Hello!

I am Dr. A.R. Jac Fredo, Ph.D., (IUSSTF Fellow, USA)

◇ Assistant Professor, IIT (BHU), Varanasi, India.

◇ You can find me at https://www.iitbhu.ac.in/dept/bme/people/jackbme
◇ You can reach me through jack.bme@iitbhu.ac.in

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 Education &
Experience
◇ B.E in Electrical and Electronics ◇ Assistant Professor in VIT University,
Engineering, 2008 Vellore, 2016
◇ M.E in Instrumentation Engineering from ◇ IUSSTF Post Doctoral Fellow in San
Madras Institute of Technology, Anna Diego State University, California,
University, 2010 USA, 2017-2018
◇ Ph.D. in Biomedical Image Processing ◇ Research Fellow in Nanyang
from Anna University through MANF Technological University, Singapore,
Fellowship, 2016 2018-2020
◇ Research Associate in Applied Mechanics, ◇ AROP Exchange Fellow, RWTH
IIT Madras, Chennai, 2016 Aachen, Germany, 2020

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 Research Seminar

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 Human Brain & Disorders
◇ Brain is a Complex structure of central
nervous system
◇ It is connected with billions of neurons
◇ It controls heart rate, respiratory rate,
memory, speech, movements, emotions and
stress
◇ Neural Disorders
￭ Neurological disorders
￭ Neuropsychiatric disorders
The structure of the human brain, 2014
￭ Substance use disorders
￭ Neurodevelopmental disorder

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 Autism Spectrum
Disorder
◇ Autism Spectrum Disorder (ASD) is neurodevelopmental disorder
characterized by social, behavioural and communication defects
◇ It is a heterogeneous disorder, with a broad range of the subtypes and
severities
◇ It is primarily diagnosed based on clinical scores and behavioral
observations
◇ However, the clinical scores are ambiguous; therefore, there is a need to
identify reliable brain biomarkers and automate the process for the diagnosis
of ASD

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 Severity scales
◇ Measures that provide autism
severity ratings,
￭ Childhood Autism Rating
Scale (CARS)
￭ Social Responsiveness Scale
(SRS)
◇ Neuroscience and intervention
researchers use,
￭ Autism Diagnostic
Observation Schedule (ADOS)
￭ Autism Diagnostic Interview-
Revised (ADI-R)

American Psychiatric Association, Diagnostic and

Statistical Manual of Mental Disorders (DSM-5) in
2013

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 Autism Prevalence
◇ Data suggests that 1 in 500 people in India are autistic
◇ About 2.3 million children are affected with autism
◇ Research conducted - four metropolitan-speech and language
abnormalities in 44.9%
◇ Teachers interpret autism either as attention deficit or slow learner
◇ 95.7% of the teachers are aware of autism - only 21% have adequate
knowledge
◇ Initial symptom recognition - 6 to 10 months late in India, compared to
Europe

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 Biomarkers of Autism
◇ Behavioral Biomarker
￭ Social deficits, communication difficulties, repetitive behaviours
and lack of interests, Cognitive delays, impaired social interaction,
verbal and nonverbal communication, limited activities
◇ Anatomical biomarker
￭ Head circumference, brain size, brainstem, cerebellum, limbic
system, Thalamus, amygdala, cerebrum, gray and white matter,
corpus callosum, hippocampus
◇ Functional biomarker
￭ Cognitive control, communication, social cognition, functional
connectivity, reward processing, encode and consolidate positive
memories of social experiences

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 Brain Imaging
◇ Structural Magnetic Resonance imaging
￭ Image gives volumes of different regions of brain in autism
subjects
◇ Functional Magnetic Resonance imaging
￭ Sensory processing, disturbances to executive function and
a reduced capacity to appreciate the mental states
◇ Diffusion Tensor Imaging
￭ Abnormalities of white matter in autism micro integrity of
white matter, particularly in prefrontal-temporal-parietal

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 Advantages
◇ Non-invasive medical imaging modality
◇ Images of internal soft tissues-very high
contrast
Sagittal view
◇ Less ionizing radiation-high-resolution
◇ Brain structures and volume-behaviour
relationships
◇ Structures include the cerebrum-
cerebellum-amygdala-hippocampus- Coronal view
thalamus-brain stem-ventricle-corpus
callosum

