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第五章、 結論與建議
已知基因之間並不是相互獨立，而是有關聯，因此基因組分析為目前重要的 研究方向。在文獻上已發表的基因組相關分析可分為統計方法和分類方法。統計 方法的主要目的為透過統計檢定方法來驗證特定基因組之顯著性；而分類方法則 期望透過分類器的建立，來尋找與連結與分類表型相關的基因組。目前尚未有作 者聯繫兩種方法。本文突破了過去的研究，將統計方法和分類方法結合提出一種 新的基因組分析方法來驗證特定基因組的顯著性。我們的方法採用隨機森林分類 方法的分類誤差率作為檢定統計量，後續並利用重抽法來產生其排列顯著值，藉 此獲得基因組的顯著性結果。我們期望透過分類方法的運用得以獲取基因組內基 因之間複雜的相關性。
文獻上有不計其數的分類方法被發展出來，此研究運用隨機森林分類方法的 重要原因為:第一、Pang 等人(2006)提出隨機森林分類方法比起其他機器學習分 類方法(例如: Naïve Bayes 等)之誤判率相對較低，且在模擬研究上，隨機森林分 類法在某些情況比支持向量機(SVM)表現較好。另外 Svetnik 等人(2003)與 Qi 等 人( 2006)也指出在基因學和蛋白質學相關研究上，隨機森林分類方法比其他學習
機器分類方法表現較好。第二、 隨機森林分類方法在計算分類誤差率上，不需
做交叉驗證就能得到有效的結果。Breiman(2001)在隨機森林程序中，應用 OOB 資料來估計分類誤差率可以有效率且獲得近似交叉驗證的結果。其中 OOB 資料 估計分類誤差率是建立在 Tibshirani 等人（1996）的研究基礎上而進一步所提出 的，Tibshirani 等人發現用交叉驗證來估計分類器的誤差率時，需要大量的計算 量，因而降低計算效率。然而隨機森林分類方法則可以在建立模型的同時計算出 OOB 的誤差率，只需增加少量的計算就可以得到近似交叉驗證的結果。 且 Breiman(2001)也指出 OOB 誤差率是無偏誤估計值。最後，隨機森林分類法可以 處理多元分類資料，比起一些分類方法只能處理二元分類，擁有更多的優勢。
由模擬研究的結果可得知，相較於其他七種基因組分析方法，本方法得以適
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當控制型一誤差率(type I error rate)，並且維持相當的檢定力(power)，故有優異表 現。而在實證分析方面上，我們分析了 4 組現有基因資料，其中特別探討 Breast 和 P53 基因資料中顯著的基因組。我們發現某些顯著的特定基因組有重要的生物 醫學意義；我們的結果也與其他不同的統計方法的發現互相對照。故由模擬研究 和實證分析上的結果，我們相信本研究方法可以有效協助生物醫學研究人員能夠 更精確地找出重要的特定基因組。
本研究的未來建議和研究方向，分為三點：(一)、更進一步探討收斂問題。
在實證分析中，我們設定隨機森林分類方法中包含 50000 棵樹，但實際上，某些 特定基因組並不會在 50000 棵達到收斂或某範圍，所以未來應該針對每個基因組 來決定適當的樹的數量，以期得到更為準確的結果。(二)、在模擬研究方面上，
因我們只針對自足型檢定去做研究，並未對競爭型檢定去做模擬研究，所以未來 可以研究出競爭型檢定的模擬設計。(三)、在檢定統計量方面上，未來可以詴著 用不同的分類方法，並探討在模擬研究和實證分析上的結果。
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相關網站:
1.The Original RF by Breiman and Cutler. Written in Fortran 77.
