SoftwAiR: High-throughput processing of real-time and high-resolution mass spectrometry analysis from exhaled air for the characterization of the human volatolome variations in disease and response to pharmacological treatments Metabolomics is the last-born “omic” approach, consisting in exploring the metabolome; i.e. the expression of all endogenous molecules located downstream (in biological terms) of those targeted by established genomic, transcriptomic and proteomic methods. In the last years, an innovative metabolomic approach focusing on exhaled breath (and therefore called “breathomics” or “volatolomics”) has emerged. It consists in a comprehensive analysis of metabolism-derived Volatile Organic Compounds (VOCs) (the volatolome) in patients' exhaled air. Those VOCs can be directly derived from pulmonary metabolism and reflect the metabolic state of the lungs, but they can also be derived from all other organs by being transported through the bloodstream to the lungs and then into the exhaled air. Recent reports suggest that volatolomics is a promising tool for personalized medicine with major advantages over classical biological investigations: the sampling is completely non-invasive, painless and fast and some instruments allow real-time analysis. Such instruments, such as proton transfer reaction-high resolution mass spectrometry (PTR-HRMS) have emerged as a powerful technology for VOC analysis in a wide range of environmental, biological and medical applications. However, several pitfalls remain to be addressed before volatolomics can be adopted in routine medical practice, the major ones being the lack of bioinformatics tools for the efficient processing and analysis of real-time PTR-MS data and of the associated statistical pipelines for biomarker discovery. Here we have built a team of experienced clinicians, biologists, and applied mathematicians to propose for the first time 1) to develop innovative algorithms and software environment for the processing of real-time analysis of VOCs in exhaled air and to implement a statistical framework for the longitudinal study of individuals’ temporal profiles, and 2) to apply this workflow to samples obtained during a clinical trial aimed at identifying biomarkers of acute rejection in lung transplant recipients. The work will be carried out with data obtained from a last-generation, high-resolution and high-sensitivity PTR-time-of-flight instrument, equipped with a CE-labelled BET-med device to collect patient’s samples. The 3-year program of a PhD student, supervised by an internationally recognized expert in metabolomic data processing and analysis from the Commissariat à l’Energie Atomique (CEA) will mainly include i) the development of the bioinformatic tools for the processing of PTR-HRMS data (peak detection and quantification, peak alignment…), ii) the development of statistical workflows for biomarker discovery and longitudinal analysis and iii) the application of the developed tools to samples obtained in clinical trials taking place at Foch Hospital, starting with a study to detect acute rejection in lung transplant recipients. The completion of this study would result in real progresses in the medical management of patients, by avoiding numbers of invasive and time-consuming diagnostic methods, improving both quality, acceptability and the medico-economic burden of medical care. The dissemination of our results and tools in publicly available repositories and online platforms will enable the use of our approaches by other teams working in the field and also in non-medical applications worldwide. Moreover, prospects do exist in several other lung and non-lung diseases for which several clinical trials are already planed for the next months (detection of fungi or mycobacteria infections in immunocompromised or cystic fibrosis patients, monitoring of the response to targeted immunotherapies in patients with asthma...).

The COMIS project aims at developing a new method for evaluating the efficiency of innovative systems in energy-efficient buildings, through an original commissioning approach focused on the first year of a building's operation, which is often particularly critical in terms of fine-tuning the active systems operation parameters in the building. The proposed commissioning approach is based on measurements and numerical simulations, and combines a virtual comparison of the considered system's actual operating conditions to theoretical "ideal" operating conditions and to a conventional reference system. The proposed methodology will be developed in 3 main steps. The first step aims at measuring the operating characteristics of the considered systems, in their respective operating environments. One of the important aspects in this field is the choice of the adequate metrology, regarding the identification of the physical parameters relative to the considered systems, the indoor conditions, and the building's usage. The developed methodology will rely on statistical procedures such as "sensitivity analysis" or "principal component analysis", in order to choose the appropriate spatial granularity and acquisition frequency for the instrumentation to be installed. Then, even before being used for the model parameters identification in the numerical simulations, the acquired measurement data need to be filtered, corrected, possibly rebuilt, and finally aggregated into high level indicators. For this purpose, a full set of data processing algorithms will be developed. These algorithms will be adapted to the nature of the measured physical parameters and to the acquisition devices used. Once the system's operating conditions and parameters have been characterized in the used building, based on the measured and processed data, the next step is to evaluate its performance against the expected theoretical performance, which is estimated from the actual weather conditions, envelope measured characteristics and real usage of the building. For this the theoretical "ideal" operating conditions of the system have to be defined, considering its internal parameters and the expected service. A behavioral model of each considered system will be developed, and their parameters will be identified from the actual measurement data acquired in the building. These behavioral models will be used to identify the parameters of the theoretical "ideal" operating conditions, defined either in terms of sizing (of its internal elements) or command and control (of each element regarding the other ones). The reliability of the developed models and performance indicators used in the project will be assessed by characterizing the influence of models input parameters uncertainties on models output results. In addition to the "ideal" operating conditions approach, the observed system will be compared to a conventional reference solution providing an identical service under identical conditions (weather, usage, building envelope intrinsic performance). The aim of this complementary approach is to assess that the rightful choice has been made during the conception phase, regarding the expected service and original choice criteria. As a final step, the COMIS project will include the study of four new or newly renovated buildings displaying ambitious energy performance targets (low consumption, passive or positive energy labels) and including innovative heating, cooling, ventilation, DHW production and management systems. The developed commissioning methodology will be implemented, tested, improved and eventually validated on these test cases.