Presentation at CIBCB2015 Peer reviewed paper was published at http://dx.doi.org/10.1109/CIBCB.2015.7300274

1. Heuristic Principal Component Analysis
Based unsupervised Feature Extraction
and its Application to Gene Expression
Analysis of Amyotrophic Lateral Sclerosis
Y­h. Taguchi, Dept. Phys.,
Mitsuo Iwadate, Dept. Bio. Sci.,
Hideaki Umeyama, Dept. Bio. Sci.,
Chuo University, Japan

2. What is PCA based unsupervised FE?
N features
Categorical
multiclasses
In contrast to usual usage of PCA, not samples but
features are embedded into Q dimensional space.
PCA
PC1
samples
M samples
N × M Matrix X (numerical values)
PC2
PC1
+
+ +
+ +
++
+
+
+
++ +
+
+
No distinction
between classes

3. Synthetic example
10 samples
10 samples
90 features 10 features
N(0)
N()
[N()+N(0)]/2
+:Top 10 outliers

Thus, extracting outliers
selects features distinct
between two classes in an
unsupervised way.
Accuracy:(100 trials)Accuracy:(100 trials)
89.5% (
52.6% (
PC1
PC2

4. PC1:９９％
f
PC２:０．４％
PC3:０．２％ PC4:０．１％
PC loadings
Fogel, B. L., Cho, E., Wahnich, A. et al. Mutation of senataxin alters
disease­specific transcriptional networks in patients with ataxia with
oculomotor apraxia type 2. Hum. Mol. Genet. 23, 4758–4769 (2014).
AOA2 patients(○）vs Healthy Controls（△）: Fibroblast cell line
（２ vs 2)
PC1: 99% contribution with
no distinction between
patients and healthy controls.
PC2,PC3,PC4 < 1%
contributions by with
distinctions
Application to ALS
Outliers extraction using
PC2, PC3, PC4 scores
attributed to genes

5. Zi=(PC 2i
σPC 2
)
2
+(PC 3i
σPC 3
)
2
+(PC 4i
σPC 4
)
2
→ P(Zi<) 2
distribution
Adjusted by Benjamini­Hochberg
P
i
<0.01
708 genes
are extracted
ith gene's PC scores
Identification of outliers

6. Biological validation1：KEGG pathway analysis (DAVID)
Alzheimer's, Parkinson's and Huntington's diseases
Other analyses
identify biological
terms, too.

7. 13
７０８ ２１１
〜２０，０００
Selected
genes
ALS related
genes (by Gendoo)
P = 4 × 10­4
708 genes have significant
overlaps with ALS related genes

8. PC２:０．７％ PC３:０．４％
○△＋：3 mutated genes – normal controls
→ aberrant gene expression independent of mutated genes
Fogel, B. L., Cho, E., Wahnich, A. et al. Mutation of senataxin alters
disease­specific transcriptional networks in patients with ataxia with
oculomotor apraxia type 2. Hum. Mol. Genet. 23, 4758–4769 (2014).
ALS related genes: No.2
Transfection of ALS related mutated genes to cell lines
4 cell lines vs 3 mutared genes

9. 715 genes extracted as outliers using PC2 and PC3
(BH criterion adjusted P <0.01)
Biological validation2：KEGG pathway analysis (DAVID)
Alzheimer's, Parkinson's and Huntington's diseases
Other analyses
identify biological
terms, too.

10. 14
715 211
〜２０，０００
Selected
genes 2
ALS related
genes (by Gendoo)
P = 2 × 10­3

11. 708 715
〜２０，０００
Selected
genes 2
Selected
genes
393

12. PPI analysis
Count(degree) degree∝ ­a
Count(betweenness) ∝
betweeness­a
△：708genes
O:715genes
degree
betweenness
Log­log plots
Real,
regulatory
networks
708genes 715genes

13. Identification of especially critical genes
← product set of top 100 genes
29
100
in
708
100
in
715
Many ALS related genes
Selected
genes 2
Selected
genes

14. Network composed of
a part of 29 genes

15. In silico drug discovery (with In­Silico Sciences Inc.In­Silico Sciences Inc. )
Target: CCR6CCR6
Facts:
T helper type 17 (Th17) cells: known inflammatory factor.
Increased in ALS patients blood
Regulatory T (Treg) cells: known anti­inflammatory factor.
Decreased in ALS patients blood
Experimental autoimmune encephalomyelitis, EAE:
CCL20 associated CCR6 induced,
but CCL20 non­associated CCR6 not induced. →
Activation/inhibition of CCR6 may be therapy target of ALS
Cf. CCL20 associated CCR6 was once targeted for
rheumatoid arthritis therapy

16. Methodology:
FAMSFAMS: Inference of Protein Structure from
amino acid sequence (homology modeling)
ChooseLDChooseLD : comparative docking of drug
compounds candidates (c.a. 1000 compounsd
screened from AkosSamples, more than
million candidates, by Tanimoto index with
known agonists/antagonists)

17. Agonist candidates
Known agonist

18. Antagonist candidates Known antagonist

19. Conclusion
1. PCA based unsupervised FE applied to
two exps. Using ALS fibroblastfibroblast cell lines.
2. Genes extracted were coincident as well as
biologically highly feasible
3. Among those identified genes, CCR6CCR6 was
selected as therapy target and in silico drug
discovery was performed.