Trans axial view

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 Neuroimaging
◇ Studies reveal that the microscopic and macroscopic synaptic
connectivity and structural or Functional Connectivity (FC)
patterns can be substantial biomarker for ASD
◇ Resting-state functional Magnetic Resonance Imaging (Rs-fMRI)
is an efficient tool to examine brain network connections

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 Data Processing
◇ The preprocessing of functional magnetic resonance imaging (fMRI)
data is necessary to remove unwanted artifacts and transform the data
into a standard format
◇ Tools like Matlab, Linux/Unix, SPM, AFNI, FSL, FreeSurfer
◇ Different data preprocessing pipelines yield differing results
￭ Anatomical pre-processing (sMRI)
￭ Moco Flirt (fMRI) (registration)
￭ Blurring and band pass filter
￭ Nuisance regression
￭ Quality assessment
￭ De-convolve (neuronal responses)
￭ Global signal regression (motion and respiration)

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 Brain parcellations
◇ Brain parcellation methods subdivide the brain into individual regions that
can be used to build a network to study its structure
◇ Glasser atlas (180 areas per hemisphere), Schaefer atlas (200 areas per
hemishpere 7 networks), Meiling (678 area)
◇ Gordan, Harvard, Diedrichsen and Desikan

Melissa Lopez-LarsonMelissa Lopez-

Larson et al., Abnormal Functional
Connectivity Between Default and
Salience Networks in Pediatric Bipolar
Disorder

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 Average time series
◇ The fMRI data is four-dimensional, composed of 3D brain images over time
◇ Each voxel of the 3D brain volume is associated with a time series of signal
intensity values
◇ The statistical measures such as mean and median were used to find the
functional changes in each voxel over time

Guixiang Ma et al., Spatio-Temporal Tensor

Analysis for Whole-Brain fMRI Classification

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 Feature Extraction
◇ The identification of patterns of activation for ASD and the
association of the patterns with neural and psychological components
contributes to the understanding of the etiology of mental disorders
◇ Baseline features such as wavelet coherence, regional homogeneity,
gradient features, voxel-based features, mean of time series and
spatial maps were employed to extract the brain connections

Joachim B et al.,
Three-Dimensional Mean-Shift
Edge Bundling for the
Visualization of Functional
Connectivity in the Brain

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 Machine Learning
◇ One of the challenges to brain imaging studies of brain disorders is
to replicate findings across larger, more demographically
heterogeneous datasets that reflect the heterogeneity of clinical
populations
◇ Machine Learning (ML) algorithms have been applied to brain
imaging data to extract replicable brain function patterns
◇ These algorithms can extract replicable, robust neural patterns
from brain imaging data of psychiatric disorder patient

Meenakshi K et al., Machine learning

in resting-state fMRI analysis
Author links open overlay panel
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 Frame work of analysis

Farzad V. Farahani etl al., Application of Graph Theory for Identifying Connectivity Patterns in Human Brain Networks: A Systematic Review
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 Study-1

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 Performance of machine learning
classification models of autism

“ using resting-state fMRI is

contingent on sample
heterogeneity
 Motivation
Previous ML studies of ASDs have mostly
included highly heterogeneous ASD samples with
respect to the range of symptom severities,

“
gender composition, medication status, and other
variables. It is currently unknown
how sample heterogeneity and homogeneity
affects the performance of ML classifiers of
ASDs.

