Section: Research Program

Imaging & Phenomics, Biostatistics

The human phenotype is associated with a multitude of heterogeneous biomarkers quantified by imaging, clinical and biological measurements, reflecting the biological and patho-physiological processes governing the human body, and essentially linked to the underlying individual genotype.In order to deepen our understanding of these complex relationships and better identify pathological traits in individuals and clinical groups, a long-term objective of e-medicine is therefore to develop the tools for the joint analysis of this heterogeneous information, termed Phenomics, within the unified modeling setting of the e-patient.

Ongoing research efforts aim at investigating optimal approaches at the crossroad between biomedical imaging and bioinformatics to exploit this diverse information. This is an exciting and promising research avenue, fostered by the recent availability of large amounts of data from joint imaging and biological studies (such as the UK biobank (http://www.ukbiobank.ac.uk/), ENIGMA (http://enigma.ini.usc.edu/.), ADNI (http://adni.loni.usc.edu/),$...$). However, we currently face important methodological challenges, which limit the ability in detecting and understanding meaningful associations between phenotype and biological information.

To date the most common approach to the analysis of the joint variation between the structure and function of organs represented in medical images, and the classical -omics modalities from biology, such as genomics or lipidomics, is essentially based on the massive univariate statistical testing of single candidate features out of the many available. This is for example the case of genome-wide association studies (GWAS) aimed at identifying statistically significant effects in pools consisting of up to millions of genetics variants. Such approaches have known limitations such as multiple comparison problems, leading to underpowered discoveries of significant associations, and usually explain a rather limited amount of data variance. Although more sophisticated machine learning approaches have been proposed, the reliability and generalization of multivariate methods is currently hampered by the low sample size relatively to the usually large dimension of the parameters space.

To address these issues this research axis investigates novel methods for the integration of this heterogeneous information within a parsimonious and unified multivariate modeling framework. The cornerstone of the project consists in achieving an optimal trade-off between modeling flexibility and ability to generalize on unseen data by developing statistical learning methods informed by prior information, either inspired by "mechanistic" biological processes, or accounting for specific signal properties (such as the structured information from spatio-temporal image time series). Finally, particular attention will be paid to the effective exploitation of the methods in the growing Big Data scenario, either in the meta-analysis context, or for the application in large datasets and biobanks.

• Modeling associations between imaging, clinical, and biological data. The essential aspect of this research axis concerns the study of data regularization strategies encoding prior knowledge, for the identification of meaningful associations between biological information and imaging phenotype data. This knowledge can be represented by specific biological mechanisms, such as the complex non-local correlation patterns of the -omics encoded in genes pathways, or by known spatio-temporal relationship of the data (such as time series of biological measurements or images). This axis is based on the interaction with research partners in clinics and biology, such as IPMC (CNRS, France), the Lenval Children's Hospital (France), and University College London (UK). This kind of prior information can be used for defining scalable and parsimonious probabilistic regression models. For example, it can provide relational graphs of data interactions that can be modelled by means of Bayesian priors, or can motivate dimensionality reduction techniques and sparse frameworks to limit the effective size of the parameter space. Concerning the clinical application, an important avenue of research will come from the study of the reduced representations of the -omics data currently available in clinics, by focusing on the modeling of the disease variants reported in previous genetic findings. The combination of this kind of data with the information routinely available to clinicians, such as medical images and memory tests, has a great potential for leading to improved diagnostic instruments. The translation of this research into clinical practice is carried out thanks to the ongoing collaboration with primary clinical partners such as the University Hospital of Nice (MNC3 partner, France), the Dementia Research Centre of UCL (UK), and the Geneva University Hospital (CH).

• Learning from collections of biomedical databases. The current research scenario is characterised by medium/small scale (typically from 50 to 1000 patients) heterogeneous datasets distributed across centres and countries. The straightforward extension of learning algorithms successfully applied to big data problems is therefore difficult, and specific strategies need to be envisioned in order to optimally exploit the available information. To address this problem, we focus on learning approaches to jointly model clinical data localized in different centres. This is an important issue emerging from recent large-scale multi-centric imaging-genetics studies in which partners can only share model parameters (e.g. regression coefficients between specific genes and imaging features), as represented for example by the ENIGMA imaging-genetics study, led by the collaborators at University of Southern California. This problem requires the development of statistical methods for federated model estimation, in order to access data hosted in different clinical institutions by simply transmitting the model parameters, that will be in turn updated by using the local available data. This approach is extended to the definition of stochastic optimization strategies in which model parameters are optimized on local datasets, and then summarized in a meta-analysis context. Finally, this project studies strategies for aggregating the information from heterogeneous datasets, accounting for missing modalities due to different study design and protocols. The developed methodology finds important applications within the context of Big Data, for the development of effective learning strategies for massive datasets in the context of medical imaging (such as with the UK biobank), and beyond.