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(neuro)science with AI: Machine learning as scientific modeling

(neuro)science with AI: Machine learning as scientific modeling

Brain sciences are in a difficult position: there is a profusion of theories, an increasing amount of data on brain and behavior, and yet no emerging framework to link them.

One roadblock to how we integrate empirical evidence in scientific theories is that we fit models to data, assuming that these models are correct, and then reason on their ingredients. This methodology can easy lead to circular reasonning. It also encourages idealized experiments on well-controled instanciations of theoretical constructs, such as mental processes, leading to models with little external validity: no ability to conclude on observations outside the given experimental paradigm.

I believe that, for the time being, we need to put less focus on idealized models and strong claims on mental constructs, their validity and organization. Rather, we should focus on models that generalize across many experimental settings, and criticize models more on their predictions than on their ingredients. This agenda has been growing with the use of machine-learning in neuroscience and can lead to more robust empirical evidence. The way forward may lie more on direct fits to behaviour rather than dissociated mental categories, though it requires putting aside short-term promises of a tidy and esthetic model of brain function.

Gael Varoquaux

June 25, 2023
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  1. (neuro)science with AI:
    Machine learning as scientific modeling
    Ga¨
    el Varoquaux
    Predictive models avoid excessive reductionism in cognitive neuroimaging
    [Varoquaux and Poldrack 2019]
    AI as statistical methods for imperfect theories
    [Varoquaux 2021]

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  2. My scientific wanderings
    Physics
    Quantum physics (PhD with Alain Aspect)
    Atom-interferometric tests of relativity
    Brain image analysis for cognition
    Statistics, machine learning, image
    analysis
    Cognitive neuroscience, psychology
    Machine learning for public health
    Informing policy?
    From absolute quantities
    to qualitative subject matters
    Ga¨
    el Varoquaux 1

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  3. Questions of interest
    How does scientific knowledge
    emerge from data?
    Can we have a statistical control on
    this process?
    What role do models play?
    Ga¨
    el Varoquaux 2

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  4. This talk
    1 Evidence in (cognitive) neuroscience
    2 Medical neuroimaging
    3 Rethinking modeling
    Ga¨
    el Varoquaux 3

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  5. 1 Evidence in (cognitive) neuroscience

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  6. Human neuroscience
    Observed at a distance,
    with difficult interventions
    The ideal experiments would
    observe all neurons
    intervene directly on them
    Neuroscience knowledge is built as
    early astronomy
    Ga¨
    el Varoquaux 5

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  7. Brain imaging
    Brain images =
    blurry recording of many neurons
    with many ongoing processes
    Very complex to model
    Complete statistical model hopeless
    Machine learning to model brain
    Ga¨
    el Varoquaux 6

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  8. Probing a mental process via opposition
    1 Craft an experimental condition that recruits it
    Ga¨
    el Varoquaux 7

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  9. Probing a mental process via opposition
    1 Craft an experimental condition that recruits it
    2 Do an elementary psychological manipulation
    Ga¨
    el Varoquaux 7

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  10. Probing a mental process via opposition
    -
    -
    Isolate
    mental
    processes
    Reason on the contrast
    Also for reaction times
    pathologies...
    Ga¨
    el Varoquaux 7

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  11. The lens of the cognitive model
    Psychological manipulations
    are designed and interpreted
    based on a cognitive model
    Experimental “paradigm”
    Task & stimuli used – should recruit the right mental processes
    Opposition used – should cancel out “nuisances”
    Ga¨
    el Varoquaux 8

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  12. The visual system: a paradigmatic example
    Successive experiments have revealed specialized regions
    Ga¨
    el Varoquaux 9
    [Hubel and Wiesel 1959, Logothetis... 1995, Kanwisher... 1997]

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  13. The visual system: a paradigmatic example
    Successive experiments have revealed specialized regions
    But evidence is tied to a theory decomposing mental processes
    Is there a car area?
    Ga¨
    el Varoquaux 9
    [Poldrack 2010]