( http://www.stat.berkeley.edu/~breiman/RandomForests/cc_software.htm) 2.基因資料來源。(http://bioinformatics.med.yale.edu/pathway-analysis/rf.htm)
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附錄
附錄 A
表 A.1、檢定力(ρ=0)
γ= 0.3 γ= 0.6 γ= 0.9 γ= 1.2 Hotelling T 0.568 0.970 1.0 1.0
PCA 0.404 0.984 1.0 1.0
SAM-GS 0.404 0.984 1.0 1.0
ANCOVA 0.184 0.874 1.0 1.0
Global 0.006 0.304 0.996 1.0
GSEA 0.075 0.276 0.621 0.912
MaxMean 0.224 0.654 0.945 0.991 RandomForests 0.342 0.950 0.999 1.000
表 A.2、檢定力(ρ=0.3)
γ= 0.3 γ= 0.6 γ= 0.9 γ= 1.2 Hotelling T 0.380 0.926 0.996 1.0
PCA 0.320 0.844 0.988 1.0
SAM-GS 0.282 0.842 0.992 1.0
ANCOVA 0.172 0.594 0.944 1.0
Global 0.058 0.348 0.836 0.992
GSEA 0.083 0.173 0.335 0.521
MaxMean 0.189 0.408 0.702 0.859 RandomForests 0.248 0.851 0.984 1.000
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表 A.3、檢定力(ρ=0.5)
γ= 0.3 γ= 0.6 γ= 0.9 γ= 1.2 Hotelling T 0.288 0.878 0.990 1.000
PCA 0.218 0.682 0.942 0.998
SAM-GS 0.200 0.704 0.962 1.000 ANCOVA 0.128 0.446 0.828 0.988 Global 0.056 0.308 0.730 0.970
GSEA 0.068 0.137 0.262 0.375
MaxMean 0.157 0.295 0.534 0.716 RandomForests 0.218 0.785 0.973 0.995
表 A.4、檢定力(ρ=0.9)
γ= 0.3 γ= 0.6 γ= 0.9 γ= 1.2 Hotelling T 0.249 0.792 0.970 0.996
PCA 0.157 0.422 0.752 0.936
SAM-GS 0.130 0.510 0.816 0.974 ANCOVA 0.097 0.270 0.624 0.864 Global 0.068 0.218 0.582 0.838
GSEA 0.056 0.113 0.168 0.217
MaxMean 0.102 0.173 0.281 0.402 RandomForests 0.145 0.643 0.889 0.976
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Null Error rate p-value (α=0.05) Mean(std)
Apoptotic signaling 22 0.1429 0.5096(0.0605) <0.0005
Arginine and proline 49 0.1429 0.5039(0.0561) <0.0005
Limonene and pinene 26 0.1429 0.5096(0.0590) <0.0005
Apoptosis___________ 92 0.1429 0.4973(0.0499) <0.0005
Bile acid biosynthesis 26 0.1429 0.5116(0.0600) <0.0005
Biosynthesis of steroids 20 0.1429 0.5146(0.0621) <0.0005
Butanoate metabolism 49 0.1429 0.5021(0.0530) <0.0005
Complement and coagulation 47 0.1429 0.5069(0.0564) <0.0005
Ascorbate and aldarate metabolism 15 0.1663 0.5150(0.0590) <0.0005
AKAP95 role in mitosis and chromosome dynamics 12 0.1663 0.5183(0.0666) <0.0005 Angiotensin II mediated activation of JNK Pathway via
Pyk2 dependent signaling
50 0.1663 0.5031(0.0541) <0.0005
Actions of Nitric Oxide in the Heart 39 0.1837 0.5083(0.0560) <0.0005
Amyotrophic lateral sclerosis 15 0.2041 0.5176(0.0636) <0.0005
akt signaling pathway 25 0.2245 0.5120(0.0626) <0.0005
Acetylation and Deacetylation of RelA in The Nucleus 12 0.2449 0.5202(0.0659) <0.0005
