Talk given on Saturday, December 9th, 2017 at the Ecole Normale Supérieure (ENS) for the ALIUS Annual Workshop Video on Facebook: https://www.facebook.com/aliusresearch/videos/1747266255570116/ More talks from the workshop and info on ALIUS Facebook page: https://www.facebook.com/aliusresearch/

1. Normative Modeling and Patients Stratification:
dealing with dimensions & categories in modern psychiatry
Guillaume Dumas 1,2,3,4,∗
1. Human Genetics & Cognitive Functions, Neuroscience Dpt., Institut Pasteur
2. SoNeTAA platform, Child & Adolescent Psychiatry, Robert-Debré Hospital
3. Human Brain & Behavior Lab., Center for Complex Systems & Brain Sciences
4. ALIUS Research Group
*. Contact: guillaume.dumas@pasteur.fr
ALIUS Workshop
Saturday, December 9th, 2017

2. Normative Modeling and Patients Stratification:
dealing with dimensions & categories in modern psychiatry
Guillaume Dumas 1,2,3,4,∗
1. Human Genetics & Cognitive Functions, Neuroscience Dpt., Institut Pasteur
2. SoNeTAA platform, Child & Adolescent Psychiatry, Robert-Debré Hospital
3. Human Brain & Behavior Lab., Center for Complex Systems & Brain Sciences
4. ALIUS Research Group
*. Contact: guillaume.dumas@pasteur.fr
ALIUS Workshop
Saturday, December 9th, 2017

3. Atelier 26: Association ARTHEMOC
Recherche transdisciplinaire sur les états modifiés de conscience.
NormalPathologiques Induits
Epistémologie
Phénoménologie
Décrire avec précision et pertinence ces états, ainsi que d’établir,
dans une optique interdisciplinaire, leur nature, utilité et portée.
Neurosciences
Psychologie Pharmacologie
AnthropologieClinique
Sociologie …
…
Schizophrénie
Autisme
Parkinson
Anxiété
Addiction
…
Hypnose
Méditation
Musique
Psychotropes
Neurofeedback
…
2009

4. Norm
Epistemology
Phenomenology
Describe precisely and appropriately these states, as well as establish,
in an interdisciplinary perspective their nature, usefulness and scope.
Neurosciences
Psychology Pharmacology
AnthropologyMedicine
Sociology …
…
Interdisciplinary research group
on the diversity of consciousness
2017

5. Pathologic Induced
Epistemology
Phenomenology
Describe precisely and appropriately these states, as well as establish,
in an interdisciplinary perspective their nature, usefulness and scope.
Neurosciences
Psychology Pharmacology
AnthropologyMedicine
Sociology …
…
Schizophrenia
Autism
Parkinson
Anxiety
Addiction
…
Hypnosis
Meditation
Transe
Psychedelics
Neurofeedback
…
NormS
Interdisciplinary research group
on the diversity of consciousness
2017

6. “Systems are not in nature, but only in the minds of men."
Claude Bernard (1865, p. 297)

7. Blashfield et al. 2014

8. "A diagnostic approach based on the biology as
well as the symptoms must not be constrained by
the current DSM categories” Thomas Insel (2013)

9. Psychosis threshold
Normal development
Paths to
schizophrenia
Adapted from McGlashan & Hoffman (2000)
"Brain comes first"

10. Williams (2016)
Precision medicine & latent variables
PFC
integrity
Fluid
intelligence
Multitasking
Kievit et al. 2014

11. Normative Modeling

12. Marquand et al. 2016
Beyond the "Cases vs Controls" approach

13. Age (in days)
SDs
Longitudinal European
Autism Project (LEAP)
Normative Model based on Gaussian Processes
Jumana
Ahmad
Z-score

14. Longitudinal European
Autism Project (LEAP)
Nonparametric Normative Model based on LOESS
Age (months)
Z-score
CTR ASD ID ASD-ID

15. Longitudinal European
Autism Project (LEAP)
Normative Scores Distributions
Nonparametric Normative Score
Density
CTR
ASD
ID
ASD-ID

16. Patients Stratification

17. “Averages must therefore be rejected, because they confuse, while
aiming to unify, and distort while aiming to simplify."
Claude Bernard (1865, p. 135)

18. Marquand et al. 2016
Beyond the "Cases vs Controls" approach

19. y0 = 1e-3 y0 = 1 y0 = 1e3
Finite mixture with a Dirichlet distribution
Unsupervised clustering