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  14. Problem: Brain signals would struggle to debunk false theories
    Successive experiments have revealed specialized regions
    But evidence is tied to a theory decomposing mental processes
    Is there a car area?
    Ingredients now considered invalid would yield significant differences
    “philoprogenitiveness”
    “alimentiveness”
    “mirthfulness”
    ...
    Ga¨
    el Varoquaux 9
    [Poldrack 2010]

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  15. Problem: The inference is the wrong way [Poldrack 2006]
    What mental process is supported
    by this brain structure?
    Salience
    Ga¨
    el Varoquaux 10

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  16. Problem: The inference is the wrong way [Poldrack 2006]
    What mental process is supported
    by this brain structure?
    Salience
    Executive control
    The experimental manipulation implies the observed response
    Ga¨
    el Varoquaux 10

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  17. Problem: The inference is the wrong way [Poldrack 2006]
    What mental process is supported
    by this brain structure?
    Pain
    Executive control
    Salience
    The experimental manipulation implies the observed response
    Empirical evidence: P(neural activity|mental process)
    Ga¨
    el Varoquaux 10

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  18. Problem: The inference is the wrong way [Poldrack 2006]
    What mental process is supported
    by this brain structure?
    Pain
    Executive control
    Salience
    Salience
    Pain
    Executive control
    The experimental manipulation implies the observed response
    Empirical evidence: P(neural activity|mental process)
    To conclude that neural activity ⇒ mental process
    High-dimensional statistics (many brain regions / neurons)
    Requires data on many / all mental processes
    Ideally would be a causal claim
    Ga¨
    el Varoquaux 10

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  19. New methodology: predicting the task
    Machine learning to predict
    mental processes from activity
    Pain
    Executive control
    Salience
    Salience
    Pain
    Executive control
    High-dimensional statistics
    Machine learning: abandonning well-posed maximum likelihood
    Requires data on many / all mental processes
    Challenge = calibrated labeling of mental processes in tasks
    (not only oppositions)
    Ideally would be a causal claim Let me come back to this
    Ga¨
    el Varoquaux 11
    [Poldrack 2011, Varoquaux... 2018, Menuet... 2022]

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  20. New methodology: AI models for less reductionist task decomposition
    Computer vision as a model for human vision
    Internal representations capture all aspects of natural stimuli
    Mapping them to brain responses with high-dimensional predictors
    Ga¨
    el Varoquaux 12
    [Yamins... 2014]

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  21. New methodology: AI models for less reductionist task decomposition
    Computer vision as a model for human vision
    Internal representations capture all aspects of natural stimuli
    Mapping them to brain responses with high-dimensional predictors
    Avoids choosing few ingredi-
    ents/facets of a cognitive process
    (excess reductionism)
    [Varoquaux and Poldrack 2019]
    Can generalize across experi-
    mental paradigms
    [Eickenberg... 2017]
    Ga¨
    el Varoquaux 12
    [Yamins... 2014]

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  22. Evidence in cognitive neuroscience
    Focus on significance rather than signal fit
    leaves open doors to wrong models
    Well-posed models must be overly simple,
    and cannot answer the questions of interest
    Machine learning / IA enables to model the
    complexity of the actual situations
    But we want understanding
    The answer does not lie in simplistic
    mechanistic models wich cannot be confronted to data
    Ga¨
    el Varoquaux 13

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  23. 2 Medical neuroimaging

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  24. Health is an observable (not a latent factor)
    We can predict it
    Machine learning for the win
    Ga¨
    el Varoquaux 15

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  25. Goals of improving
    health
    Goals of improving
    health
    Easier, no “construct”,
    “understanding”...
    Easier, no “construct”,
    “understanding”...
    Easier!?
    Easier!?
    Ga¨
    el Varoquaux 16

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  26. Success! Predicting mental disorders despite heterogeneity
    Autism = heterogeneous, symptom-defined disorder
    Can brain imaging give universal diagnostic criteria?
    Accuracy
    Fraction of subjects used
    Prediction to new sites works as well
    with enough data (n = 1 000)
    Ga¨
    el Varoquaux 17
    [Abraham... 2017]

