This work represents the first attempt to provide an overview of how to face data integration as the result of a dialogue between neuroscientists and computer scientists. Indeed, data integration is fundamental for studying complex multifactorial diseases, such as the neurodegenerative diseases. This work aims at warning the readers of common pitfalls and critical issues in both medical and data science fields. In this context, we define a road map for data scientists when they first approach the issue of data integration in the biomedical domain, highlighting the challenges that inevitably emerge when dealing with heterogeneous, large-scale and noisy data and proposing possible solutions. Here, we discuss data collection and statistical analysis usually seen as parallel and independent processes, as cross-disciplinary activities. Finally, we provide an exemplary application of data integration to address Alzheimer's Disease (AD), which is the most common multifactorial form of dementia worldwide. We critically discuss the largest and most widely used datasets in AD, and demonstrate how the emergence of machine learning and deep learning methods has had a significant impact on disease's knowledge particularly in the perspective of an early AD diagnosis.

Graphical models allow to describe the interplay among variables of a system through a compact representation, suitable when relations evolve over time. For example, in a biological setting, genes interact differently depending on external environmental or metabolic factors. To incorporate this dynamics a viable strategy is to estimate a sequence of temporally related graphs assuming similarity among samples in different time points. While adjacent time points may direct the analysis towards a robust estimate of the underlying graph, the resulting model will not incorporate long-term or recurrent temporal relationships. In this work we propose a dynamical network inference model that leverages on kernels to consider general temporal patterns (such as circadian rhythms or seasonality). We show how our approach may also be exploited when the recurrent patterns are unknown, by coupling the network inference with a clustering procedure that detects possibly non-consecutive similar networks. Such clusters are then used to build similarity kernels. The convexity of the functional is determined by whether we impose or infer the kernel. In the first case, the optimisation algorithm exploits efficiently proximity operators with closed-form solutions. In the other case, we resort to an alternating minimisation procedure which jointly learns the temporal kernel and the underlying network. Extensive analysis on synthetic data shows the efficacy of our models compared to state-of-the-art methods. Finally, we applied our approach on two realworld applications to show how considering long-term patterns is fundamental to have insights on the behaviour of a complex system.

We present an algorithm for dictionary learning that is based on the alternating proximal algorithm studied by Attouch, Bolte, Redont, and Soubeyran (2010), coupled with a reliable and efficient dual algorithm for computation of the related proximity operators. This algorithm is suitable for a general dictionary learning model composed of a Bregman-type data fit term that accounts for the goodness of the representation and several convex penalization terms on the coefficients and atoms, explaining the prior knowledge at hand. As Attouch et al. recently proved, an alternating proximal scheme ensures better convergence properties than the simpler alternating minimization. We take care of the issue of inexactness in the computation of the involved proximity operators, giving a sound stopping criterion for the dual inner algorithm, which keeps under control the related errors, unavoidable for such a complex penalty terms, providing ultimately an overall effective procedure. Thanks to the generality of the proposed framework, we give an application in the context of genome-wide data understanding, revising the model proposed by Nowak, Hastie, Pollack, and Tibshirani (2011). The aim is to extract latent features (atoms) and perform segmentation on array-based comparative genomic hybridization (aCGH) data. We improve several important aspects that increase the quality and interpretability of the results. We show the effectiveness of the proposed model with two experiments on synthetic data, which highlight the enhancements over the original model.

In this work we present and discuss in detail a novel vector-valued regression technique: our approach allows for an all-at-once estimation, as opposed to solve a number of scalar-valued regression tasks. Despite its general purpose nature, the method has been designed to solve a delicate medical issue: a reliable and non-invasive assessment of body-iron overload. The Magnetic Iron Detector (MID) measures the magnetic track of a person, which depends on the anthropometric characteristics and the body-iron burden. We aim to provide an estimate of this signal in absence of iron overload. We show how this question can be formulated as the estimation of a vector-valued function which encompasses the prior knowledge on the shape of the magnetic track. This is accomplished by designing an appropriate vector-valued feature map. We successfully applied the method on a dataset of 84 volunteers.

