Correlation between RPPA expression and clinical features
Overview
Introduction

This pipeline uses various statistical tests to identify RPPAs whose expression levels correlated to selected clinical features.

Summary

Testing the association between 142 genes and 12 clinical features across 409 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 9 clinical features related to at least one genes.

  • 1 gene correlated to 'Time to Death'.

    • PIK3CA |PI3K-P110-ALPHA

  • 21 genes correlated to 'AGE'.

    • ESR1|ER-ALPHA ,  STMN1|STATHMIN ,  CDC2|CDK1 ,  KIT|C-KIT ,  AR|AR ,  ...

  • 2 genes correlated to 'NEOPLASM.DISEASESTAGE'.

    • COL6A1|COLLAGEN_VI ,  MAPK14|P38_PT180_Y182

  • 8 genes correlated to 'PATHOLOGY.T.STAGE'.

    • MAPK14|P38_PT180_Y182 ,  MET|C-MET_PY1235 ,  COL6A1|COLLAGEN_VI ,  PRKCD|PKC-DELTA_PS664 ,  CHEK2|CHK2_PT68 ,  ...

  • 1 gene correlated to 'PATHOLOGY.N.STAGE'.

    • EIF4E|EIF4E

  • 2 genes correlated to 'GENDER'.

    • ACACA|ACC1 ,  RPS6KB1|P70S6K

  • 17 genes correlated to 'HISTOLOGICAL.TYPE'.

    • CDH1|E-CADHERIN ,  CTNNB1|BETA-CATENIN ,  CTNNA1|ALPHA-CATENIN ,  ERBB3|HER3_PY1289 ,  TP53|P53 ,  ...

  • 5 genes correlated to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

    • MAPK14|P38_PT180_Y182 ,  MET|C-MET_PY1235 ,  MRE11A|MRE11 ,  BAX|BAX ,  CHEK2|CHK2_PT68

  • 2 genes correlated to 'RACE'.

    • SCD1|SCD1 ,  PECAM1|CD31

  • No genes correlated to 'PATHOLOGY.M.STAGE', 'NUMBER.OF.LYMPH.NODES', and 'ETHNICITY'.

Results
Overview of the results

Complete statistical result table is provided in Supplement Table 1

Table 1.  Get Full Table This table shows the clinical features, statistical methods used, and the number of genes that are significantly associated with each clinical feature at P value < 0.05 and Q value < 0.3.

Clinical feature Statistical test Significant genes Associated with                 Associated with
Time to Death Cox regression test N=1 shorter survival N=1 longer survival N=0
AGE Spearman correlation test N=21 older N=7 younger N=14
NEOPLASM DISEASESTAGE Kruskal-Wallis test N=2        
PATHOLOGY T STAGE Spearman correlation test N=8 higher stage N=3 lower stage N=5
PATHOLOGY N STAGE Spearman correlation test N=1 higher stage N=0 lower stage N=1
PATHOLOGY M STAGE Kruskal-Wallis test   N=0        
GENDER Wilcoxon test N=2 male N=2 female N=0
HISTOLOGICAL TYPE Kruskal-Wallis test N=17        
RADIATIONS RADIATION REGIMENINDICATION Wilcoxon test N=5 yes N=5 no N=0
NUMBER OF LYMPH NODES Spearman correlation test   N=0        
RACE Kruskal-Wallis test N=2        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'Time to Death'

One gene related to 'Time to Death'.

Table S1.  Basic characteristics of clinical feature: 'Time to Death'

Time to Death Duration (Months) 0.1-189 (median=28.7)
  censored N = 345
  death N = 51
     
  Significant markers N = 1
  associated with shorter survival 1
  associated with longer survival 0
List of one gene differentially expressed by 'Time to Death'

Table S2.  Get Full Table List of one gene significantly associated with 'Time to Death' by Cox regression test

HazardRatio Wald_P Q C_index
PIK3CA |PI3K-P110-ALPHA 2.9 0.0004201 0.06 0.594
Clinical variable #2: 'AGE'

21 genes related to 'AGE'.

Table S3.  Basic characteristics of clinical feature: 'AGE'

AGE Mean (SD) 57.89 (13)
  Significant markers N = 21
  pos. correlated 7
  neg. correlated 14
List of top 10 genes differentially expressed by 'AGE'

Table S4.  Get Full Table List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

SpearmanCorr corrP Q
ESR1|ER-ALPHA 0.3839 9.718e-16 1.38e-13
STMN1|STATHMIN -0.228 3.384e-06 0.000477
CDC2|CDK1 -0.2209 6.847e-06 0.000959
KIT|C-KIT -0.2162 1.077e-05 0.0015
AR|AR 0.2093 2.084e-05 0.00288
EGFR|EGFR -0.2086 2.214e-05 0.00303
MET|C-MET_PY1235 -0.2076 2.436e-05 0.00331
CDH3|P-CADHERIN -0.2066 2.671e-05 0.00361
PDK1|PDK1_PS241 0.193 8.938e-05 0.012
NOTCH1|NOTCH1 -0.1921 9.624e-05 0.0128
Clinical variable #3: 'NEOPLASM.DISEASESTAGE'

2 genes related to 'NEOPLASM.DISEASESTAGE'.

