Statistics in systems biology and translationnal medicine – SISTM

The team is devoted to the development of statistical methods for the integrative analysis of data in medicine and biology. Thanks to the technological improvements, clinical and biological research is generating massive amounts of data. Of importance are the « omics » data such as genomics (gene expression) and proteomics but also other types of data, for which modern technologies have strongly increased the amount of information (e.g. medical imaging, cell counts).
This SISTM team is labelled by both Inserm and Inria.

Objectives

The challenge is to analyze these BIG DATA to answer clinical and biological questions by using appropriate statistical methods. With data on the machinery of a cell to the clinical status of individuals in any circumstances including in clinical trials, new tools are needed to translate information obtained from complex systems into knowledge. This has led to the field of « systems biology » and « systems medicine » by extension, which naturally takes place in the context of translational medicine that links clinical and biological research.
The statistical analysis of these data is facing several issues:

  • There are more parameters (p) to estimate than individuals (n)
  • The types/nature of data are various
  • The relationship between variables is often complex (e.g. non linear) and can change over time to tackle these issues we are developing specific approaches for these questions, often related to immunology.

The methods are mainly based on either mecanistic modeling using differential equation systems or on statistical learning methods. The general paradigm of our approach is to include as much information as available to answer a given question. This information comes from the available data but also from prior biological information available defining the structure of the model or restricting the space of the parameter values. We develop and apply our methods mainly for applications belonging to clinical research especially HIV immunology. For instance, several projects are devoted to the modelling of the response to antiretroviral treatments, immune interventions or vaccine in HIV infected patients.

Applications are provided by the Vaccine Research Institute (VRI), other teams in the research centre and the Bordeaux Hospital Clinical Trial Unit (CTU).

 

Research area

Axis 1: Mecanistic modelling

When studying the dynamics of a given marker, say the HIV concentration in the blood (HIV viral load), one can for instance use descriptive models summarizing the dynamics over time in term of slopes of the trajectories. These slopes can be compared between treatment groups or according to patients’ characteristics. Another way for analyzing these data is to define a mathematical model based on the biological knowledge of what drives infection dynamics. Having a good mechanistic model in a biomedical opens doors to various applications beyond a good understanding of the data.

 

Axis 2: High dimensional data

Working on omics data such as genomics (DNA), transcriptomics (RNA) or proteomics (proteins), but also other types of data, such as those arising from the combination of large observational databases (e.g. in pharmacoepidemiology or environmental epidemiology), the challenge is that data sets usually contain many variables, much more than the observations.

Furthermore, conventional methods, such as linear models, are inefficient and most of the time even inapplicable. Therefore, more than the storage and calculation capacities, the challenge is the comprehensive analysis of these datasets from molecular pathways to clinical response of a population of patients needs specific approaches and a very close collaboration with the providers of data (the immunologists, the virologists, the clinicians…). The objective is either to select the relevant information or to summarize it for understanding or prediction purposes.

 

Axis 3: Translational vaccinology

During early phase clinical vaccine development (phase I, II trials, translational trials) there is no validated surrogate endpoints to predict the clinical efficacy of a vaccine strategy based on immunogenicity results. A methodological research is needed at the interface between disciplines: biostatistics, immunology and vaccinology. The objectives of this axis is to elucidate the effects and mechanisms of action of vaccines and immunotherapies thanks to integrative statistical analyzes applied to immunological responses. But also better inform the choice of evaluation schemes for the development of vaccines and immunotherapies thanks to methodological developments.



