Correlation between miRseq expression and clinical features
Skin Cutaneous Melanoma (Metastatic)
02 April 2015  |  analyses__2015_04_02
Maintainer Information
Citation Information
doi:10.7908/C1SQ8ZGB
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2015): Correlation between miRseq expression and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1SQ8ZGB
Overview
Introduction

This pipeline uses various statistical tests to identify miRs whose log2 expression levels correlated to selected clinical features.

Summary

Testing the association between 590 miRs and 14 clinical features across 343 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 9 clinical features related to at least one miRs.

  • 4 miRs correlated to 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'.

    • HSA-MIR-625 ,  HSA-MIR-1976 ,  HSA-MIR-155 ,  HSA-MIR-100

  • 30 miRs correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

    • HSA-MIR-551A ,  HSA-MIR-3680 ,  HSA-MIR-181A-2 ,  HSA-MIR-3127 ,  HSA-MIR-607 ,  ...

  • 4 miRs correlated to 'YEARS_TO_BIRTH'.

    • HSA-MIR-3200 ,  HSA-MIR-204 ,  HSA-MIR-375 ,  HSA-MIR-125B-1

  • 30 miRs correlated to 'PRIMARY_SITE_OF_DISEASE'.

    • HSA-MIR-379 ,  HSA-MIR-150 ,  HSA-MIR-410 ,  HSA-MIR-134 ,  HSA-MIR-758 ,  ...

  • 28 miRs correlated to 'PATHOLOGY_T_STAGE'.

    • HSA-MIR-1537 ,  HSA-MIR-656 ,  HSA-MIR-582 ,  HSA-MIR-155 ,  HSA-MIR-29B-2 ,  ...

  • 14 miRs correlated to 'PATHOLOGY_N_STAGE'.

    • HSA-MIR-338 ,  HSA-MIR-10A ,  HSA-MIR-3909 ,  HSA-MIR-29A ,  HSA-MIR-29B-1 ,  ...

  • 14 miRs correlated to 'MELANOMA_ULCERATION'.

    • HSA-MIR-191 ,  HSA-MIR-2277 ,  HSA-MIR-301A ,  HSA-LET-7E ,  HSA-LET-7A-2 ,  ...

  • 30 miRs correlated to 'BRESLOW_THICKNESS'.

    • HSA-MIR-1537 ,  HSA-MIR-1243 ,  HSA-MIR-100 ,  HSA-MIR-125B-1 ,  HSA-MIR-873 ,  ...

  • 14 miRs correlated to 'GENDER'.

    • HSA-MIR-361 ,  HSA-LET-7A-1 ,  HSA-LET-7A-2 ,  HSA-LET-7A-3 ,  HSA-MIR-10B ,  ...

  • No miRs correlated to 'NEOPLASM_DISEASESTAGE', 'PATHOLOGY_M_STAGE', 'MELANOMA_PRIMARY_KNOWN', 'RACE', 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 miRs that are significantly associated with each clinical feature at P value < 0.05 and Q value < 0.3.

Clinical feature Statistical test Significant miRs Associated with                 Associated with
TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP Cox regression test N=4 shorter survival N=0 longer survival N=4
DAYS_TO_DEATH_OR_LAST_FUP Cox regression test N=30 shorter survival N=20 longer survival N=10
YEARS_TO_BIRTH Spearman correlation test N=4 older N=1 younger N=3
PRIMARY_SITE_OF_DISEASE Kruskal-Wallis test N=30        
NEOPLASM_DISEASESTAGE Kruskal-Wallis test   N=0        
PATHOLOGY_T_STAGE Spearman correlation test N=28 higher stage N=19 lower stage N=9
PATHOLOGY_N_STAGE Spearman correlation test N=14 higher stage N=12 lower stage N=2
PATHOLOGY_M_STAGE Wilcoxon test   N=0        
MELANOMA_ULCERATION Wilcoxon test N=14 yes N=14 no N=0
MELANOMA_PRIMARY_KNOWN Wilcoxon test   N=0        
BRESLOW_THICKNESS Spearman correlation test N=30 higher breslow_thickness N=23 lower breslow_thickness N=7
GENDER Wilcoxon test N=14 male N=14 female N=0
RACE Kruskal-Wallis test   N=0        
ETHNICITY Wilcoxon test   N=0        
Clinical variable #1: 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

4 miRs related to 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'.

