal data. Further, we showed that our prognostic index predicts individualised rates of future tau accumulation with high accuracy and regional specificity in an independent sample of cognitively unimpaired individuals. Overall, our work used machine learning to combine continuous information from AD biomarkers predicting pathophysiological changes at different stages in the AD cascade. The approaches presented in this thesis provide an excellent framework to support personalised clinical interventions and guide effective drug discovery trials

Investigating data mining techniques for extracting information from Alzheimer\u27s disease data

Data mining techniques have been used widely in many areas such as business, science, engineering and more recently in clinical medicine. These techniques allow an enormous amount of high dimensional data to be analysed for extraction of interesting information as well as the construction of models for prediction. One of the foci in health related research is Alzheimer\u27s disease which is currently a non-curable disease where diagnosis can only be confirmed after death via an autopsy. Using multi-dimensional data and the applications of data mining techniques, researchers hope to find biomarkers that will diagnose Alzheimer\u27s disease as early as possible. The primary purpose of this research project is to investigate the application of data mining techniques for finding interesting biomarkers from a set of Alzheimer\u27s disease related data. The findings from this project will help to analyse the data more effectively and contribute to methods of providing earlier diagnosis of the disease