Linear Discriminant Analysis

Applied to a Multicenter First

Episode Sample
Elissaios Karageorgiou1, S. Charles Schulz1,Randy L.
Gollub2, Nancy Andreasen3, B.C. Ho3, John Lauriello4,5,
Vince Calhoun4,5, H. Jeremy Bockholt4, Scott R.
Sponheim1, Apostolos Georgopoulos1

University of Minnesota, 2Massachusetts General Hospital/Harvard University,

1
3
University of Iowa, 4The MIND Institute, 5University of New Mexico

Presented at the 1st Schizophrenia International Research Society Conference, Venice, Italy,
June 21-25, 2008; submitted to Neuroinformatics, July 2010
 Objectives
• Comment on limitations of individual imaging
and neuropsychological measures in
schizophrenia, bipolar disorder, and controls
• Discuss the use of linear discriminant analysis
(LDA) as a technique to discriminate diagnostic
groups
• Present data from the MIND Research Network
Clinical Consortium using LDA as a diagnostic
tool
 Results – Neuropsychology Tests Only
1. Stepwise LDA: Sensitivity = 78.5%, Specificity 85.1%
DX SZ HC
Predicted SZ 22 7
Predicted HC 6 40

2. PCA-LDA: Sensitivity 78.5%, Specificity 91.5%

DX SZ HC
Predicted SZ 22 4
Predicted HC 6 43
 Results – sMRI Only
1. Stepwise LDA: Sensitivity = 53.6%, Specificity 74.5%
DX SZ HC
Predicted SZ 15 12
Predicted HC 13 35

2. PCA-LDA: Sensitivity 67.9%, Specificity = 72.3%

DX SZ HC
Predicted SZ 19 13
Predicted HC 9 34
 Results – Neuropsychology and sMRI
1. Stepwise LDA: Sensitivity = 60.7%, Specificity = 72.3%

DX SZ HC
Predicted SZ 17 13
Predicted HC 11 34

2. PCA – LDA: Sensitivity = 89.3%, Specificity = 93.6%

DX SZ HC

Predicted SZ 25 3
Predicted HC 3 44
 Discussion
• The results of the study are consistent with the early
study of adolescents in separating groups (Pardo et al.
2006)
• The benefit of PCA-LDA over stepwise LDA in all three
settings is related to more of the variance being included
• The actual error rates can only be verified by a new set
of test-set subjects
• The better performance of the neuropsychological
measures alone compared to sMRI may reflect greater
cognitive difficulties at this early stage of illness
• Further work to identify the specific variables that lead to
discrimination are under way and a new first episode
sample utilizing more advanced MRI is about to be
studied.
 Multimodal Imaging Studies of Early
Stages and Persistent Schizophrenia
S. Charles Schulz1,4
Juan Bustillo2
John Lauriello2
Oliver Freudenreich3
Donald Goff3
Jeremy Bockholt4
Kelvin Lim1
Jazmin Camchong1

1. University of Minnesota
2. University of New Mexico and Mind Research Network (MRN)
3. MGH and Harvard University
4. Mind Research Network (MRN)
 Introduction
• Brain imaging studies conducted over the last 35 years
have demonstrated differences between schizophrenic
patients and controls utilizing a number of measures
including structure, connectivity, blood flow and
metabolic activity.
• Early studies of brain structure led to observations of
consistent measures leading to neurodevelopmental
hypotheses; however, more recent studies of first
episode patients indicate that brain structure may be
more dynamic.
• The results of a single parameter of brain imaging may
indicate implications for other measures – hypotheses
that can be assessed by multi-modal imaging.
 Study Goals
• To address the role of glutamate/glutamine in
schizophrenia, first episode and persistently ill
patients were assessed utilizing a new MRI
spectroscopy technique.
• Also, an overall MRI sequence was designed to
asses connectivity (DTI), structure (SMRI) and
function (resting fMRI). Thus, results of different
measures could be compared to determine the
relationship of different brain imaging theories.
• Specifically for this presentation of the group’s pilot
data, the results of spectroscopy and white matter will
be presented.
Model of neurometabolic changes in cortical gray and
white matter during the course of schizophrenia
Healthy Control FE Schizophrenia Chronic Schizophrenia

I ↑Glu

II

III

IV

VI

WM ↓NAAc

Bustillo, J. et al., ACNP, 2009

 NAAc: lower in Chronic Schizophrenia in white matter

14
P<0.05
*
12

10

SzFE
8
ConYou
SzCh
6
ConOld

0
WM GM

F(3, 63)=6.37, p=0.0008

 Glutamate plus Glutamine: higher in First Episode
Schizophrenia in gray matter

20 P<0.05
18 *
16

14
12 SzFE
ConYou
10
SzCh
8 ConOld
6

0
WM GM

F(3, 63)=4.23, p=0.0087

 Summary - Conclusions
• Increased cortical concentrations of Glx in gray
matter suggest overall hypermetabolism, with
increased turnover of glutamate neurotramission in
glial activation early in schizophrenia.
• Later in the disease, glutamate-driven dendritic
retraction may result in diffuse axonal dysfunction,
with reduced NAAc concentration in white matter
• PEPSI at 3T and short echo, is a robust and
clinically feasible methodology to examine for
evidence of glutamatergic-related neuronal
damage in schizophrenia across sites.