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  27. Addressing the crave for data: proxy measures [Liem... 2017]
    Use common health outcome ⇒ more data
    Capturing aging by associating brain image to chronological age
    Discrepancy with chronological age (brain-age delta)
    correlates with cognitive impairment
    0 2 4
    Brain aging discrepancy
    (years)
    -0.38
    0.74
    1.72
    Objective Cognitive
    Impairment group
    Normal
    Mild
    Major
    Brain proxy of aging
    Avoids simplistic
    disease dichotomy
    Ga¨
    el Varoquaux 18

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  28. Population imaging with proxy measures [Dadi... 2021]
    Elusive constructs of mental health: intelligence, neuroticism
    Make proxy measures: empirically-tuned across many subjects
    Aging, neuroticism, fluid intelligence:
    proxy measures
    relate more to real-life health behavior
    than canonical assessments
    Ga¨
    el Varoquaux 19

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  29. Population imaging with proxy measures [Dadi... 2021]
    Elusive constructs of mental health: intelligence, neuroticism
    Make proxy measures: empirically-tuned across many subjects
    Aging, neuroticism, fluid intelligence:
    proxy measures
    relate more to real-life health behavior
    than canonical assessments
    Socio-demographics + questionnaires relate more than brain images
    Imaging seen as desirable to give intervention targets
    A causal, not correlational question
    Ga¨
    el Varoquaux 19

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  30. Medical analysis of brain images
    Machine learning promising for diagnosis, prognosis
    Given sufficient labels, machine-learning
    biases in data + labels, epidemiology 101
    [Varoquaux and Cheplygina 2022]
    For more data, defining new labels: proxy measures
    Medical research: intervention targets?
    Must be framed as a causal / counterfactual question
    Drugs validated by randomized trials, not mechanisms
    Ga¨
    el Varoquaux 20

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  31. 3 Rethinking modeling
    AI as statistical methods
    for imperfect theories

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  32. Scientific progress and statistical evidence
    Dominant framework of statistical reasoning:
    Formulating a probabilistic model from mechanical hypotheses
    Integrating empirical evidence (data) by fitting this model
    Reasoning from model parameters
    Rigour breaks down with wrong modeling ingredients
    Science needs more reasoning from model outputs
    For statistics: robustness to mis-specification
    Generalization grounds scientific theories
    Black-box phenomenological data models are good for science
    Ga¨
    el Varoquaux 22

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  33. Statistical evidence in science and data science
    1. Model the data
    Based on the knowledge and constructs of the field
    & the understanding of data collection
    m
    d2
    dt2

    x = ⃗
    F

    F = q (⃗
    E +
    d
    dt

    x × ⃗
    B)
    Intelligence
    Fluid
    intelligence
    Crystallized
    intelligence
    Ga¨
    el Varoquaux 23

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  34. Statistical evidence in science and data science
    1. Model the data
    Based on the knowledge and constructs of the field
    & the understanding of data collection
    2. Statistical inference
    Fit model to data (typically maximizing likelihood)
    Reason from the model and its parameters
    Relies on statistical modeling [Cox 2006]
    Ga¨
    el Varoquaux 23

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  35. Example: studying brain brain activity
    Neural support of mental process
    Model of task and mental processes
    ⇒ brain maps
    Ga¨
    el Varoquaux 24

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  36. Example: studying brain brain activity
    Neural support of mental process
    Model of task and mental processes
    ⇒ brain maps
    Uncontrolled variability
    In modeling across teams
    [Botvinik-Nezer... 2019]
    Across software for same model
    [Bowring... 2019]
    Even experts cannot chose the “right” model
    Ga¨
    el Varoquaux 24

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  37. Teachings from history of science
    Current view of physics, maths,
    chemistry...
    Building models from the right ingredi-
    ents – “first principles”
    The past
    Refining relevant constructs
    from wrong models
    Ga¨
    el Varoquaux 25

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  38. The birth of mechanics
    Early scientists (eg ancient Greece)
    “natural motion of objects”, no notion of force, or acceleration.
    Observation of planetary motion (eg Kepler)
    Search for regularities in planets – “harmonies”
    The period squared is proportional to the cube of the major diameter of the orbit
    Modern laws of dynamics (Newton)
    Differential calculus ⇒ laws with force and acceleration
    Unite observations of celestial and earthly motions
    Ga¨
    el Varoquaux 26

