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

Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues

An Introduction to Recursive Partitioning: Rationale, Application and Characteristics of Classification and Regression Trees, Bagging and Random Forests

Recursive partitioning methods have become popular and widely used tools for nonparametric regression and classification in many scientific fields. Especially random forests, that can deal with large numbers of predictor variables even in the presence of complex interactions, have been applied successfully in genetics, clinical medicine and bioinformatics within the past few years. High dimensional problems are common not only in genetics, but also in some areas of psychological research, where only few subjects can be measured due to time or cost constraints, yet a large amount of data is generated for each subject. Random forests have been shown to achieve a high prediction accuracy in such applications, and provide descriptive variable importance measures reflecting the impact of each variable in both main effects and interactions. The aim of this work is to introduce the principles of the standard recursive partitioning methods as well as recent methodological improvements, to illustrate their usage for low and high dimensional data exploration, but also to point out limitations of the methods and potential pitfalls in their practical application. Application of the methods is illustrated using freely available implementations in the R system for statistical computing

Estimating the heritability of psychological measures in the Human Connectome Project dataset

The Human Connectome Project (HCP) is a large structural and functional MRI dataset with a rich array of behavioral and genotypic measures, as well as a biologically verified family structure. This makes it a valuable resource for investigating questions about individual differences, including questions about heritability. While its MRI data have been analyzed extensively in this regard, to our knowledge a comprehensive estimation of the heritability of the behavioral dataset has never been conducted. Using a set of behavioral measures of personality, emotion and cognition, we show that it is possible to re-identify the same individual across two testing times (fingerprinting), and to identify identical twins significantly above chance. Standard heritability estimates of 37 behavioral measures were derived from twin correlations, and machine-learning models (univariate linear model, Ridge classifier and Random Forest model) were trained to classify monozygotic twins and dizygotic twins. Correlations between the standard heritability metric and each set of model weights ranged from 0.36 to 0.7, and questionnaire-based and task-based measures did not differ significantly in their heritability. We further explored the heritability of a smaller number of latent factors extracted from the 37 measures and repeated the heritability estimation; in this case, the correlations between the standard heritability and each set of model weights were lower, ranging from 0.05 to 0.43. One specific discrepancy arose for the general intelligence factor, which all models assigned high importance, but the standard heritability calculation did not. We present a thorough investigation of the heritabilities of the behavioral measures in the HCP as a resource for other investigators, and illustrate the utility of machine-learning methods for qualitative characterization of the differential heritability across diverse measures