Table S1.  Basic characteristics of clinical feature: 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP Duration (Months) 0-346.5 (median=46.9)
  censored N = 113
  death N = 118
     
  Significant markers N = 4
  associated with shorter survival 0
  associated with longer survival 4
List of 4 miRs differentially expressed by 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

Table S2.  Get Full Table List of 4 miRs significantly associated with 'Time from Specimen Diagnosis to Death' by Cox regression test

HazardRatio Wald_P Q C_index
HSA-MIR-625 0.74 0.0005381 0.26 0.411
HSA-MIR-1976 0.75 0.0009537 0.26 0.414
HSA-MIR-155 0.86 0.001434 0.26 0.397
HSA-MIR-100 0.85 0.001747 0.26 0.409
Clinical variable #2: 'DAYS_TO_DEATH_OR_LAST_FUP'

30 miRs related to 'DAYS_TO_DEATH_OR_LAST_FUP'.

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

DAYS_TO_DEATH_OR_LAST_FUP Duration (Months) 0.2-369.9 (median=50.9)
  censored N = 165
  death N = 177
     
  Significant markers N = 30
  associated with shorter survival 20
  associated with longer survival 10
List of top 10 miRs differentially expressed by 'DAYS_TO_DEATH_OR_LAST_FUP'

Table S4.  Get Full Table List of top 10 miRs significantly associated with 'Time to Death' by Cox regression test

HazardRatio Wald_P Q C_index
HSA-MIR-551A 1.23 3.263e-05 0.019 0.621
HSA-MIR-3680 1.26 0.0001613 0.035 0.593
HSA-MIR-181A-2 1.28 0.0001788 0.035 0.584
HSA-MIR-3127 1.32 0.0002481 0.035 0.591
HSA-MIR-607 1.33 0.0002962 0.035 0.587
HSA-MIR-3150B 1.19 0.0004065 0.04 0.579
HSA-MIR-100 0.86 0.0005318 0.045 0.412
HSA-MIR-144 1.14 0.0006236 0.046 0.585
HSA-MIR-625 0.8 0.001032 0.068 0.421
HSA-MIR-3170 1.19 0.00119 0.07 0.575
Clinical variable #3: 'YEARS_TO_BIRTH'

4 miRs related to 'YEARS_TO_BIRTH'.

Table S5.  Basic characteristics of clinical feature: 'YEARS_TO_BIRTH'

YEARS_TO_BIRTH Mean (SD) 56.27 (16)
  Significant markers N = 4
  pos. correlated 1
  neg. correlated 3
List of 4 miRs differentially expressed by 'YEARS_TO_BIRTH'

Table S6.  Get Full Table List of 4 miRs significantly correlated to 'YEARS_TO_BIRTH' by Spearman correlation test

SpearmanCorr corrP Q
HSA-MIR-3200 -0.2329 1.863e-05 0.011
HSA-MIR-204 -0.2194 5.374e-05 0.0159
HSA-MIR-375 0.1952 0.0003333 0.0656
HSA-MIR-125B-1 -0.1802 0.0009232 0.136
Clinical variable #4: 'PRIMARY_SITE_OF_DISEASE'

30 miRs related to 'PRIMARY_SITE_OF_DISEASE'.