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 Objectives
◇ To gather four samples of children and adolescents between
the ages of six and eighteen, with varying levels of
heterogeneity in gender composition and autism symptom
severity
◇ To construct diagnostic classifiers for each group using
resting-state fMRI data
◇ To check the classification accuracy with greater sample
homogeneity
◇ To identify the brain connections corresponding to the
heterogeneous and homogeneous samples

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 Autism Diagnostic Observation
Schedule
◇ The Autism Diagnostic Observation Schedule) is widely accepted as a “gold
standard” diagnostic instrument
◇ It helps to assess communication, reciprocal social interaction,
imagination/creativity and stereotyped behaviours and restricted interests to
inform diagnosis of autism spectrum disorders
◇ The ADOS was conducted as part of a clinical or research evaluation
◇ Lower values of ADOS represents less symptom severity and higher values of
ADOS represents high symptom severity

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 fMRI Data
◇ Age: 6-18 years, eyes open condition, RMSD<0.2
◇ Age, motion matched Typical Developing (TD) and ASD (N=400 each set):
￭ set (1)
￮ Male and female TD vs Male and female ASD participants with
Autism Diagnostic Observation Schedule (ADOS)=2-24
￭ set (2)
￮ Male TD vs Male ASD participants with ADOS=2-24
￭ set (3)
￮ Male and female TD vs Male and female ASD participants with
ADOS≥10
￭ set (4)
￮ Male TD vs Male ASD participants with ADOS≥10

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 Participant information of sample set (1) (Male and female
participants with ADOS=2- 24)
  ASD, Mean±SD TD, Mean±SD p-value
(range) (range) (2 sample t-test)
Training sample      
160 (R-107, L-12, 160 (R-118, L-10,
N (Handedness) -
M-11, ND-30) M-6, ND-26)
12.15±3.04 12.02±2.77
Age (years) 0.68
(6.41-18) (6.36-18.55)
0.095±0.04 0.09±0.039
Motion (mm) 0.31
(0.021-0.197) (0.02-0.188)
105.8±17.88 111.25±13.11
PIQ/FIQ 0.002
(53-149) (67-138)
Testing sample      
40 (R-27, L-1, 40 (R-26, L-1,
N (Handedness) -
M-1, ND-11) M-1, ND-12)
12.02±2.96 12.78±2.52
Age (years) 0.22
(7.15-17.53) (8.74-17.1)
0.09±0.043 0.083±0.034
Motion (mm) 0.44
(0.036-0.172) (0.03-0.177)
106.1±17.4 109.2±13.93
PIQ/FIQ 0.38
(81-145) (62-131)

24 SD-Standard Deviation, N-Number of samples, R-Right, L-Left, M-Mixed, ND-No data

 Participant information of sample set (2) (Males only with
ADOS=2-24)

  ASD, Mean±SD TD, Mean±SD p-value

(range) (range)  (2 sample t-test) 
Training sample
160 (R-108, L-11, 160 (R-121, L-9,
N (Handedness) -
M-8, ND-33) M-5, ND-25)
12.16±2.76 12.03±2.9
Age (years) 0.7
(6.41-17.94) (6.36-18.8)
0.094±0.041 0.09±0.037
Motion (mm) 0.32
(0.021-0.191) (0.026-0.191)
106.8±16.67 111.9±12.78
PIQ/FIQ 0.002
(69-146) (83-147)
Testing sample      
40 (R-24, L-1, 40 (R-23, L-2,
N (Handedness) -
M-1, ND-14) M-3, ND-12)
12.06±2.67 12.82±2.57
Age (years) 0.19
(7.15-17.5) (8.06-18.21)
0.088±0.41 0.08±0.045
Motion (mm) 0.43
(0.035-0.172) (0.027-0.177)
105.5±17.19 111.8±16.17
PIQ/FIQ 0.095
(77-145) (62-147)

25 SD-Standard Deviation, N-Number of samples, R-Right, L-Left, M-Mixed, ND-No data

 Participant information of sample set (3) (Male and female participants with
ADOS≥10)
  ASD, Mean±SD TD, Mean±SD p-value
(range) (range) (2 sample t-test)
Training sample      
160 (R-111, L-12, M-9, ND- 160 (R-120, L-11, M-5, ND-
N (Handedness) -
28) 24)
11.9±2.69 11.7±2.62
Age (years) 0.68
(6.41-18) (6.36-18.55)
0.097±0.04 0.092±0.041
Motion (mm) 0.29
(0.031-0.197) (0.023-0.191)
105.1±17.16 111.6±13.3
PIQ/FIQ 0.0001
(53-146) (77-139)
Testing sample      
N (Handedness) 40 (R-24, L-1, M-2, ND-13) 40 (R-30, L-1, M-1, ND-8) -
12.53±2.89 11.79±2.78
Age (years) 0.24
(8.78-18.58) (7.25-17.5)
0.092±0.038 0.084±0.046
Motion (mm) 0.41
(0.027-0.154) (0.021-0.177)
110.05±16.38 109.3±14.65
PIQ/FIQ 0.82
(82-142) (62-140)