Biotin metabolism 1 0.2653 0.5874(0.0839) <0.0005
1_4-Dichlorobenzene 3 0.2653 0.5399(0.0718) <0.0005
Antigen Processing and Presentation 13 0.2653 0.5251(0.0651) <0.0005
Aspirin Blocks Signaling Pathway Involved in Platelet Activation
22 0.2653 0.5112(0.0606) <0.0005 Activation of cAMP-dependent protein kinase, PKA 10 0.2653 0.5268(0.0689) <0.0005
Classical Complement Pathway 8 0.2857 0.5317(0.0700) <0.0005
Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia
33 0.2857 0.5037(0.0544) <0.0005
BCR Signaling Pathway 47 0.2857 0.5046(0.0544) <0.0005
Cells and Molecules involved in local acute inflammatory response
14 0.2857 0.5182(0.0624) 0.0005
Circadian Rhythms 8 0.2857 0.5255(0.0654) 0.0005
Activation of Src by Protein-tyrosine phosphatase alpha 6 0.2857 0.5286(0.0693) 0.0010
BC-Cell Cycle G2-MC 18 0.2857 0.5152(0.0633) 0.0010
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Null Error rate p-value (α=0.05) Mean(std)
Apoptotic signaling 22 0.1429 0.2424(0.0695) 0.0860
Arginine and proline 49 0.1429 0.1847(0.0456) 0.2415
Limonene and pinene 26 0.1429 0.2283(0.0649) 0.1070
Apoptosis___________ 92 0.1429 0.1588(0.0331) 0.4605
Bile acid biosynthesis 26 0.1429 0.2289(0.0668) 0.1005
Biosynthesis of steroids 20 0.1429 0.2490(0.0745) 0.0695
Butanoate metabolism 49 0.1429 0.1845(0.0471) 0.2585
Complement and coagulation 47 0.1429 0.1902(0.0492) 0.2195
Ascorbate and aldarate metabolism 15 0.1663 0.2764(0.0839) 0.0610
AKAP95 role in mitosis and chromosome dynamics 12 0.1663 0.3004(0.0901) 0.0660 Angiotensin II mediated activation of JNK Pathway via
Pyk2 dependent signaling
50 0.1663 0.1847(0.0464) 0.4410
Actions of Nitric Oxide in the Heart 39 0.1837 0.2001(0.0534) 0.5020
Amyotrophic lateral sclerosis 15 0.2041 0.2766(0.0815) 0.2305
akt signaling pathway 25 0.2245 0.2294(0.0644) 0.4655
Acetylation and Deacetylation of RelA in The Nucleus 12 0.2449 0.2982(0.0859) 0.3270
Biotin metabolism 1 0.2653 0.5525(0.0988) 0.0050
1_4-Dichlorobenzene 3 0.2653 0.4416(0.1067) 0.0665
Antigen Processing and Presentation 13 0.2653 0.2901(0.0896) 0.0945
Activation of cAMP-dependent protein kinase, PKA 22 0.2653 0.3165(0.0946) 0.3510 Aspirin Blocks Signaling Pathway Involved in Platelet
Activation
10 0.2653 0.2419(0.0713 0.7110
Classical Complement Pathway 8 0.2857 0.3351(0.0948) 0.3660
Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia
33 0.2857 0.2102(0.0585) 0.9160
BCR Signaling Pathway 47 0.2857 0.1905(0.0484) 0.9720