Table S7.  Basic characteristics of clinical feature: 'PRIMARY_SITE_OF_DISEASE'

PRIMARY_SITE_OF_DISEASE Labels N
  DISTANT METASTASIS 61
  PRIMARY TUMOR 4
  REGIONAL CUTANEOUS OR SUBCUTANEOUS TISSUE 69
  REGIONAL LYMPH NODE 208
     
  Significant markers N = 30
List of top 10 miRs differentially expressed by 'PRIMARY_SITE_OF_DISEASE'

Table S8.  Get Full Table List of top 10 miRs differentially expressed by 'PRIMARY_SITE_OF_DISEASE'

kruskal_wallis_P Q
HSA-MIR-379 4.003e-09 2.36e-06
HSA-MIR-150 1.613e-08 4.76e-06
HSA-MIR-410 9.304e-08 1.34e-05
HSA-MIR-134 9.979e-08 1.34e-05
HSA-MIR-758 1.138e-07 1.34e-05
HSA-MIR-342 1.868e-07 1.69e-05
HSA-MIR-127 2.01e-07 1.69e-05
HSA-MIR-654 2.288e-07 1.69e-05
HSA-MIR-382 3.184e-07 2.09e-05
HSA-MIR-136 4.275e-07 2.52e-05
Clinical variable #5: 'NEOPLASM_DISEASESTAGE'

No miR related to 'NEOPLASM_DISEASESTAGE'.

Table S9.  Basic characteristics of clinical feature: 'NEOPLASM_DISEASESTAGE'

NEOPLASM_DISEASESTAGE Labels N
  I OR II NOS 12
  STAGE 0 7
  STAGE I 27
  STAGE IA 16
  STAGE IB 27
  STAGE II 22
  STAGE IIA 12
  STAGE IIB 18
  STAGE IIC 11
  STAGE III 35
  STAGE IIIA 14
  STAGE IIIB 30
  STAGE IIIC 60
  STAGE IV 19
     
  Significant markers N = 0
Clinical variable #6: 'PATHOLOGY_T_STAGE'

28 miRs related to 'PATHOLOGY_T_STAGE'.

Table S10.  Basic characteristics of clinical feature: 'PATHOLOGY_T_STAGE'

PATHOLOGY_T_STAGE Mean (SD) 2.44 (1.2)
  N
  T0 23
  T1 37
  T2 72
  T3 72
  T4 64
     
  Significant markers N = 28
  pos. correlated 19
  neg. correlated 9
List of top 10 miRs differentially expressed by 'PATHOLOGY_T_STAGE'

Table S11.  Get Full Table List of top 10 miRs significantly correlated to 'PATHOLOGY_T_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
HSA-MIR-1537 0.2702 6.994e-05 0.0413
HSA-MIR-656 0.3116 0.0004508 0.0676
HSA-MIR-582 0.2111 0.0005021 0.0676
HSA-MIR-155 -0.211 0.0005059 0.0676
HSA-MIR-29B-2 -0.209 0.0005725 0.0676
HSA-MIR-1262 0.2047 0.0008985 0.0752
HSA-MIR-1243 0.2262 0.0009373 0.0752
HSA-MIR-29B-1 -0.1985 0.00109 0.0752
HSA-MIR-29C -0.1976 0.001147 0.0752
HSA-MIR-449A 0.2779 0.001938 0.114
Clinical variable #7: 'PATHOLOGY_N_STAGE'

14 miRs related to 'PATHOLOGY_N_STAGE'.

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

PATHOLOGY_N_STAGE Mean (SD) 0.9 (1.1)
  N
  N0 162
  N1 60
  N2 38
  N3 47
     
  Significant markers N = 14
  pos. correlated 12
  neg. correlated 2
List of top 10 miRs differentially expressed by 'PATHOLOGY_N_STAGE'

Table S13.  Get Full Table List of top 10 miRs significantly correlated to 'PATHOLOGY_N_STAGE' by Spearman correlation test