Table S5.  Basic characteristics of clinical feature: 'NEOPLASM.DISEASESTAGE'

NEOPLASM.DISEASESTAGE Labels N
  STAGE I 32
  STAGE IA 30
  STAGE IB 4
  STAGE IIA 137
  STAGE IIB 94
  STAGE IIIA 62
  STAGE IIIB 13
  STAGE IIIC 15
  STAGE IV 14
  STAGE X 8
     
  Significant markers N = 2
List of 2 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

Table S6.  Get Full Table List of 2 genes differentially expressed by 'NEOPLASM.DISEASESTAGE'

ANOVA_P Q
COL6A1|COLLAGEN_VI 0.0001783 0.0253
MAPK14|P38_PT180_Y182 0.001238 0.175
Clinical variable #4: 'PATHOLOGY.T.STAGE'

8 genes related to 'PATHOLOGY.T.STAGE'.

Table S7.  Basic characteristics of clinical feature: 'PATHOLOGY.T.STAGE'

PATHOLOGY.T.STAGE Mean (SD) 1.98 (0.73)
  N
  1 94
  2 246
  3 50
  4 18
     
  Significant markers N = 8
  pos. correlated 3
  neg. correlated 5
List of 8 genes differentially expressed by 'PATHOLOGY.T.STAGE'

Table S8.  Get Full Table List of 8 genes significantly correlated to 'PATHOLOGY.T.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
MAPK14|P38_PT180_Y182 -0.1836 0.0001922 0.0273
MET|C-MET_PY1235 0.181 0.0002376 0.0335
COL6A1|COLLAGEN_VI -0.1669 0.000713 0.0998
PRKCD|PKC-DELTA_PS664 0.1645 0.0008531 0.119
CHEK2|CHK2_PT68 0.1622 0.001011 0.139
CAV1|CAVEOLIN-1 -0.1598 0.001199 0.164
BCL2|BCL-2 -0.1527 0.001981 0.269
YBX1|YB-1_PS102 -0.1518 0.002112 0.285
Clinical variable #5: 'PATHOLOGY.N.STAGE'

One gene related to 'PATHOLOGY.N.STAGE'.

Table S9.  Basic characteristics of clinical feature: 'PATHOLOGY.N.STAGE'

PATHOLOGY.N.STAGE Mean (SD) 0.77 (0.9)
  N
  0 193
  1 132
  2 52
  3 25
     
  Significant markers N = 1
  pos. correlated 0
  neg. correlated 1
List of one gene differentially expressed by 'PATHOLOGY.N.STAGE'

Table S10.  Get Full Table List of one gene significantly correlated to 'PATHOLOGY.N.STAGE' by Spearman correlation test

SpearmanCorr corrP Q
EIF4E|EIF4E -0.1573 0.001557 0.221
Clinical variable #6: 'PATHOLOGY.M.STAGE'

No gene related to 'PATHOLOGY.M.STAGE'.

Table S11.  Basic characteristics of clinical feature: 'PATHOLOGY.M.STAGE'

PATHOLOGY.M.STAGE Labels N
  CM0 (I+) 1
  M0 387
  M1 14
  MX 7
     
  Significant markers N = 0
Clinical variable #7: 'GENDER'

2 genes related to 'GENDER'.

Table S12.  Basic characteristics of clinical feature: 'GENDER'

GENDER Labels N
  FEMALE 404
  MALE 5
     
  Significant markers N = 2
  Higher in MALE 2
  Higher in FEMALE 0
List of 2 genes differentially expressed by 'GENDER'

Table S13.  Get Full Table List of 2 genes differentially expressed by 'GENDER'. 0 significant gene(s) located in sex chromosomes is(are) filtered out.

W(pos if higher in 'MALE') wilcoxontestP Q AUC
ACACA|ACC1 1824 0.001958 0.278 0.903
RPS6KB1|P70S6K 1820 0.002061 0.291 0.901
Clinical variable #8: 'HISTOLOGICAL.TYPE'

17 genes related to 'HISTOLOGICAL.TYPE'.