26 SD-Standard Deviation, N-Number of samples, R-Right, L-Left, M-Mixed, ND-No data

 Participant information of sample set (4) (Males only with ADOS≥10)

  ASD, Mean±SD TD, Mean±SD p-value

(range) (range) (2 sample t-test)
Training sample      
160 (R-106, L-13, M-7, ND- 160 (R-116, L-10, M-3, ND-
N (Handedness) -
34) 31)
12.25±2.84 12.13±2.87
Age (years) 0.71
(6.41-18.65) (6.66-18.8)
0.096±0.04 0.091±0.04
Motion (mm) 0.31
(0.017-0.197) (0.027-0.191)
105.45±16.77 110.65±12.92
PIQ/FIQ 0.002
(67-146) (76-138)
Testing sample      
N (Handedness) 40 (R-24, L-1, M-3, ND-12) 40 (R-25, L-1, M-1, ND-13) -
12.93±2.81 12.11±2.67
Age (years) 0.18
(8.06-18.15) (8-18.24)
0.082±0.043 0.089±0.043
Motion (mm) 0.44
(0.03-0.17) (0.027-0.19)
109.8±16.74 106.9±15.66
PIQ/FIQ 0.43
(62-147) (82-137)

27 SD-Standard Deviation, N-Number of samples, R-Right, L-Left, M-Mixed, ND-No data

 Process pipeline
Feature
Image Feature
fMRI data Pre-processing Reduction &
Processing Extraction
Classification

• Mask
• Conditional
preparation Pearson
Online ABIDE Random
Standard • True values Correlation
and In-house Forest (CRF)
pipeline in ROIs from ROIs with
data • Random
• Mean time 80% true value
Forest (RF)
series

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 Methods
Image Processing Feature Extraction Feature Reduction Classification
◇ Identified all voxels of ◇ 214 of 333 ROIs from ◇ CRF with 2000 trees, ◇ Model built using CRF
the brain which Gordon’s cortical atlas calculate the is tested in a new
included BOLD signal Conditional validation set using the
◇ 14 subcortical,
in 95% of participants. Permutation RF classifier
Harvard Oxford atlas
Importance (CPI) ◇ Tree number of 20000
◇ Next, calculated the
◇ 9 of 26 cerebellar
80% percentage of ◇ Features correspond to ◇
ROIs from the Desikan Most informative
voxels in each ROI the positive values of network contributed
cerebellar atlas
that included true CPI is considered for the classification
signal ◇ Mean time series ◇ Process is repeated up
◇ Pearson correlation co- to features are reduced
efficent up to a level equal to 2

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 Results

(a) (b) (c) (d) (e) (f)

Sample Set 4 (a) Sum coverage map of all the 400 participants, (b) Mask of 95% of TD participants
have brain coverage, (c) Mask of 95% ASD participants have brain coverage (d) Mask of 95% all the
participants have brain coverage (e) Mask of 95% all, TD and ASD participants (overlapped with cyan,
green and red) and (f) Cortical, subcortical and cerebellar ROIs on the mask.
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 Results

(a) (b) (c)

RF OOB error rate, sensitivity and specificity after each

dimension reduction for the validation data (a) Male and
female participants with ADOS=2-24, (b) Males only with
ADOS=2-24, (c) Male and female participants with ADOS≥10
and (d) Males only with ADOS≥10.