 International relationships

  • Vaccine Research Institute (Hôpital Henri Mondor, Creteil) As “Labex”, the labovatory of Excellence is an extension of ANRS (French research HIV Hepatitis) program to accelerate the vaccines development of against HIV and the hepatitis C. Video : What is the VRI ?
  • Immunobiology department, Institute of Child Health, University College London
  • Statistical Center for HIV/AIDS Research & Prevention (SHARP),
  • Vaccine and Infectious Diseases Division of the Fred Hutchinson Cancer Research Center
  • Department of Systems and Computational Biology at Albert Einstein College of Medicine, New York
  • School of Mathematics and Physics at the University of Queensland
  • The SWAGR Associate Team is part of the Inria@SiliconValley program, and aims at bringing together a Statistical Workforce for Advanced Genomics using RNAseq between the SISTM team and the Statistics group at the RAND Corporation, in an effort to improve RNAseq data analysis methods by developing a flexible, robust, and mathematically principled framework for detecting differential gene expression
  • The DYNAMHIC Associate Team is dedicated to the analysis of unique pre-clinical data in non-human primates of HIV cure interventions. The novelty of the approach is to propose an integrative project studying complex biological processes with novel mathematical and statistical models, which has the potential to yield predictive computational tools to assist in the design of both therapeutic products and clinical trials for HIV cure

Regularly international researchers and students visit the SISTM team they are working with such as :

International projects:

  • The EBOVAC2 was funded under IMI2 Ebola+ programme that was launched in response to the Ebola virus disease outbreak. The project aims to assess the safety and efficacy of a novel prime boost preventive vaccine regimen against Ebola Virus Disease (EVD). The project is coordinating by Inserm U897 under the scientific responsibility of Professor Rodolphe Thiébaut.
  • European HIV Vaccine Alliance (EHVA), EU Horizon 2020 project, is a major milestone as an EU platform for the discovery and evaluation of novel prophylactic and therapeutic vaccine candidates.



Main publications

1) Prague M, Commenges D, Drylewicz J, Thiébaut R. Treatment Monitoring of HIV-Infected Patients based on Mechanistic Models. Biometrics, 2012; 68:902-11.
2) Liquet B, Le Cao KA, Hocini H, Thiebaut R. A novel approach for biomarker selection and the integration of repeated measures experiments from two assays. BMC Bioinformatics. 2012;13:325.
3) Avalos M, Adroher ND, Lagarde E, Thiessard F, Grandvalet Y, Contrand B, Orriols L; CESIR Research Group. Prescription-drug-related risk in driving: comparing conventional and lasso shrinkage logistic regressions. Epidemiology. 2012;23:706-12.
4) Furman D*, Hejblum BP*, Simon N, Jojic V, Dekker CL, Thiébaut R, Tibshirani RJ, Davis MM. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proceedings of the National Academy of Sciences of the United States of America. 2014;111:869-874. * equally contributor
5) Thiébaut R, Drylewicz J, Prague M, Lacabaratz C, Beq S, Jarne A, Croughs T, Sekaly RP, Lederman MM, Sereti I, Commenges D, Lévy Y. Quantifying and predicting the effect of exogenous interleukin-7 on CD4+ T cells in HIV-1 infection. PLoS Computational Biology. 2014 May 22;10(5):e1003630.


Details

Link : Inria

  • Director : 
    Prof (PUPH)
    Directeur adjoint centre de recherche / Deputy director research centre
    Directeur d’équipe / Director INRIA SISTM
    Responsable médical USMR / Head CTU
    Coordinateur/Coordinator Master 2 Epidemiology

    Parcours

    Directeur de Recherche de deuxième classe à l’Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche U897 « Epidémiologie et Biostatistiques » (DR2 01/11/2010-01/09/2013, CR1 du 01/11/2006 au 30/10/2010, CR2 du 01/11/2002 au 31/10/2006)

    Médecin attaché à l’Unité de Soutien Méthodologique à la Recherche Clinique et Epidémiologique du CHU de Bordeaux (depuis le 01/01/2003, contrat d’interface INSERM-CHU depuis le 01/01/2008)

    Principaux Diplômes

    Habilité à diriger les recherches (Université Bordeaux 2, depuis le 15/12/2004)

    Docteur de l’Université Bordeaux 2, section « sciences biologiques et médicales » option « Santé Publique / Biostatistique» (depuis le 17/12/2002)

    Docteur en médecine, spécialité Santé Publique (Université Bordeaux 2, depuis le 10/10/2000)

     

  • Contact : Sandrine Darmigny


News

Members


  • Marta Avalos
    MdC Biostatistique

    Parcours

     Education

    2004 PhD Information and Systems Technologies, Technology Univ., Compiègne.

    2001 MD Public Health, Paris-Sud Univ., Orsay.

    2000 MD Mathematics, Barcelona Univ., Barcelona (Spain).

    Position

    2005 – Assistant professor with tenure (Maître de Conférences), Bordeaux Univ., Bordeaux, ISPED.