Cells and Molecules involved in local acute inflammatory response
14 0.2857 0.2792(0.0832) 0.5940
Circadian Rhythms 8 0.2857 0.3407(0.0990) 0.3475
Activation of Src by Protein-tyrosine phosphatase alpha 6 0.2857 0.3687(0.1016) 0.2525
BC-Cell Cycle G2-MC 18 0.2857 0.2590(0.0771) 0.1360
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Null Error rate p-value (α=0.05) Mean(std)
MAP00230_Purine_metabolism 98 0.26 0.3673(0.0336) 0.0080
SA_CASPASE_CASCADE 32 0.26 0.3807(0.0423) 0.0085
FRASOR_ER_UP 44 0.26 0.3824(0.0441) 0.0120
amiPathway 34 0.26 0.3829(0.0453) 0.0145
eea1Pathway 12 0.26 0.4064(0.0582) 0.0150
MAP00860_Porphyrin_and_chloroph
yll_metabolism 21 0.26 0.3862(0.0468) 0.0150
cell_surface_receptor_linked_signal_
transduction 187 0.28 0.3553(0.0238) 0.0095
cell_proliferation 200 0.28 0.3581(0.0288) 0.0195
ca_nf_at_signalling 175 0.28 0.3646(0.0311) 0.0205
fatty_acid_metabolism 30 0.28 0.3830(0.0431) 0.0220
MAP00500_Starch_and_sucrose_met
abolism 24 0.28 0.3812(0.0476) 0.0230
breast_cancer_estrogen_signalling 180 0.28 0.3680(0.0343) 0.0230
INSULIN_2F_DOWN 41 0.28 0.3762(0.0400) 0.0235
Muscle myosin 18 0.28 0.3911(0.0470) 0.0235
GO_ROS 32 0.28 0.3772(0.0404) 0.0245
nos1Pathway 37 0.28 0.3798(0.0420) 0.0245
GLYCOGEN 24 0.28 0.3885(0.0467) 0.0255
extrinsicPathway 13 0.28 0.3974(0.0524) 0.0260
Glycogen Metabolism 50 0.28 0.3798(0.0411) 0.0270
CR_REPAIR 72 0.28 0.3773(0.0406) 0.0270
hsp27Pathway 33 0.28 0.3835(0.0447) 0.0270
cftrPathway 19 0.28 0.3994(0.0533) 0.0295
tnf_and_fas_network 46 0.28 0.3825(0.0456) 0.0300
fibrinolysisPathway 12 0.28 0.4012(0.0561) 0.0340
mitochondr 459 0.30 0.3587(0.0274) 0.0405
CR_PROTEIN_MOD 240 0.30 0.3608(0.0287) 0.0425
human_mitoDB_6_2002 452 0.30 0.3584(0.0273) 0.0440
MAP00052_Galactose_metabolism 23 0.30 0.3829(0.0456) 0.0465
(續)
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plcePathway 19 0.30 0.3971(0.0520) 0.0490
MAP00195_Photosynthesis 17 0.30 0.3991(0.0520) 0.0500
intrinsicPathway 28 0.30 0.3848(0.0452) 0.0510
SA_DAG1 12 0.30 0.3998(0.0522) 0.0515
ctlPathway 24 0.30 0.3901(0.0478) 0.0515
rbPathway 26 0.30 0.3914(0.0482) 0.0520
arfPathway 30 0.30 0.3894(0.0474) 0.0535
CR_TRANSPORT_OF_VESICLES 26 0.30 0.3877(0.0460) 0.0540
srcRPTPPathway 22 0.30 0.3886(0.0486) 0.0545
Il12Pathway 28 0.30 0.3784(0.0421) 0.0555
thelperPathway 17 0.30 0.3948(0.0513) 0.0590
ck1Pathway 19 0.30 0.3880(0.0475) 0.0600
HOXA9_DOWN 17 0.30 0.3982(0.0536) 0.0605
no2il12Pathway 21 0.30 0.3844(0.0461) 0.0615
TCA 55 0.30 0.3757(0.0417) 0.0690