31 (d)
 Results
Summary of classification accuracy, sensitivity, specificity, number of features contributed and top four ROIs for four
sample sets

Sample sets Features Accuracy (%) Sensitivity (%) Specificity (%) Top Four ROIs Top connection
ADOS total (2-24),
COTC, Visual,
Males and 72 62.5 60 65 DA to SMH
DA, SMH
Females
ADOS total (2-24), COTC, DA,
143 65 65 65 COTC to DA
Males Visual, FPTC
ADOS total ≥10,
COTC, DA,
Males and 329 70 67.5 72.5 within COTC
Visual, VA
Females
COTC to
ADOS total ≥10, COTC, Visual, default and
319 73.75 75 72.5
Males SMH, Default subcortical to
COTC

COTC -Cingulo-Opercular Task Control, DA-Dorsal Attention, SMH-Somatosensory Motor Hand, FPTC-Fronto-Parietal Task Control, VA-
Ventral Attention

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 Results

(a) (b) (c)

ROI participation in most informative features, separated by

network (a) Male and female participants with ADOS=2-24,
(b) Males only with ADOS=2-24, (c) Male and female
participants with ADOS≥10 and (d) Males only with
ADOS≥10.

33 (d)
 Results

(a) (b) (c)

Heat map show the brain network connections in (a) Male

and female participants with ADOS=2-24 (DA to SMH), (b)
Males only with ADOS=2-24, (COTC to DA) (c) Male and
female participants with ADOS≥10 (within COTC) and (d)
Males only with ADOS≥10 (COTC to default and subcortical to
COTC)
(d)
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 Limitations
◇ Low availability of sufficiently large samples of low-motion fMRI data
from a multisite source like ABIDE presents unavoidable constraints
◇ Lack of an all-female comparison group was an unavoidable limitation
◇ Age-related heterogeneity likely impacts fMRI findings of group
differences
◇ Although we tried to match groups on IQ, the effect of heterogeneity on
diverse cognitive and behavioral variables remained beyond the scope of
our study

35
 Conclusion
◇ We examined the impact of sample heterogeneity on
diagnostic classification of ASD
◇ Reduced heterogeneity with respect to gender and range of
symptom severity was associated with improved
performance of RF classifiers
◇ Greater homogeneity of samples impacted both
classification accuracy and selection of most informative
features
◇ Differences in sample heterogeneity may account
for often conflicting findings in the neuroimaging literature
on ASDs

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 Publication

37
 Study-2

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 Objectives
◇ The first objective of our study is to compare the fully and
partially brain estimation methods in the machine
learning classification of ASD and TD participants based
on their neural patterns
◇ The second goal is to identify the significant neural patterns
associated with ASD classification
◇ Third goal is to interpret the networks of the brain
corresponding to these neural patterns and to check the
consistency of the brain networks and its connections

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 Participant information of sample set

  ASD, TD, P-VALUE (2

MEAN±SD MEAN±SD SAMPLE T-
(RANGE) (RANGE) TEST)
N 300 (R-198, L- 300 (R-220, L-

“
(HANDEDNE 20, M-17, ND- 19, M-9, ND- -
SS) 65) 52)
MALES
260 (40) 223 (77) -
(FEMALES)
AGE IN 11.87±2.75 11.85±2.74
0.93
YEARS (6.41-18) (6.36-18.8)
MOTION IN 0.093±0.041 0.09±0.039
0.97
MM (0.021-0.197) (0.02-0.191)
105.48±17.1 111.15±13.75
PIQ/FIQ 0.08E-4
(53-149) (62-147)

Number of samples chosen from each ABIDE

SD-Standard Deviation, N-Number of samples, R-Right, L-Left, M-Mixed, ND-No data
scanning site.

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 Process pipeline
Feature
Image Feature
fMRI data Pre-processing Reduction &
Processing Extraction
Classification

• Conditional
Random
Forest
• Random
• Mask
Forest
preparation • PCCE
• Oblique
Online ABIDE Standard • True values • GLASSO
random
database pipeline in ROIs • MDMC
forest
• Mean time
• Support
series
vector
machines
• Deep
learning
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 Methods
Image Processing Feature Extraction Feature Reduction Classification
◇ Identified all voxels of ◇ 215of 333 ROIs from ◇ Identified different set ◇ Optimized the tree
the brain which Gordon’s cortical atlas of significant features number, kernel,
included BOLD signal through CRF feature parameters for the
◇ 14 subcortical,
in 95% of participants. reduction method classifier using inner
Harvard Oxford atlas
◇ Optimized the CRF fold cross-validation
◇ Next, calculated the
◇ 9 of 26 cerebellar
80% percentage of trees, using inner fold ◇ Feature set, kernel and
ROIs from the Desikan
voxels in each ROI cross-validation parameters of the
cerebellar atlas
that included true kernel that yielded the
signal highest inner loop test
accuracy is chosen as
optimal