    2004 – 2005 Assistant lecturer (ATER), Paris Diderot Univ., Paris.

    2001 – 2004 PhD student (Allocataire de recherche), Compiègne Technology Univ., Compiègne.

  • Sandrine Darmigny
  • Mélany Durand
    Ingénieur d’étude

    2015-2017 Master Santé Publique, parcours Biostatistique à l’ISPED (Université de Bordeaux)

  • Vishwa Elankumaran
  • Robin Genuer
    Maître de Conférences
  • Boris Hejblum
    Chercheur (Chargé de Recherche à l’Inserm)

    Parcours

    • 2021 – en cours Chargé de Recherche en Biostatistique à l’Inserm Bordeaux-Population-Health — équipe SISTM
    • 2016 – 2021 Maître de Conférences section 26 en Biostatistique à l’ISPED
    • 2015 – 2016 Post-doctorant à la Harvard T.H. Chan School of Public Health avec Tianxi Cai
    • 2015 Docteur en Santé Publique – option Biostatistique de l’université de Bordeaux
      Thèse “Analyse intégrative de données de grande dimension appliquée à la recherche vaccinale” effectuée sous la direction de Rodolphe Thiébaut et de François Caron à l’ISPED (Institut de Santé Publique, d’Epidémiologie et de Developpement) ; Inserm U897, au sein l’équipe Biostatistiques
    • 2011 Ingénieur en Statistique de l’ENSAI (École Nationale de la Statistique et de l’Analyse de l’Information) –  spécialité Statistique pour les Sciences de la Vie
    • 2011 Master en Statistique, Économétrie de l’Université de Rennes 1
  • Benjamin Hivert
  • Melanie Huchon
    Ingénieure d’études

    2019-2021 : Master Santé Publique parcours Biostatistique à l’ISPED (Bordeaux, 33)

    2016-2019 : Licence Mathématiques, Informatique, Statistiques (MIS) parcours Statistiques à l’Université Bretagne Sud (Vannes, 56)

  • Edouard Lhomme
    MD, PhD
    MCU-PH Santé Publique
    2011 – 2016

    Interne en médecine, spécialité Santé Publique et médecine sociale / Medical resident in Public Health

    University of Bordeaux – CHU Bordeaux

    2016 – 2020

    Assistant Hospitalo-Universitaire / Assistant Professor | Santé Publique / Public Health

    University of Bordeaux – CHU Bordeaux

    2020 – 2021

    Scientific advisor COVID19 

    Cellule interministerielle recherche, Pole Recherche et Innovation, Centre de Crise Sanitaire

    Ministère des Solidarités et de la Santé (DGS)

    Sept 2021 – now

    Maître de conférences des universités-praticien hospitalier (MCU-PH) / Associate Professor | Santé Publique / Public Health

    University of Bordeaux – CHU Bordeaux

  • Anton Ottavi
    Coordinateur de Projets Internationaux

    Parcours Professionnel :

    Coordinateur de projet international pour l’Inserm – Bordeaux (mars 2015 – Aujourd’hui) 

    Responsable Projets Européens et Internationaux à la Fondation Voir et Entendre -Paris (Septembre 2014 – Mars 2015)

    Management de projets internationaux à Inserm Transfert SA –Paris, Clermont-Ferrand, Lyon (2004 –2014)

    Formateur-Consultant pour Optigest Formation – La Rochelle (2002 – 2004)                                

    Chef de projet de recherche pour VALTTEC SA – Poitiers (1997 – 2000)                                                                                  

