By integrating advantages in both pathway analysis and network analysis, we
developed a methodology that is able to perform deep investigations in dysregulated
pathways and to perform exploratory analyses based on these pathways. This
methodology was applied to our own dataset of lung cancer microarrays and the results
were consistent with that of a public lung cancer dataset (GSE7670). A knowledge
database was constructed in the very beginning, and all needed information during
analysis is available within this database.
In section 4.3, both Tian method and modified Tian method were applied on the
datasets to identify dysregulated pathways. Table A-3 showed the better statistical
power of these two methods than that of another pathway analysis method GSEA. In
network analysis, one dysregulated pathway in common to both dataset was selected by
each method, respectively: cell cycle pathway was selected by Tian method and focal
adhesion pathway was selected by modified Tian method.
In section 4.4, we attempted to find the most differential component inside
dysregulated pathways from the viewpoint of biomolecular interaction network, and this
component was then referred to as a module or a main component. The main component
in cell cycle and focal adhesion pathway, which were presented in section 4.4, found in
64
our dataset were consistent with that in the GSE7670 dataset.
In section 4.5.1, members of main components and leading edge subsets obtained
by GSEA were simultaneously overlaid on the conceptualized pathway map. In addition,
potential interactions absent in predefined pathways were complemented by information
in interaction database. Figure 4-6 revealed the advantage of incorporating biomolecular
interaction network during analysis: it showed that despite the members of these two
sets overlapped to some degree, the main component was topologically more connected
than the leading edge subset did.
Furthermore, these modules were analyzed by DAVID to elucidate the underlying
biological meaning in terms of different gene ontology categories. It was shown in
section 4.5.2 that compared to the original pathways, the main components indeed show
a specialized functionality and such trend of specialization appeared consistently in both
leading edge subset and main component of these two pathways. However, the main
component is more advantageous than the leading edge subset in two aspects: the size
of leading edge subset is much larger than that of main component and makes the main
component seemed much easier to be further investigated; the leading edge subset does
not take interaction between genes into consideration as is done in this methodology.
Therefore, the main component would be more biologically meaningful in terms of
65 analysis procedures.
With the confidence to extract biologically meaningful modules by this
methodology, further focus-oriented investigations would be easier to be conducted. For
example, a preliminary attempt was made in section 4.6 to search for possible missing
components in pathways or cross-talks between pathways by extending the search space
to outside the dysregulated pathways.
Although it is in spirit an ad-hoc procedure, this methodology provides an adequate
tool that implements problem-specific algorithm to investigate topics of interest. It is
valuable in terms of application since it help researchers to highlight on their research
interests. Undoubtedly, this methodology could be extensively applied to other array
experiments of similar design regardless of the disease under study.
66
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70
APPENDIX
Figure A-1. Top cancer killers in Taiwan in 2008. See [54] for the source of this figure.
Table A-1. Statistics of t-scores in two datasets.
33.8 33.3
71
Figure A-2. The most significant subnetwork identified by GXNA. The result obtained by GXNA program was visualized using Pathway Designer in IPA .
72 Table A-2. Parameters set during pathway analysis.
GSEA NTUH_real_t (f0) NTUH_abs_t (f1)
set_min 10 10
Table A-3. Significant pathways identified by different methods.
73
Table A-4. Lists of significant pathways identified by f0 and f1 scoring function.
Pathways with q-value < 0.05 under f0 scoring scheme
Pathway Name Size Average t-score
GLUTAMATE_METABOLISM 23 3.80
PYRIMIDINE_METABOLISM 59 3.32
HSA00240_PYRIMIDINE_METABOLISM 74 3.28
CELL_CYCLE_KEGG 85 3.09
integrin signaling 175 -1.03
HSA04010_MAPK_SIGNALING_PATHWAY 240 -1.13
Pathways with Bonferroni adjusted p-value < 0.05 under f1 scoring scheme
Pathway Name Size Average t-score
CARDIACEGFPATHWAY 18 5.949233
74
Table A-5. Annotations of genes present in Figure 4-5.