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  39. The birth of mechanics
    Early scientists (eg ancient Greece)
    “natural motion of objects”, no notion of force, or acceleration.
    Lacking key ingredients
    Observation of planetary motion (eg Kepler)
    Search for regularities in planets – “harmonies”
    The period squared is proportional to the cube of the major diameter of the orbit
    Phenomenological model1 crucial
    Modern laws of dynamics (Newton)
    Differential calculus ⇒ laws with force and acceleration
    Unite observations of celestial and earthly motions
    Validity established by strong generalizability
    Ga¨
    el Varoquaux 26

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  40. Modern physics does not need phenomenological models?
    Vulcan: false discovery of a planet (19th century)
    Anomaly in Mercury’s orbit not explained by Newtonian physics
    ⇒ invent and “observe” an additional planet, Vulcan
    Theory laden observations
    Ga¨
    el Varoquaux 27

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  41. Modern physics does not need phenomenological models?
    Vulcan: false discovery of a planet (19th century)
    Anomaly in Mercury’s orbit not explained by Newtonian physics
    ⇒ invent and “observe” an additional planet, Vulcan
    Theory laden observations
    Particle physics builds evidence with machine learning (today)
    Fundamental laws of the universe = most precise theory ever
    Particle detection by discriminating physics model
    with non-parametric background
    “Pure” models insufficient for “dirty” reality
    Ga¨
    el Varoquaux 27

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  42. Phenomenological data fits have been crucial to science
    Science uses false models as means for truer theory
    [Wimsatt 2007]
    The reductionist aesthetics of “pure” simple mathematical theories
    is not adapted to the messy world beyond pure physics
    Generalization or prediction failures make or break scientific theories
    Ga¨
    el Varoquaux 28

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  43. Statistics and scientific evidence
    Validity
    Reasonning
    = more than formal problems
    Ga¨
    el Varoquaux 29

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  44. Validity of scientific findings – much more than statistical validity
    External validity [Cook and Campbell 1979]
    External validity asserts that findings apply beyond the study
    Generalizability
    Ga¨
    el Varoquaux 30

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  45. Validity of scientific findings – much more than statistical validity
    External validity [Cook and Campbell 1979]
    External validity asserts that findings apply beyond the study
    Generalizability
    Constructs and their validity [Cronbach and Meehl 1955]
    Construct = abstract ingredients such as “intelligence”
    Construct validity: measures and manipulations
    actually capture the theoretical construct
    Ga¨
    el Varoquaux 30

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  46. Validity of scientific findings – much more than statistical validity
    External validity [Cook and Campbell 1979]
    External validity asserts that findings apply beyond the study
    Generalizability
    Constructs and their validity [Cronbach and Meehl 1955]
    Construct = abstract ingredients such as “intelligence”
    Construct validity: measures and manipulations
    actually capture the theoretical construct
    Implicit realistic stances in theories
    Realism = objective and mind-independent unobservable entities
    Is intelligence a valid construct? How about a center of gravity?
    Places implicit preferences on models beyond empirical evidence
    Ga¨
    el Varoquaux 30

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  47. Reasoning with statistical tools
    Model reasoning [Cox 2006]
    Carefully craft a probabilistic model of the data
    Estimated model parameters are interpreted within its logic
    “data descriptions that are potentially causal” [Cox 2001]
    Warranted reasoning [Baiocchi and Rodu 2021]
    Relies on warrants in the experiment (eg randomization)
    Output reasoning [Breiman 2001, Baiocchi and Rodu 2021]
    Relies on capacity to approximate relations
    Ga¨
    el Varoquaux 31

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  48. Benefits of reasoning on outputs
    rather than models
    Science needs black-box output
    reasoning
    Ga¨
    el Varoquaux 32

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  49. For statistical validity
    Even expert modeling choices explore meaningful variability
    Model reasoning is conditional to the model
    parameters have a meaning in a model
    Imperfect science: 70 different teams of brain-imaging experts
    qualitatively different neuroscience findings [Botvinik-Nezer... 2020]
    Analytical variability breaks statistical control
    Output reasoning: milder conditions for statistical control
    Theoretical results in mispecified settings [Hsu... 2014]
    Multi-colinearity no longer an issue
    Higher-dimensional settings
    ⇒ Forces less reductionist choices
    Ga¨
    el Varoquaux 33

