Diapositive 1

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MONOLIX An academic project Pr France
MentréINSERM U738, Université Paris Diderot Pr
Marc LavielleINRIA Saclay
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• Outline
• The SAEM algorithm
• The MONOLIX group
• MONOLIX use in academia

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• 1. The SAEM Algorithm
• An algorithm developed by mathematicians from
  French universities
• Delyon, Lavielle Moulines (1999). Convergence
  of a stochastic approximation version of the EM
  procedure. Ann Stat, 27 94-128.
• with extention to nonlinear mixed effect models
• Kuhn Lavielle (2004). Coupling a stochastic
  approximation version of EM with a MCMC
  procedure. ESAIM PS, 8 115-131.
• Kuhn Lavielle (2005). Maximum likelihood
  estimation in nonlinear mixed effects models.
  Comput Stat Data Analysis, 49 1020-1038.
• which has proven theoritical convergence

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• 2. The MONOLIX Group (1)
• Multidiciplinary academic working group
• Created in October 2003 by M. Lavielle and F.
  Mentré
• Involves members of various French academic
  institutions (Universities, INSERM, INRA,
  INRIA,)
• International collaborations with several
  academic groups

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• The MONOLIX Group (2)
• A common goal develop new methods for the study
  and use of nonlinear mixed effect models
• Develop new methods/algorithms means
• 1) Study their theoritical properties (and
  publish them)
• 2) Implement them in sofwtare,
• 3) Apply them to real problems (and publish
  them).

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• The MONOLIX Group (3)
• Two main research projects
• - estimation and model selection
• - design optimisation
• Two software
• - MONOLIX
• - PFIM
• Main area of application
• pharmacometrics

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• Strong French Academic Support
• Universities Paris 5, 7 11, INRIA, INSERM
• Salaries (professors, researchers, ingeneers,
  PhD, posdoc)
• Housing
• Agence Nationale de la Recherche
• Specific grant (2005-2008)
• Project selected for talk at Cité des Sciences,
  Paris (February 2009)
• also grants from industry (PhD, Ingeneers)

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• Main statistical developments
• Models with ordinary or stochastic differential
  equations
• Handling left-censored data (BQL)
• Inter-occasion variability and cross over designs
• REML estimation
• Criteria for model selection model evaluation
• Mixed models for discrete and count data
• Hiden Markov models
• ...

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• Main applications in MONOLIX group
• In pharmacometrics
• Pharmacokinetics and pharmacogenetics of
  antiretroviral agents in HIV
• Pharmacokinetics of antibiotics and emergence of
  resistance
• Viral kinetic models (HIV, HCV)
• Modelling epilepsy seizure counts
• And also
• Animal genetics, Agronomy, Neuroimaging,

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• Scientific productions
• 50 Published articles
• Computational Statistics Data Analysis,
  Statistics in Medicine, Biostatistics, European
  Series in Applied Mathematics Probability
  Statistics, Journal of Biopharmaceutical
  Statistics, Computer Methods and Programs in
  Biomedecine, Communication in Statistics Theory
  Methods, Statistics Computing, Biometrical
  Journal, Journal of Statistical Planning
  Inference,
• Journal of Pharmacokinetics Pharmacdoynamics,
  European Journal of Clinical Pharmacology,
  British Journal of Clinical Pharmacology,
  Pharmaceutical Research, Clinical
  Pharmacokinetics, Journal of Agricultural
  Biological and Environemental Statistics, Genetic
  Research, Neuroimaging,
• 20 Invited talks in conferences
• IBC, ISCB, JSM, JDS, SMAI,JOBIM,
• PAGANZ, PAGE, ACOP, PKUK,

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• 7 obtained PhDs
• 2003
• Estelle Kuhn (direction M Lavielle), MCF Paris 11
• Sylvie Retout (direction F Mentré), Roche
• 2006
• Adeline Samson (direction F Mentré M.
  Lavielle), MCF Paris-Descartes
• Sophie Donnet (direction M Lavielle), MCF Paris
  Dauphine
• Cristian Meza (direction J.L. Foulley M.
  Lavielle), Professeur, Univ. Valparaiso, Chili
• Karl Brendel (direction F Mentré), Servier
• Xavière Panhard (direction F Mentré), medical
  internship