Genes in the main component of cell cycle pathway. (Fig. 4-4A)
Gene Symbolʳ Fold Changeʳ p-valueʳ Normal Expression Tumor Expression
CDH1ʳ 2.4ʳ 1.26E-13 1994.5²381.8ʳ 4752.1²1690ʳ
75
Genes in the main component of focal adhesion pathway. (Fig. 4-4B)
Gene Symbol Fold Change p-value Normal Expression Tumor Expression
SPP1 29.7 1.02E-15 310.8²476.6 9227.8²5885.9
PDGFA -1.2 5.43E-04 96.8²28 80²24.5
PDGFB -1.8 2.25E-09 264.9²80.4 147.2²59.4
PDGFC 2.1 4.57E-07 1006²221.2 2145.3²1055
COL1A1 13.5 1.50E-13 125.4²96.9 1698.6²1360.4
COL1A2 4.6 1.07E-10 2443.1²1279.9 11195.9²6145
LAMA1 1.1 5.91E-04 43.7²6 48.5²6
TNC 2.9 0.0012183 862.4²535.4 2537.8²2580.6
VWF -3.1 2.53E-11 4647.6²1467.5 1479.5²1131.8
FYN -2.6 2.71E-10 421.8²158.3 165²115.1
PDGFRA -1.3 7.42E-04 2110.7²752.4 1682.4²989.7
CAV1 -6.4 2.17E-14 9715.3²2470.9 1509²1142.2
CAV2 -5.1 1.12E-11 4455.4²1139.8 876.3²658.2
ITGA2 2.1 7.72E-08 269.1²90.6 576.7²364.1
ITGA5 -1.7 1.40E-07 880.6²498 517.1²360.2
ITGA8 -2.7 1.60E-09 552.3²203.9 203.5²157.2
ITGAV 1.4 4.10E-04 2059.6²491.8 2815.4²1051.6
ITGB5 1.3 0.0018841 519.2²88.9 659.2²190.2
ITGA2B -1.3 7.16E-04 35.3²11.7 27.3²5.1
PAK1 1.7 1.05E-05 47.7²13.3 82.5²51.8
ROCK1 -1.4 2.15E-06 1952.1²387.7 1425.7²394.7
PXN -1.5 1.47E-08 624.4²126.9 425²122.2
PPP1CB -1.7 4.68E-12 1207.2²291.1 708.6²220.1
PPP1R12A -1.5 1.63E-08 1162.9²225 776.2²215.6
PTEN -1.4 7.32E-07 163.8²54.5 116.9²43.2
! !
76 (A)
(B)
Figure A-3. Main component obtained by f2 scoring method. Genes with symbol in bold face represent key nodes. Rectangles indicate genes also found by f1 scoring method.
77
Table A-6. Annotations of genes present in Figure A-3.
Genes in the main component of cell cycle pathway. (Fig. S3A)
Gene Symbol Fold Change p-value Normal Tumor Key node
CDH1ʳ 2.4ʳ 1.26E-13 1994.5²381.8 4752.1²1690ʳ noʳ
CCNB2ʳ 5.6ʳ 5.75E-11 69.8²23.3ʳ 388.4²401.5ʳ noʳ
CDKN1Aʳ -1.8ʳ 9.71E-05 2557.9²1746.5 1384.7²886.7ʳ yesʳ
BUB1ʳ 4.6ʳ 8.02E-09 31.6²9.9ʳ 144.9²144.1ʳ noʳ
BUB1Bʳ 6.0ʳ 1.56E-10 57.3²20.8ʳ 344.6²354.3ʳ noʳ
CDC2ʳ 3.5ʳ 1.33E-08 155.5²45.5ʳ 540.5²521.6ʳ noʳ
ORC6Lʳ 2.6ʳ 8.60E-09 125.2²33.6ʳ 327.4²219ʳ noʳ
MAD2L1ʳ 5.1ʳ 4.78E-08 56.3²23.3ʳ 284.9²315.1ʳ noʳ CDC45Lʳ 2.3ʳ 5.14E-09 63.1²19.6ʳ 145.9²108.8ʳ noʳ
CCNB1ʳ 6.3ʳ 1.32E-08 59.4²20.7ʳ 371.6²482.8ʳ noʳ
CDC20ʳ 7.1ʳ 5.01E-10 58.9²15.4ʳ 415.8²460.9ʳ noʳ