SpearmanCorr corrP Q
HSA-MIR-338 0.2197 0.0001041 0.0614
HSA-MIR-10A -0.2002 0.0004178 0.123
HSA-MIR-3909 0.1999 0.0006869 0.135
HSA-MIR-29A 0.1877 0.0009492 0.14
HSA-MIR-29B-1 0.1775 0.001793 0.17
HSA-MIR-365-1 0.1767 0.001879 0.17
HSA-MIR-10B -0.1726 0.002402 0.17
HSA-MIR-135B 0.1743 0.002538 0.17
HSA-MIR-365-2 0.1698 0.002833 0.17
HSA-MIR-3934 0.1696 0.003156 0.17
Clinical variable #8: 'PATHOLOGY_M_STAGE'

No miR related to 'PATHOLOGY_M_STAGE'.

Table S14.  Basic characteristics of clinical feature: 'PATHOLOGY_M_STAGE'

PATHOLOGY_M_STAGE Labels N
  class0 301
  class1 20
     
  Significant markers N = 0
Clinical variable #9: 'MELANOMA_ULCERATION'

14 miRs related to 'MELANOMA_ULCERATION'.

Table S15.  Basic characteristics of clinical feature: 'MELANOMA_ULCERATION'

MELANOMA_ULCERATION Labels N
  NO 125
  YES 85
     
  Significant markers N = 14
  Higher in YES 14
  Higher in NO 0
List of top 10 miRs differentially expressed by 'MELANOMA_ULCERATION'

Table S16.  Get Full Table List of top 10 miRs differentially expressed by 'MELANOMA_ULCERATION'

W(pos if higher in 'YES') wilcoxontestP Q AUC
HSA-MIR-191 6869 0.0003183 0.124 0.6465
HSA-MIR-2277 6264 0.0004212 0.124 0.6471
HSA-MIR-301A 6575 0.0007193 0.141 0.6388
HSA-LET-7E 3957 0.001719 0.163 0.6276
HSA-LET-7A-2 3993 0.002276 0.163 0.6242
HSA-MIR-449A 1523 0.002491 0.163 0.6811
HSA-LET-7A-1 4005 0.002496 0.163 0.6231
HSA-MIR-590 6471 0.002543 0.163 0.6237
HSA-LET-7A-3 4009 0.002573 0.163 0.6227
HSA-MIR-2276 3422 0.002773 0.163 0.6448
Clinical variable #10: 'MELANOMA_PRIMARY_KNOWN'

No miR related to 'MELANOMA_PRIMARY_KNOWN'.

Table S17.  Basic characteristics of clinical feature: 'MELANOMA_PRIMARY_KNOWN'

MELANOMA_PRIMARY_KNOWN Labels N
  NO 42
  YES 300
     
  Significant markers N = 0
Clinical variable #11: 'BRESLOW_THICKNESS'

30 miRs related to 'BRESLOW_THICKNESS'.

Table S18.  Basic characteristics of clinical feature: 'BRESLOW_THICKNESS'

BRESLOW_THICKNESS Mean (SD) 3.44 (4.8)
  Significant markers N = 30
  pos. correlated 23
  neg. correlated 7
List of top 10 miRs differentially expressed by 'BRESLOW_THICKNESS'

Table S19.  Get Full Table List of top 10 miRs significantly correlated to 'BRESLOW_THICKNESS' by Spearman correlation test

SpearmanCorr corrP Q
HSA-MIR-1537 0.332 1.662e-06 0.000981
HSA-MIR-1243 0.2757 9.59e-05 0.0283
HSA-MIR-100 -0.2286 0.0002675 0.0526
HSA-MIR-125B-1 -0.219 0.0004862 0.0625
HSA-MIR-873 0.2339 0.0005297 0.0625
HSA-MIR-508 0.2009 0.001409 0.12
HSA-MIR-211 0.2005 0.001435 0.12
HSA-MIR-509-1 0.1984 0.001621 0.12
HSA-MIR-335 -0.1954 0.001905 0.125
HSA-MIR-509-2 0.1936 0.002145 0.127
Clinical variable #12: 'GENDER'

14 miRs related to 'GENDER'.