    Principaux Diplômes :

    DESS (Master 2) Certificat d’Aptitude à l’Administration des Entreprises – IAE de Poitiers, Mention AB (2002)

    Doctorat de Biologie Cellulaire – Université de Limoges, Mention Très Honorable et Félicitations du Jury (1997)

    DEA (Master 2) Biologie Santé – Université Bordeaux II, Mention AB (1992)

  • Mélanie Prague
    Chargé de Recherche Inria

    CR Inria depuis 2016. J’ai obtenu une thèse en Santé publique option Biostatistiques à l’université de Bordeaux en 2013 sur le “monitoring des patients infectés par le VIH”. Avant cela, je suis ingénieur en statistiques de l’ENSAI et possède un master en statistiques mathématiques et économétrie. Suite à ma thèse, j’ai effectué un court séjour postdoctoral à l’université d’Oslo (Norvège), puis un postdoctorat de 2 ans 1/2 à l’école de santé publique d’Harvard (Boston, USA). 

     

    CR INRIA since 2016. I got a PhD in Public Health option Biostatistics at the University of Bordeaux in 2013 on the “monitoring of patients infected with HIV.” Before that, I‘m a engineer in statistics  from ENSAI  and have a master degree in mathematical statistics and econometrics. Following my thesis, I conducted a short postdoctoral stay at the University of Oslo (Norway), then I was a postdoctoral fellow for 2 1/2 years at Harvard School of Public Health (Boston, USA).
     
  • Myrtille Richard
    Public Health MD, Research engineer
  • Laura Richert
  • Rodolphe Thiebaut
    Prof (PUPH)
    Directeur adjoint centre de recherche / Deputy director research centre
    Directeur d’équipe / Director INRIA SISTM
    Responsable médical USMR / Head CTU
    Coordinateur/Coordinator Master 2 Epidemiology

    Parcours

    Directeur de Recherche de deuxième classe à l’Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche U897 « Epidémiologie et Biostatistiques » (DR2 01/11/2010-01/09/2013, CR1 du 01/11/2006 au 30/10/2010, CR2 du 01/11/2002 au 31/10/2006)

    Médecin attaché à l’Unité de Soutien Méthodologique à la Recherche Clinique et Epidémiologique du CHU de Bordeaux (depuis le 01/01/2003, contrat d’interface INSERM-CHU depuis le 01/01/2008)

    Principaux Diplômes

    Habilité à diriger les recherches (Université Bordeaux 2, depuis le 15/12/2004)

    Docteur de l’Université Bordeaux 2, section « sciences biologiques et médicales » option « Santé Publique / Biostatistique» (depuis le 17/12/2002)

    Docteur en médecine, spécialité Santé Publique (Université Bordeaux 2, depuis le 10/10/2000)

     

  • Linda Wittkop
    MD PhD
    Directrice du CMG-EC Inserm-ANRS – Maladies Infectieuses et Vaccinologie/Director of clinical trial unit Inserm-ANRS – Infectious Disease and Vaccinology

    Parcours


    2015  Habilitation, Ecole Doctorale Scoiétés, Politique, Santé Publique, Speciality: Public Health, University of Bordeaux, France
    2010    PhD in Science, Technology and Health, Speciality: Epidemiology and Public Health, University of Bordeaux, Bordeaux, France.
    2007   MD, Justus Liebig University, Giessen, Germany.
    2007  MSc in Epidemiology and Biostatics, University of Bordeaux, ISPED, Bordeaux, France.
    2004  Approbation – German official license to practice as a doctor, Federal State examination board for therapeutic professions – Hessisches Landesprüfungsamt für Heilberufe, Frankfurt am Main, Hessen, Germany.
    2003     Certificate of the Medical Examination, Federal State examination board for therapeutic professions – Hessisches Landesprüfungsamt für Heilberufe, Frankfurt am Main, Hessen, Germany.
    1997-2003  Medical School, Justus Liebig University, Giessen, Germany and Universidad Autonoma, Madrid, Spain.
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