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• 10 Current PhDs
• Third year
• Julie Bertrand (direction F Mentré E Comets)
• Caroline Bazzoli (direction F Mentré)
• Second year
• Anne Dubois (direction F Mentré)
• Merlin Keller (direction M Lavielle)
• Cyprien Mbogning (direction M Lavielle)
• Starting
• Thu-Thuy N'guyen (direction F Mentré)
• Maud Delattre (direction M Lavielle)
• Julie Marcellin (direction M Lavielle)
• Cyrielle Dumont (direction F Mentré)
• Hoai-Thu Thai (direction E Comets)

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• 2 Post Docs
• 2008
• Anna Karina Firmin (now MCF Paris 11)
• 2009
• Rada Savic (now post doc in Stanford University,
  USA)

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• 11 MONOLIX courses
• PAGE 2009, St-Petersbourg, Russia, June 2009
• University of Buffalo, USA, March 2009
• University of Sheffield, UK, January 2009
• Hoffmann-La Roche, Basel, Switzerland, December
  2008
• PAGE 2008, Marseille, France, June 2008
• Johnson Johnson, Beerse, Belgium, May 2008
• Novartis Pharma, Cambridge, USA, May 2008
• Novartis Pharma, East Hanover, USA, May 2008
• UCB, Braine lAllaud, Belgium, March 2008
• Novartis Pharma, Bâle, Switzerland, November 2007
  
• PAGANZ 2007, Singapour, February 2007

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3. MONOLIX use in academia Download of MONOLIX
from academia Universities Iowa, Utah,
Massachusetts, Kentucky, Maryland, Pennsylvania,
Pittsburgh, Buffalo, Brown, Uppsala, Utrecht,
Bern, Gdansk, Belfast, Melbourne, Paris, Lyon,
Marseille, Auckland, Cape Town, Teheran, Karachi,
Heilongjiang, Kyushu, Kyoto, Yogyaka, Naresuan,
Okayama, French Research Institutes INSERM,
CHU, CNRS, INRA, ENVT,
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• Survey
• Mail send on November 9 to 40 researchers from
  academia who downloaded MONOLIX
• Answers from 27
• 20 not in MONOLIX group
• 7 in MONOLIX group
• Country of answers
• France 7 (not including members of MONOLIX
  group)
• USA 4
• Iran 2
• Italy, UK, Germany, Malawi, Yemen, New Zealand,
  India

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• Use of MONOLIX for teaching
• Students
• Master or PhD
• Pharmacy, Bioingeneering, Medicine, Statistics
• Universities of
• Marseille, Paris 7, Paris 5, Lyon
• Utah (USA), Ahwaz (Iran),Tehran (Iran), Thamar
  (Yemen), Aukland (NZ)

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• Use of MONOLIX for academic research
• Type of data
• PK or PKPD 17
• Simulation 8
• Others earthquake observations, viral load,
  microbial growth kinetics, hematotoxicity, tumor
  growth
• Application area Neurology, Addiction, HIV,
  Cancer, Pregnancy, Food microbiology, Anasthesia,
  Sedation, Analgesia, Oral anticoagulants,
  Pharmacogenetics, Immunosuppressive drugs,
  Paediatric, Preclinical studies, Infection,
  Malaria, Influenza

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• COMMENTS
• Useful program, Bravi!
• Great piece of software , easy to use, very
  stable
• Delighted with the tools it provided
• Much easier to use than WinNonLin V
• Shift the PhD students from NONMEM to MONOLIX
• Great program for teaching basic concepts of
  population modelling
• Reinforce concept difficult to teach using NONMEM
• A useful tool especially for limited sampled data
  sets seen in pediatrics
• User-friendly
• Much better at handling sparse data
• A treasure for the scientific community
• Unbelievable thats it's free
• Great tool! Very pedagogical