Table S14.  Basic characteristics of clinical feature: 'HISTOLOGICAL.TYPE'

HISTOLOGICAL.TYPE Labels N
  INFILTRATING DUCTAL CARCINOMA 354
  INFILTRATING LOBULAR CARCINOMA 30
  MEDULLARY CARCINOMA 1
  MIXED HISTOLOGY (PLEASE SPECIFY) 8
  MUCINOUS CARCINOMA 2
  OTHER SPECIFY 14
     
  Significant markers N = 17
List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

Table S15.  Get Full Table List of top 10 genes differentially expressed by 'HISTOLOGICAL.TYPE'

ANOVA_P Q
CDH1|E-CADHERIN 6.117e-15 8.69e-13
CTNNB1|BETA-CATENIN 3.291e-13 4.64e-11
CTNNA1|ALPHA-CATENIN 2.777e-09 3.89e-07
ERBB3|HER3_PY1289 3.3e-05 0.00459
TP53|P53 0.000215 0.0297
DVL3|DVL3 0.0002716 0.0372
YBX1|YB-1 0.0005491 0.0747
COL6A1|COLLAGEN_VI 0.0006173 0.0833
SCD1|SCD1 0.0007706 0.103
CAV1|CAVEOLIN-1 0.0008035 0.107
Clinical variable #9: 'RADIATIONS.RADIATION.REGIMENINDICATION'

5 genes related to 'RADIATIONS.RADIATION.REGIMENINDICATION'.

Table S16.  Basic characteristics of clinical feature: 'RADIATIONS.RADIATION.REGIMENINDICATION'

RADIATIONS.RADIATION.REGIMENINDICATION Labels N
  NO 144
  YES 265
     
  Significant markers N = 5
  Higher in YES 5
  Higher in NO 0
List of 5 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

Table S17.  Get Full Table List of 5 genes differentially expressed by 'RADIATIONS.RADIATION.REGIMENINDICATION'

W(pos if higher in 'YES') wilcoxontestP Q AUC
MAPK14|P38_PT180_Y182 14280 2.631e-05 0.00374 0.6258
MET|C-MET_PY1235 23303 0.0002173 0.0306 0.6107
MRE11A|MRE11 23219 0.0002896 0.0405 0.6085
BAX|BAX 15488 0.001659 0.231 0.5941
CHEK2|CHK2_PT68 22617 0.001954 0.27 0.5927
Clinical variable #10: 'NUMBER.OF.LYMPH.NODES'

No gene related to 'NUMBER.OF.LYMPH.NODES'.

Table S18.  Basic characteristics of clinical feature: 'NUMBER.OF.LYMPH.NODES'

NUMBER.OF.LYMPH.NODES Mean (SD) 1.85 (3.5)
  Significant markers N = 0
Clinical variable #11: 'RACE'

2 genes related to 'RACE'.

Table S19.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  AMERICAN INDIAN OR ALASKA NATIVE 1
  ASIAN 27
  BLACK OR AFRICAN AMERICAN 29
  WHITE 294
     
  Significant markers N = 2
List of 2 genes differentially expressed by 'RACE'

Table S20.  Get Full Table List of 2 genes differentially expressed by 'RACE'

ANOVA_P Q
SCD1|SCD1 0.0001167 0.0166
PECAM1|CD31 0.001517 0.214
Clinical variable #12: 'ETHNICITY'

No gene related to 'ETHNICITY'.

Table S21.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 6
  NOT HISPANIC OR LATINO 297
     
  Significant markers N = 0
Methods & Data
Input

  • Expresson data file = BRCA-TP.rppa.txt

  • Clinical data file = BRCA-TP.merged_data.txt

  • Number of patients = 409

  • Number of genes = 142

  • Number of clinical features = 12

Survival analysis

For survival clinical features, Wald's test in univariate Cox regression analysis with proportional hazards model (Andersen and Gill 1982) was used to estimate the P values using the 'coxph' function in R. Kaplan-Meier survival curves were plot using the four quartile subgroups of patients based on expression levels

Correlation analysis

For continuous numerical clinical features, Spearman's rank correlation coefficients (Spearman 1904) and two-tailed P values were estimated using 'cor.test' function in R

ANOVA analysis

For multi-class clinical features (ordinal or nominal), one-way analysis of variance (Howell 2002) was applied to compare the log2-expression levels between different clinical classes using 'anova' function in R

Student's t-test analysis

For two-class clinical features, two-tailed Student's t test with unequal variance (Lehmann and Romano 2005) was applied to compare the log2-expression levels between the two clinical classes using 't.test' function in R

Q value calculation

For multiple hypothesis correction, Q value is the False Discovery Rate (FDR) analogue of the P value (Benjamini and Hochberg 1995), defined as the minimum FDR at which the test may be called significant. We used the 'Benjamini and Hochberg' method of 'p.adjust' function in R to convert P values into Q values.

References
[1] Andersen and Gill, Cox's regression model for counting processes, a large sample study, Annals of Statistics 10(4):1100-1120 (1982)
[2] Spearman, C, The proof and measurement of association between two things, Amer. J. Psychol 15:72-101 (1904)
[3] Howell, D, Statistical Methods for Psychology. (5th ed.), Duxbury Press:324-5 (2002)
[4] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)
[5] Benjamini and Hochberg, Controlling the false discovery rate: a practical and powerful approach to multiple testing, Journal of the Royal Statistical Society Series B 59:289-300 (1995)
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