Table S20.  Basic characteristics of clinical feature: 'GENDER'

GENDER Labels N
  FEMALE 128
  MALE 215
     
  Significant markers N = 14
  Higher in MALE 14
  Higher in FEMALE 0
List of top 10 miRs differentially expressed by 'GENDER'

Table S21.  Get Full Table List of top 10 miRs 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
HSA-MIR-361 9752 6.425e-06 0.00379 0.6456
HSA-LET-7A-1 16879 0.0004464 0.0735 0.6133
HSA-LET-7A-2 16863 0.0004776 0.0735 0.6128
HSA-LET-7A-3 16853 0.0004982 0.0735 0.6124
HSA-MIR-10B 10819 0.0009309 0.11 0.6069
HSA-MIR-766 10810 0.001296 0.127 0.6041
HSA-LET-7F-2 16375 0.003244 0.257 0.595
HSA-MIR-590 11001 0.003992 0.257 0.5933
HSA-MIR-511-1 11141 0.004479 0.257 0.592
HSA-MIR-320D-2 12506 0.004527 0.257 0.5984
Clinical variable #13: 'RACE'

No miR related to 'RACE'.

Table S22.  Basic characteristics of clinical feature: 'RACE'

RACE Labels N
  ASIAN 5
  BLACK OR AFRICAN AMERICAN 1
  WHITE 329
     
  Significant markers N = 0
Clinical variable #14: 'ETHNICITY'

No miR related to 'ETHNICITY'.

Table S23.  Basic characteristics of clinical feature: 'ETHNICITY'

ETHNICITY Labels N
  HISPANIC OR LATINO 7
  NOT HISPANIC OR LATINO 329
     
  Significant markers N = 0
Methods & Data
Input

  • Expresson data file = SKCM-TM.miRseq_RPKM_log2.txt

  • Clinical data file = SKCM-TM.merged_data.txt

  • Number of patients = 343

  • Number of miRs = 590

  • Number of clinical features = 14

Selected clinical features

  • For clinical features selected for this analysis and their value conozzle.versions, please find a documentation on selected CDEs .

  • Survival time data

    • Survival time data is a combined value of days_to_death and days_to_last_followup. For each patient, it creates a combined value 'days_to_death_or_last_fup' using conversion process below.

      • if 'vital_status'==1(dead), 'days_to_last_followup' is always NA. Thus, uses 'days_to_death' value for 'days_to_death_or_fup'

      • if 'vital_status'==0(alive),

        • if 'days_to_death'==NA & 'days_to_last_followup'!=NA, uses 'days_to_last_followup' value for 'days_to_death_or_fup'

        • if 'days_to_death'!=NA, excludes this case in survival analysis and report the case.

      • if 'vital_status'==NA,excludes this case in survival analysis and report the case.

    • cf. In certain diesase types such as SKCM, days_to_death parameter is replaced with time_from_specimen_dx or time_from_specimen_procurement_to_death .

  • This analysis excluded clinical variables that has only NA values.

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

Wilcoxon rank sum test (Mann-Whitney U test)

For two groups (mutant or wild-type) of continuous type of clinical data, wilcoxon rank sum test (Mann and Whitney, 1947) was applied to compare their mean difference using 'wilcox.test(continuous.clinical ~ as.factor(group), exact=FALSE)' function in R. This test is equivalent to the Mann-Whitney test.

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.

Download Results

In addition to the links below, the full results of the analysis summarized in this report can also be downloaded programmatically using firehose_get, or interactively from either the Broad GDAC website or TCGA Data Coordination Center Portal.

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] Mann and Whitney, On a Test of Whether one of Two Random Variables is Stochastically Larger than the Other, Annals of Mathematical Statistics 18 (1), 50-60 (1947)
[4] 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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