CDC14Aʳ -1.7ʳ 4.11E-08 37.3²11.2ʳ 22.3²7.6ʳ noʳ
E2F1ʳ 1.4ʳ 3.45E-05 114.2²15.3ʳ 155.1²71ʳ noʳ
E2F3ʳ 2.0ʳ 1.28E-07 270²87.5ʳ 543.4²295.3ʳ noʳ
E2F4ʳ 1.2ʳ 4.20E-07 606.6²140.3ʳ 739.5²213.7ʳ noʳ HDAC1ʳ 1.9ʳ 1.20E-07 1181²222.6ʳ 2198.6²1099.5ʳ noʳ TP53ʳ 1.6ʳ 8.12E-05 198.9²53.5ʳ 314.8²129.4ʳ yesʳ
HDAC3ʳ 1.3ʳ 7.30E-06 467.5²45ʳ 604.7²156.6ʳ noʳ
CCNE1ʳ 5.5ʳ 7.38E-06 99.2²24ʳ 548.6²1757ʳ noʳ
PTTG1ʳ 4.8ʳ 1.27E-09 476.2²166.2ʳ 2262.6²2763.6ʳ noʳ HDAC4ʳ -1.6ʳ 1.05E-07 260.4²75.8ʳ 161.8²80.4ʳ noʳ
Genes in the main component of focal adhesion pathway. (Fig. S3B)
Gene Symbol Fold Change p-value Normal Tumor Key node
SPP1ʳ 29.7ʳ 1.02E-15 310.8²476.6ʳ 9227.8²5885.9ʳ noʳ
PDGFAʳ -1.2ʳ 5.43E-04 96.8²28ʳ 80²24.5ʳ noʳ
PDGFBʳ -1.8ʳ 2.25E-09 264.9²80.4ʳ 147.2²59.4ʳ noʳ PDGFCʳ 2.1ʳ 4.57E-07 1006²221.2ʳ 2145.3²1055ʳ noʳ COL1A1ʳ 13.5ʳ 1.50E-13 125.4²96.9ʳ 1698.6²1360.4ʳ noʳ COL1A2ʳ 4.6ʳ 1.07E-10 2443.1²1279.9 11195.9²6145ʳ noʳ
78
COL3A1ʳ 4.5ʳ 1.24E-11 1266.8²787.7 5732.3²2430.5ʳ noʳ COL5A1ʳ 4.2ʳ 1.56E-10 591²290.9ʳ 2470.4²1754.9ʳ noʳ TNCʳ 2.9ʳ 1.22E-03 862.4²535.4ʳ 2537.8²2580.6ʳ yesʳ THBS1ʳ 1.4ʳ 1.97E-02 402.5²317.4ʳ 552.2²351.5ʳ yesʳ VWFʳ -3.1ʳ 2.53E-11 4647.6²1467.5 1479.5²1131.8ʳ noʳ
FYNʳ -2.6ʳ 2.71E-10 421.8²158.3ʳ 165²115.1ʳ noʳ
ILKʳ -1.2ʳ 5.99E-05 1962.9²481.1 1609²364.9ʳ yesʳ PDGFRAʳ -1.3ʳ 7.42E-04 2110.7²752.4 1682.4²989.7ʳ yesʳ ITGA2ʳ 2.1ʳ 7.72E-08 269.1²90.6ʳ 576.7²364.1ʳ noʳ ITGA5ʳ -1.7ʳ 1.40E-07 880.6²498ʳ 517.1²360.2ʳ noʳ ITGAVʳ 1.4ʳ 4.10E-04 2059.6²491.8 2815.4²1051.6ʳ noʳ ITGB6ʳ -1.1ʳ 6.31E-02 121.9²136ʳ 109.9²201.1ʳ yesʳ ITGA8ʳ -2.7ʳ 1.60E-09 552.3²203.9ʳ 203.5²157.2ʳ noʳ
CAV1ʳ -6.4ʳ 2.17E-14 9715.3²2470.9 1509²1142.2ʳ noʳ CAV2ʳ -5.1ʳ 1.12E-11 4455.4²1139.8 876.3²658.2ʳ noʳ RAC1ʳ 1.3ʳ 1.21E-07 6237.6²726.4 7932.8²1485.3ʳ noʳ MYLKʳ -1.8ʳ 2.76E-08 3154.5²1181.1 1746.1²1214.2ʳ noʳ PIK3R1ʳ -1.9ʳ 3.88E-09 1025.9²382.9 538.1²273.8ʳ noʳ ROCK1ʳ -1.4ʳ 2.15E-06 1952.1²387.7 1425.7²394.7ʳ yesʳ
SRCʳ 1.3ʳ 2.08E-04 331.7²63.5ʳ 439.3²191.3ʳ yesʳ
FLNBʳ 1.6ʳ 1.54E-08 331.7²93.7ʳ 546.5²222.3ʳ noʳ
PARVBʳ -1.6ʳ 1.48E-08 287.9²100.9ʳ 177.9²73.9ʳ noʳ
PXNʳ -1.5ʳ 1.47E-08 624.4²126.9ʳ 425²122.2ʳ noʳ
PPP1R12Aʳ -1.5ʳ 1.63E-08 1162.9²225ʳ 776.2²215.6ʳ noʳ PPP1CBʳ -1.7ʳ 4.68E-12 1207.2²291.1 708.6²220.1ʳ noʳ
PTENʳ -1.4ʳ 7.32E-07 163.8²54.5ʳ 116.9²43.2ʳ noʳ
Table A-7. How the main components overlap with the leading edge subset.