20. Crespi et al. 2010
Comparative etiology

21. Phenotypical Stratification
Lombardo et al. 2016
DiscoveryReplication ASC TD

22. Kwang-Il Goh et al. (2007)
Networks as Bridges between Phenotypes & Genotypes

23. Genotype Network Phenotype
Network Based Stratification (NBS)
Yang-Min
Kim

24. Network Based Stratification (NBS)
Large cohort
Heterogeneous genetic profiles
Individuals
Hofree et al. (2013)
Clusters
Homogeneous genetic profiles

25. Network Based Stratification (NBS) Hofree et al. (2013)
CBT (Cognitive Behavioral Therapy)
Response
Drug Response
Clusters
Homogeneous genetic profiles

26. Towards precision psychiatry
26
NRXN-NLGN
SHANK
mTOR
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxEPh ≈ G + E +GxEPh ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
Ph ≈ G + E +GxE
???

27. Perspectives: Stratification & Normative models
1
2
3
4
5
6
Normative Scores
across tasks
Patients
Eva
Loth
Identification of
cross-domain
cognitive
subtypes
in autism

28. Perspectives: Deeper and Higher

29. Autoencoder
Perspectives: Deeper and Higher

30. improved Deep Embedded Clustering (iDEC)
Guo et al. 2017
Song et al. 2013
Perspectives: Deeper and Higher

31. Noble (2007)
Perspectives: going multiscale

32. Noble (2007)
S
Perspectives: going multiscale

33. ExperimentalComputational
Kelso, Dumas, Tognoli (2013)
Perspectives: going multiscale

34. ESSENCE
Early Symptomatic Syndromes Eliciting
Neurodevelopmental Clinical Examinations
Gillberg (2010)
Christopher
Gillberg
Perspectives: add development

35. ESSENCE
Early Symptomatic Syndromes Eliciting
Neurodevelopmental Clinical Examinations
Gillberg (2010)
Christopher
Gillberg
Perspectives: add development

36. Boly et al. 2013 Fazekas et al. 2016
“from bedside to bench"
Perspectives: going back to ASC

37. Carhart-Harris et al. 2016
Perspectives: going back to ASC

38. Lutz et al. 2015
Perspectives: neurophenomenology

39. Perspectives: dynamical systems modeling

40. Networks of States & Transitions
Perspectives: dynamical systems modeling

41. Borsboom (2017)
A network theory of mental disorders
Perspectives: from descriptive to prescriptive

42. Subjective
experience
(semiology)
Brain activity
(physiology)
Disease
(nosology)
Cause
(etiology)
Additional criteria for delimitation
(epidemiology, sociology)
Adapted from Micoulaud-Franchi et al. 2016
2 additional levels to take into account:
- Metrology: the question of measurement
- Phenomenology: link between lived experience and physiology
Perspectives: make semiotic great again

43. Step 1 Step 2
+
Clinical description based on
psychiatric signs and symptoms
Disorder theory based on
neurophysiological mechanism
RDC and DSM
projects
Disorder 1 Disorder 2
Disorder 3 Disorder 4
?
Brain functions and
mechanism of dysfunction
RDoC
projectClinical manifestation
Dimensional approach
?
Redefining psychiatric
semiological classification
Step 2 Step 1
Impact of disorder classification
on clinical description
Micoulaud-Franchi et al. (in preps)
Perspectives: make semiotic great again

44. Old-Paris Team
Jacqueline Nadel
Jacques Martinerie
Robert Soussignan
Mario Chavez
Boca Raton Team
New-Paris Team
Collaborators
JA Micoulaud-Franchi
Clélia Quiles
Leonhard Schilbach
Danilo Bzdok
Elvis Dohmatob
Denis Engemann
Eva Loth
Jumana Ahmad
Thomas Bourgeron
Richard Delorme
Aline Lefebvre
Yang-Min Kim
Thomas Rolland
Freddy Cliquet
Alexandre Mathieu
Freddy Cliquet
Roberto Toro
Anita Beggiato
Anna Maruani
Hany Goubran-Botros
J.A. Scott Kelso
Emmanuelle Tognoli
Gonzalo DeGuzman
Armin Fuchs
Mengsen Zhang
Merle Fairhurst
Benno Schwikowski
Viviane Kostrubiec
Alexandre Lehmann
Asaf Bachrach
Julien Laroche
Acknowledgements