Krebs-TCA_Cycle 33 0.30 0.3829(0.0442) 0.0635
GLYCOL 25 0.30 0.3885(0.0490) 0.0640
GLUCOSE_DOWN 261 0.30 0.3617(0.0315) 0.0690
GLUT_UP 406 0.30 0.3708(0.0273) 0.1080
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Null Error rate p-value (α=0.05) Mean(std)
MAP00860_Porphyrin_and_chloroph
yll_metabolism 21 0.26 0.3592(0.0503) 0.0440
amiPathway 34 0.26 0.3476(0.0444) 0.0465
hivnefPathway 111 0.26 0.3268(0.0345) 0.0485
SA_CASPASE_CASCADE 32 0.26 0.3464(0.0456) 0.0490
FRASOR_ER_UP 44 0.26 0.3416(0.0434) 0.0550
MAP00230_Purine_metabolism 98 0.26 0.3275(0.0355) 0.0555
extrinsicPathway 13 0.28 0.3738(0.0541) 0.0665
MAP00500_Starch_and_sucrose_met
abolism 24 0.28 0.3579(0.0476) 0.0685
fibrinolysisPathway 12 0.28 0.3749(0.0572) 0.0700
Muscle myosin 18 0.28 0.3663(0.0527) 0.0705
cftrPathway 19 0.28 0.3644(0.0530) 0.0825
CR_REPAIR 72 0.28 0.3328(0.0390) 0.0885
GLYCOGEN 24 0.28 0.3541(0.0487) 0.0925
fatty_acid_metabolism 30 0.28 0.3516(0.0473) 0.0945
GO_ROS 32 0.28 0.3481(0.0455) 0.0950
hsp27Pathway 33 0.28 0.3475(0.0451) 0.0990
nos1Pathway 37 0.28 0.3467(0.0450) 0.0995
INSULIN_2F_DOWN 41 0.28 0.3427(0.0443) 0.1070
Glycogen Metabolism 50 0.28 0.3377(0.0412) 0.1150
tnf_and_fas_network 46 0.28 0.3390(0.0422) 0.1155
cell_surface_receptor_linked_signal_
transduction 187 0.28 0.3219(0.0307) 0.1405
breast_cancer_estrogen_signalling 180 0.28 0.3218(0.0317) 0.1530
ca_nf_at_signalling 175 0.28 0.3212(0.0319) 0.1580
cell_proliferation 200 0.28 0.3171(0.0290) 0.1650
SA_DAG1 12 0.30 0.3735(0.0561) 0.1310
MAP00195_Photosynthesis 17 0.30 0.3676(0.0529) 0.1320
HOXA9_DOWN 17 0.30 0.3664(0.0544) 0.1485
srcRPTPPathway 22 0.30 0.3577(0.0481) 0.1510
plcePathway 19 0.30 0.3625(0.0531) 0.1565
(續)
‧ 國
立 政 治 大 學
‧
N a tio na
l C h engchi U ni ve rs it y
thelperPathway 17 0.30 0.3643(0.0557) 0.1565
intrinsicPathway 28 0.30 0.3547(0.0482) 0.1645
ctlPathway 24 0.30 0.3544(0.0464) 0.1665
Il12Pathway 28 0.30 0.3525(0.0472) 0.1670
MAP00052_Galactose_metabolism 23 0.30 0.3552(0.0488) 0.1670
rbPathway 26 0.30 0.3553(0.0489) 0.1710
GLYCOL 25 0.30 0.3555(0.0501) 0.1780
ck1Pathway 19 0.30 0.3537(0.0512) 0.1805
arfPathway 30 0.30 0.3509(0.0464) 0.1820
CR_TRANSPORT_OF_VESICLES 26 0.30 0.3468(0.0460) 0.1960
Krebs-TCA_Cycle 33 0.30 0.3466(0.0455) 0.1985
TCA 55 0.30 0.3390(0.0401) 0.2250
GLUCOSE_DOWN 261 0.30 0.3194(0.0299) 0.3630
CR_PROTEIN_MOD 240 0.30 0.3189(0.0298) 0.3715
human_mitoDB_6_2002 452 0.30 0.3194(0.0299) 0.3630
GLUT_UP 406 0.30 0.3158(0.0273) 0.4070
mitochondr 459 0.30 0.3147(0.0274) 0.4400