!
79
! Figure A-4. GO term hierarchy for cluster C in Fig. 4-6. Rectangles filled with color
represent the cluster enriched in focal adhesion pathway in terms of cellular component category in GO.
80
!
Figure A-5. GO term hierarchy for terms involved in Fig. 4-7.
Rectangles filled with color represent the terms enriched in focal adhesion pathway in terms of molecular function category in GO.
81
Figure A-6. GO term hierarchy for cluster A and term B,C in Fig. 4-8.
Rectangles filled with color represent terms enriched in cell cycle pathway in terms of biological process category in GO.
82
! Figure A-7. GO term hierarchy for cluster C,D,E in Fig. 4-9.
Rectangles filled with color represent the the cluster enriched in cell cycle pathways in terms of cellular component category in GO.
83
! Figure A-8. Histogram of pathway sizes in our database.
Table A-8. Annotations of genes present in Figure 4-11.
Genes in the main component of cell cycle pathway. (Fig. 4-10A) Gene
Symbol
Fold
Change p-value Normal Tumor
Member of Cell Cycle
Pathway S1PR1ʳ -4.3ʳ 1.06E-14 1028.9²368.1ʳ 240.1²210.4ʳ noʳ
EDNRBʳ -7.4ʳ 3.80E-14 724²440ʳ 98.2²90.3ʳ noʳ
FYNʳ -2.6ʳ 2.71E-10 421.8²158.3ʳ 165²115.1ʳ noʳ
GRK5ʳ -5.7ʳ 5.90E-17 2126²496.4ʳ 372.7²263.8ʳ noʳ TEKʳ -5.9ʳ 8.99E-15 902.3²293.9ʳ 154.1²135.8ʳ noʳ CAV1ʳ -6.4ʳ 2.17E-14 9715.3²2470.9ʳ 1509²1142.2ʳ noʳ CDH1ʳ 2.4ʳ 1.26E-13 1994.5²381.8ʳ 4752.1²1690ʳ yesʳ
CDH3ʳ 6.1ʳ 7.44E-13 156.3²80.1ʳ 949.4²683.9ʳ noʳ
CDH5ʳ -4.5ʳ 1.78E-14 1356.6²453.8ʳ 299.7²214.9ʳ noʳ PECAM1ʳ -2.8ʳ 1.07E-13 7238.7²1866.3ʳ 2586.2²1354.8ʳ noʳ
84
PTPRAʳ 1.1ʳ 7.21E-02 457.9²127.8ʳ 507.2²171.3ʳ yesʳ PTPRBʳ -4.5ʳ 6.49E-16 435.5²194.9ʳ 95.7²68.1ʳ noʳ PTPRMʳ -2.0ʳ 1.93E-13 878²140.9ʳ 437.5²148.9ʳ noʳ CD36ʳ -7.7ʳ 7.05E-15 1762.2²865.5ʳ 228.1²179.2ʳ noʳ GAB2ʳ -2.0ʳ 9.98E-11 1014.2²158.4ʳ 518.8²180.3ʳ noʳ PTPN11ʳ -1.3ʳ 1.65E-10 2514²333.8ʳ 1905.2²343ʳ noʳ ABL1ʳ -1.1ʳ 4.25E-01 681.6²260.8ʳ 636.2²205.1ʳ yesʳ H3F3Aʳ -2.7ʳ 3.03E-14 1700.5²410.7ʳ 632.7²261.5ʳ noʳ NEDD9ʳ -2.6ʳ 2.03E-12 1030.6²359.5ʳ 399.4²222ʳ noʳ
SKP2ʳ 2.2ʳ 8.03E-05 240.5²66.3ʳ 521.9²454ʳ yesʳ
TAL1ʳ -5.9ʳ 6.97E-16 494.7²281.7ʳ 83.5²87.9ʳ noʳ
CBFA2T3ʳ -2.6ʳ 1.74E-13 172²54.8ʳ 67.3²29.9ʳ noʳ
E2F2ʳ -1.1ʳ 6.38E-02 38.5²5.3ʳ 36.6²5.8ʳ yesʳ
EP300ʳ -1.2ʳ 2.35E-03 124.4²31.4ʳ 106.3²29.4ʳ yesʳ HDAC1ʳ 1.9ʳ 1.20E-07 1181²222.6ʳ 2198.6²1099.5ʳ yesʳ HDAC2ʳ 1.3ʳ 8.48E-02 910.7²136.8ʳ 1150.9²548.1ʳ yesʳ
TCF3ʳ 1.6ʳ 5.96E-11 120.6²19ʳ 187²48.3ʳ noʳ
SMARCA5ʳ -1.4ʳ 7.64E-10 1337.3²179.8ʳ 968.8²223.4ʳ noʳ SMC1Aʳ 1.5ʳ 2.48E-06 1249.1²152.1ʳ 1858.2²710.7ʳ yesʳ
!