The search for predictive biomarkers of disease from high-throughput mass spectrometry (MS) data requires a complex analysis path. Preprocessing and machine-learning modules are pipelined, starting from raw spectra, to set up a predictive classifier based on a shortlist of candidate features. As a machine-learning problem, proteomic profiling on MS data needs caution like the microarray case. The risk of overfitting and of selection bias effects is pervasive: not only potential features easily outnumber samples by 10(3) times, but it is easy to neglect information-leakage effects during preprocessing from spectra to peaks. The aim of this review is to explain how to build a general purpose design analysis protocol (DAP) for predictive proteomic profiling: we show how to limit leakage due to parameter tuning and how to organize classification and ranking on large numbers of replicate versions of the original data to avoid selection bias. The DAP can be used with alternative components, i.e. with different preprocessing methods (peak clustering or wavelet based), classifiers e.g. Support Vector Machine (SVM) or feature ranking methods (recursive feature elimination or I-Relief). A procedure for assessing stability and predictive value of the resulting biomarkers' list is also provided. The approach is exemplified with experiments on synthetic datasets (from the Cromwell MS simulator) and with publicly available datasets from cancer studies.

MOTIVATION: We propose a method for studying the stability of biomarker lists obtained from functional genomics studies. It is common to adopt resampling methods to tune and evaluate marker-based diagnostic and prognostic systems in order to prevent selection bias. Such caution promotes honest estimation of class prediction, but leads to alternative sets of solutions. In microarray studies, the difference in lists may be bewildering, also due to the presence of modules of functionally related genes. Methods for assessing stability understand the dependency of the markers on the data or on the predictor's type and help selecting solutions. RESULTS: A computational framework for comparing sets of ranked biomarker lists is presented. Notions and algorithms are based on concepts from permutation group theory. We introduce several algebraic indicators and metric methods for symmetric groups, including the Canberra distance, a weighted version of Spearman's footrule. We also consider distances between partial lists and an aggregation of sets of lists into an optimal list based on voting theory (Borda count). The stability indicators are applied in practical situations to several synthetic, cancer microarray and proteomics datasets. The addressed issues are predictive classification, presence of modules, comparison of alternative biomarker lists, outlier removal, control of selection bias by randomization techniques and enrichment analysis. AVAILABILITY: Supplementary Material and software are available at the address http://biodcv.fbk.eu/listspy.html

In this paper, we present a method for predictive profiling of mass spectrometry data. The method integrates a spectra preprocessing pipeline with a complete validation setup aimed at identifying the discriminating peaks and at providing an unbiased estimate of the predictive classification error, based on SVM classifiers and on Entropy-based RFE procedure. A particular emphasis is placed upon avoiding selection bias effects throughout all the analysis steps, from preprocessing to peak importance ranking.

In the statistical learning framework, the use of appropriate kernels may be the key for substantial improvement in solving a given problem. In essence, a kernel is a similarity measure between input points satisfying some mathematical requirements and possibly capturing the domain knowledge. In this paper, we focus on kernels for images: we represent the image information content with binary strings and discuss various bitwise manipulations obtained using logical operators and convolution with nonbinary stencils. In the theoretical contribution of our work, we show that histogram intersection is a Mercer's kernel and we determine the modifications under which a similarity measure based on the notion of Hausdorff distance is also a Mercer's kernel. In both cases, we determine explicitly the mapping from input to feature space. The presented experimental results support the relevance of our analysis for developing effective trainable systems.

In this paper we address the problem of classifying images, by exploiting global features that describe color and illumination properties, and by using the statistical learning paradigm. The contribution of this paper is twofold. First, we show that histogram intersection has the required mathematical properties to be used as a kernel function for support vector machines (SVMs). Second, we give two examples of how a SVM, equipped with such a kernel, can achieve very promising results on image classification based on color information.