42
 Cross-validation
  Fold-1 Fold-2 Fold-3 Fold-4 Fold-5
Trial-1 Test Train Train Train Train
Trial -2 Train Test Train Train Train
Trial -3 Train Train Test Train Train
Trial -4 Train Train Train Test Train
Trial -5 Train Train Train Train Test

Five-fold outer loop cross-validation

F2 F3 F4 F5 F1 F3 F4 F5 F1 F2 F4 F5
Test Train Train Train Test Train Train Train Test Train Train Train
Train Test Train Train Train Test Train Train Train Test Train Train
Train Train Test Train Train Train Test Train Train Train Test Train
Train Train Train Test Train Train Train Test Train Train Train Test
(a) (b) (c)
F1 F2 F3 F5 F1 F2 F3 F4 Inner loop cross-validation for
Test Train Train Train Test Train Train Train (a) Trial-1 (b) Trial-2 (c) Trial-3
Train Test Train Train Train Test Train Train
Train Train Test Train
(d) Trial-4 and (e) Trial-5. (F1-
Train Train Test Train
Train Train Train Test Train Train Train Test Fold-1, F2-Fold-2, F3-Fold-3,
F4-Fold-4, F5-Fold-5).
(d) (e)

43
 Parameters of CNN
Parameters Value/Type
Number of convolution layers 1, 2
Number of pooling layers 1
Number of fully connected layers 1, 2
Number of convolution filters 16, 32, 64
Dimension of convolution filters 1x3, 1x5
Number of hidden layer neurons 100, 500
Activation function ReLU
Maximum number of iterations 10000

44
 Results
Average cross-validation results for different combination of feature extraction methods and classifiers

 Test Data
Precisio Top Top
Method Accuracy Sensitivity Specificity
n AUC networks connections
(%) (%) (%)
(%)
GLASSO-RF 62.16 62.66 61.66 60.43 0.62 COTC, SMH,
within COTC,
GLASSO-ORF 62.99 56.66 69.32 60.8 0.61 cerebellum,
within cerebellum,
GLASSO-SVM 64.49 67.33 61.66 63.81 0.65 DMN,
within SMH
GLASSO-CNN 61.15 62.33 60.66 61.89 0.61 subcortical
MDMC-RF 68.33 66 70.66 67.39 0.69
DMN, VA, within DMN, visual
MDMC-ORF 66.66 57.66 75.66 65.68 0.69
visual, COTC, to COTC, VA to
MDMC-SVM 68.49 66.66 70.33 67.17 0.71
auditory SMH
MDMC-CNN 68.66 69.33 68 68.4 0.68
PCCE-RF 68.49 71.33 65.66 63.31 0.69
DA, COTC, COTC to DA,
PCCE-ORF 67.16 59.66 74.66 64.47 0.69
SMH, COTC to SMH and
PCCE-SVM 69 67.66 70.32 69.59 0.72
subcortical DA to SMH
PCCE-CNN 70.31 67.66 73 71.55 0.73

45
 Conclusions
◇ The processing pipeline that includes selected PCCE features
obtained through CRF, followed by a CNN classifier can
discriminate the diagnostic groups.
◇ We found that the CNN is one of the best method for the
diagnostic classification of ASD

46
 Application of DL in MD

47
 Thanks!
◇ Indo-Us Science and Technology Forum (IUSSTF) and Science Engineering
Research Board (SERB) Fellowship
◇ Autism Speaks Weatherstone Fellowship #10609
◇ National Institutes of Health (grant R01-MH081023, R01-MH1173)
◇ NAM Advanced Biomedical Imaging Program (FY2016)
◇ AROP Exchange Fellowship

Any questions?
You can find me at:
◇ jack.bme@iitbhu.ac.in

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