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  50. For understanding?
    “Nobody understands quantum mechanics” Richard Feynman
    Narrative truth versus operational truth
    Humans need stories, for teaching, for intuitions, for “selling”
    these simplifications are not “truth”
    Ga¨
    el Varoquaux 34

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  51. For understanding counterfactual reasonning
    “Nobody understands quantum mechanics” Richard Feynman
    Narrative truth versus operational truth
    Humans need stories, for teaching, for intuitions, for “selling”
    these simplifications are not “truth”
    Counterfactual reasoning & causal inference
    We want to reason on new situations
    Causal, not correlational knowledge
    Bad health is associated with hospitals, but seldom caused by.
    Predictive models enable counterfactual reasoning if
    - they extrapolate enough
    - they build on the right variables (confounds, not colliders)
    Ga¨
    el Varoquaux 34
    [Rose and Rizopoulos 2020, Doutreligne and Varoquaux 2023]

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  52. For broader scientific validity of findings
    The only strong evidence is strong generalization
    Model reasoning favors internal validity
    Model reasoning often need “pure” models with little generalization
    Fields without a unifying formal theory
    tackle empirical evidence with overly reductionist lenses
    Machine learning/AI can model the full problem space
    and give testable generalization
    Ga¨
    el Varoquaux 35

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  53. For broader scientific validity of findings
    The only strong evidence is strong generalization
    Model reasoning favors internal validity
    Model reasoning often need “pure” models with little generalization
    Fields without a unifying formal theory
    tackle empirical evidence with overly reductionist lenses
    Machine learning/AI can model the full problem space
    and give testable generalization
    Relating to more general constructs
    Theories & models are written in terms of constructs (eg attention)
    To help generalizing across vastly different situations
    Must ground these directly on observations
    Ga¨
    el Varoquaux 35

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  54. AI gives statistical methods for imperfect theories
    Model reasoning has no guarantees for imperfect models
    Scientific roadblocks are on model ingredients, not functional forms
    Proposal
    Gauge models more on their predictions than their ingredients
    Scientific inference from model predictions as in [Eickenberg... 2017]
    counterfactual reasoning, model comparison, feature importances
    For neuroscience
    Build predictive models with strong general-
    ization rather than mechanistic explanations
    @GaelVaroquaux

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  55. References I
    A. Abraham, M. P. Milham, A. Di Martino, R. C. Craddock, D. Samaras, B. Thirion, and
    G. Varoquaux. Deriving reproducible biomarkers from multi-site resting-state data: An
    autism-based example. NeuroImage, 147:736–745, 2017.
    M. Baiocchi and J. Rodu. Reasoning using data: Two old ways and one new. Observational
    Studies, 7(1):3–12, 2021.
    R. Botvinik-Nezer, F. Holzmeister, C. F. Camerer, A. Dreber, J. Huber, M. Johannesson,
    M. Kirchler, R. Iwanir, J. A. Mumford, A. Adcock, ... Variability in the analysis of a single
    neuroimaging dataset by many teams. bioRxiv, 2019.
    R. Botvinik-Nezer, F. Holzmeister, C. F. Camerer, A. Dreber, J. Huber, M. Johannesson,
    M. Kirchler, R. Iwanir, J. A. Mumford, R. A. Adcock, ... Variability in the analysis of a single
    neuroimaging dataset by many teams. Nature, 582(7810):84–88, 2020.
    A. Bowring, C. Maumet, and T. E. Nichols. Exploring the impact of analysis software on task
    fmri results. Human brain mapping, 40(11):3362–3384, 2019.
    L. Breiman. Statistical modeling: The two cultures (with comments and a rejoinder by the
    author). Statistical science, 16(3):199–231, 2001.