85
Genes in the main component of focal adhesion pathway. (Fig. 4-10B) Gene
Symbol
Fold
Change p-value Normal Tumor
Member of Focal Adhesion
Pathway FIGFʳ -6.6484ʳ 6.54E-13 1370.9²422.7ʳ 206.2²194.5ʳ yesʳ
VCLʳ -1.1844ʳ 9.24E-06 32.1²7.9ʳ 27.1²5ʳ yesʳ
ADRB2ʳ -4.2686ʳ 3.33E-14 1006.5²387.9ʳ 235.8²160.3ʳ noʳ S1PR1ʳ -4.2861ʳ 1.06E-14 1028.9²368.1ʳ 240.1²210.4ʳ noʳ
EDNRBʳ -7.3741ʳ 3.80E-14 724²440ʳ 98.2²90.3ʳ noʳ
ERBB2ʳ 1.6518ʳ 5.70E-07 904.2²175.7ʳ 1493.7²638.1ʳ yesʳ FYNʳ -2.5571ʳ 2.71E-10 421.8²158.3ʳ 165²115.1ʳ yesʳ GRK5ʳ -5.7049ʳ 5.90E-17 2126²496.4ʳ 372.7²263.8ʳ noʳ
KDRʳ -3.0059ʳ 8.41E-13 1263.7²462.6ʳ 420.4²229.3ʳ yesʳ TEKʳ -5.8555ʳ 8.99E-15 902.3²293.9ʳ 154.1²135.8ʳ noʳ CAV1ʳ -6.4383ʳ 2.17E-14 9715.3²2470.9ʳ 1509²1142.2ʳ yesʳ CAV2ʳ -5.0843ʳ 1.12E-11 4455.4²1139.8ʳ 876.3²658.2ʳ yesʳ CDH1ʳ 2.3826ʳ 1.26E-13 1994.5²381.8ʳ 4752.1²1690ʳ noʳ CDH3ʳ 6.0747ʳ 7.44E-13 156.3²80.1ʳ 949.4²683.9ʳ noʳ CDH5ʳ -4.5269ʳ 1.78E-14 1356.6²453.8ʳ 299.7²214.9ʳ noʳ PECAM1ʳ -2.799ʳ 1.07E-13 7238.7²1866.3ʳ 2586.2²1354.8ʳ noʳ PTPRBʳ -4.5494ʳ 6.49E-16 435.5²194.9ʳ 95.7²68.1ʳ noʳ PTPRMʳ -2.0071ʳ 1.93E-13 878²140.9ʳ 437.5²148.9ʳ noʳ CD36ʳ -7.7251ʳ 7.05E-15 1762.2²865.5ʳ 228.1²179.2ʳ noʳ SRCʳ 1.3244ʳ 2.08E-04 331.7²63.5ʳ 439.3²191.3ʳ yesʳ PXNʳ -1.4692ʳ 1.47E-08 624.4²126.9ʳ 425²122.2ʳ yesʳ PTENʳ -1.4013ʳ 7.32E-07 163.8²54.5ʳ 116.9²43.2ʳ yesʳ PTPN11ʳ -1.3195ʳ 1.65E-10 2514²333.8ʳ 1905.2²343ʳ noʳ
H3F3Aʳ -2.6879ʳ 3.03E-14 1700.5²410.7ʳ 632.7²261.5ʳ noʳ NEDD9ʳ -2.5803ʳ 2.03E-12 1030.6²359.5ʳ 399.4²222ʳ noʳ CORO2Bʳ -3.2862ʳ 1.53E-14 144.8²54ʳ 44.1²21.6ʳ noʳ
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