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  56. References II
    T. Cook and D. Campbell. Quasi-experimentation: Design and analysis issues for field settings
    1979 Boston. MA Houghton Mifflin, 1979.
    D. R. Cox. [statistical modeling: The two cultures]: Comment. Statistical science, 16(3):
    216–218, 2001.
    D. R. Cox. Principles of statistical inference. Cambridge university press, 2006.
    L. J. Cronbach and P. E. Meehl. Construct validity in psychological tests. Psychological
    Bulletin, 52:281, 1955.
    K. Dadi, G. Varoquaux, J. Houenou, D. Bzdok, B. Thirion, and D. Engemann. Population
    modeling with machine learning can enhance measures of mental health. GigaScience, 10
    (10):giab071, 2021.
    M. Doutreligne and G. Varoquaux. How to select predictive models for decision making or
    causal inference? working paper or preprint, 2023. URL
    https://hal.science/hal-03946902.
    M. Eickenberg, A. Gramfort, G. Varoquaux, and B. Thirion. Seeing it all: Convolutional network
    layers map the function of the human visual system. NeuroImage, 152:184–194, 2017.

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  57. References III
    D. Hsu, S. Kakade, and T. Zhang. Random design analysis of ridge regression. Foundations of
    Computational Mathematics, 14, 2014.
    D. H. Hubel and T. N. Wiesel. Receptive fields of single neurones in the cat’s striate cortex. J.
    Physiol., 148:574–591, 1959.
    N. Kanwisher, J. McDermott, and M. M. Chun. The fusiform face area: a module in human
    extrastriate cortex specialized for face perception. J. Neurosci., 17(11):4302–4311, 1997.
    F. Liem, G. Varoquaux, J. Kynast, F. Beyer, S. K. Masouleh, J. M. Huntenburg, L. Lampe,
    M. Rahim, A. Abraham, R. C. Craddock, ... Predicting brain-age from multimodal imaging
    data captures cognitive impairment. NeuroImage, 2017.
    N. K. Logothetis, J. Pauls, and T. Poggio. Shape representation in the inferior temporal cortex
    of monkeys. Current Biology, 5:552, 1995.
    R. Menuet, R. Meudec, J. Dock`
    es, G. Varoquaux, and B. Thirion. Comprehensive decoding
    mental processes from web repositories of functional brain images. Scientific Reports, 12
    (1):1–14, 2022.

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  58. References IV
    R. Poldrack. Can cognitive processes be inferred from neuroimaging data? Trends in cognitive
    sciences, 10:59, 2006.
    R. A. Poldrack. Mapping mental function to brain structure: how can cognitive neuroimaging
    succeed? Perspectives on psychological science, 5:753, 2010.
    R. A. Poldrack. Inferring mental states from neuroimaging data: from reverse inference to
    large-scale decoding. Neuron, 72:692, 2011. This review show how decoding can be used
    on large-scale databases to ground formal reverse inference, capturing how selectively a
    brain area is activated by a mental process.
    S. Rose and D. Rizopoulos. Machine learning for causal inference in biostatistics. Biostatistics,
    21(2):336–338, 2020.
    G. Varoquaux. Ai as statistical methods for imperfect theories. In NeurIPS 2021 AI for Science
    Workshop, 2021.
    G. Varoquaux and V. Cheplygina. Machine learning for medical imaging: methodological
    failures and recommendations for the future. NPJ digital medicine, 5(1):48, 2022.

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  59. References V
    G. Varoquaux and R. A. Poldrack. Predictive models avoid excessive reductionism in cognitive
    neuroimaging. Current opinion in neurobiology, 55:1–6, 2019.
    G. Varoquaux, Y. Schwartz, R. A. Poldrack, B. Gauthier, D. Bzdok, J.-B. Poline, and B. Thirion.
    Atlases of cognition with large-scale human brain mapping. PLOS Computational Biology,
    14(11):1–18, 11 2018.
    W. C. Wimsatt. Re-engineering philosophy for limited beings: Piecewise approximations to
    reality. Harvard University Press, 2007.
    D. L. Yamins, H. Hong, C. F. Cadieu, E. A. Solomon, D. Seibert, and J. J. DiCarlo.
    Performance-optimized hierarchical models predict neural responses in higher visual cortex.
    Proc Natl Acad Sci, page 201403112, 2014. This study shows that models of neural
    response based on computer-vision artificial networks explain brain activity better than
    classic theoretical-neuroscience models of vision.

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