Correlation between APOBEC signature variables and clinical features

Skin Cutaneous Melanoma (Metastatic)

28 January 2016 | analyses__2016_01_28

Maintainer Information

Citation Information

Maintained by Juok Cho (Broad Institute)

Cite as Broad Institute TCGA Genome Data Analysis Center (2016): Correlation between APOBEC signature variables and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1348JV7

Overview

Introduction

This pipeline uses various statistical tests to identify selected clinical features related to APOBEC signature variables.

Summary

Testing the association between 3 variables and 14 clinical features across 290 samples, statistically thresholded by P value < 0.05 and Q value < 0.3, 5 clinical features related to at least one variables.

1 variable correlated to 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'.

TCW_TO_G+TCW_TO_T

1 variable correlated to 'DAYS_TO_DEATH_OR_LAST_FUP'.

TCW_TO_G+TCW_TO_T

2 variables correlated to 'MELANOMA_ULCERATION'.

TCW_TO_G+TCW_TO_T , APOBEC_MUTLOAD_MINESTIMATE

2 variables correlated to 'GENDER'.

TCW_TO_G+TCW_TO_T , APOBEC_MUTLOAD_MINESTIMATE

3 variables correlated to 'RACE'.

TCW_TO_G+TCW_TO_T , APOBEC_MUTLOAD_MINESTIMATE , [TCW_TO_G+TCW_TO_T]_PER_MUT

No variables correlated to 'YEARS_TO_BIRTH', 'PATHOLOGIC_STAGE', 'PATHOLOGY_T_STAGE', 'PATHOLOGY_N_STAGE', 'PATHOLOGY_M_STAGE', 'MELANOMA_PRIMARY_KNOWN', 'BRESLOW_THICKNESS', 'RADIATION_THERAPY', 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 variables that are significantly associated with each clinical feature at P value < 0.05 and Q value < 0.3.

Clinical feature	Statistical test	Significant variables	Associated with		Associated with
TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP	Cox regression test	N=1		N=NA		N=NA
DAYS_TO_DEATH_OR_LAST_FUP	Cox regression test	N=1		N=NA		N=NA
YEARS_TO_BIRTH	Spearman correlation test	N=0
PATHOLOGIC_STAGE	Kruskal-Wallis test	N=0
PATHOLOGY_T_STAGE	Spearman correlation test	N=0
PATHOLOGY_N_STAGE	Spearman correlation test	N=0
PATHOLOGY_M_STAGE	Wilcoxon test	N=0
MELANOMA_ULCERATION	Wilcoxon test	N=2	yes	N=2	no	N=0
MELANOMA_PRIMARY_KNOWN	Wilcoxon test	N=0
BRESLOW_THICKNESS	Spearman correlation test	N=0
GENDER	Wilcoxon test	N=2	male	N=2	female	N=0
RADIATION_THERAPY	Wilcoxon test	N=0
RACE	Kruskal-Wallis test	N=3
ETHNICITY	Wilcoxon test	N=0

Clinical variable #1: 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

One variable 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=47.3)
	censored	N = 97
	death	N = 103

	Significant markers	N = 1
	associated with shorter survival	NA
	associated with longer survival	NA

List of one variable associated with 'TIME_FROM_SPECIMEN_DX_TO_DEATH_OR_LAST_FUP'

Table S2. Get Full Table List of one variable significantly associated with 'Time from Specimen Diagnosis to Death' by Cox regression test. For the survival curves, it compared quantile intervals at c(0, 0.25, 0.50, 0.75, 1) and did not try survival analysis if there is only one interval.

	logrank_P	Q	C_index
TCW_TO_G+TCW_TO_T	0.00014	0.00042	0.416

Clinical variable #2: 'DAYS_TO_DEATH_OR_LAST_FUP'

One variable 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=53.9)
	censored	N = 128
	death	N = 161

	Significant markers	N = 1
	associated with shorter survival	NA
	associated with longer survival	NA

List of one variable associated with 'DAYS_TO_DEATH_OR_LAST_FUP'

Table S4. Get Full Table List of one variable significantly associated with 'Time to Death' by Cox regression test. For the survival curves, it compared quantile intervals at c(0, 0.25, 0.50, 0.75, 1) and did not try survival analysis if there is only one interval.

	logrank_P	Q	C_index
TCW_TO_G+TCW_TO_T	0.000339	0.001	0.423

Clinical variable #3: 'YEARS_TO_BIRTH'

No variable related to 'YEARS_TO_BIRTH'.

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


YEARS_TO_BIRTH	Mean (SD)	55.92 (16)
	Significant variables	N = 0

Clinical variable #4: 'PATHOLOGIC_STAGE'

No variable related to 'PATHOLOGIC_STAGE'.

Table S6. Basic characteristics of clinical feature: 'PATHOLOGIC_STAGE'


PATHOLOGIC_STAGE	Labels	N
	I/II NOS	10
	STAGE 0	6
	STAGE I	25
	STAGE IA	10
	STAGE IB	25
	STAGE II	18
	STAGE IIA	10
	STAGE IIB	14
	STAGE IIC	10
	STAGE III	36
	STAGE IIIA	14
	STAGE IIIB	26
	STAGE IIIC	43
	STAGE IV	16

	Significant variables	N = 0

Clinical variable #5: 'PATHOLOGY_T_STAGE'

No variable related to 'PATHOLOGY_T_STAGE'.

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


PATHOLOGY_T_STAGE	Mean (SD)	2.41 (1.3)
		N
	T0	23
	T1	30
	T2	62
	T3	60
	T4	55

	Significant variables	N = 0

Clinical variable #6: 'PATHOLOGY_N_STAGE'

No variable related to 'PATHOLOGY_N_STAGE'.

Table S8. Basic characteristics of clinical feature: 'PATHOLOGY_N_STAGE'


PATHOLOGY_N_STAGE	Mean (SD)	0.85 (1.1)
		N
	N0	143
	N1	53
	N2	34
	N3	35

	Significant variables	N = 0

Clinical variable #7: 'PATHOLOGY_M_STAGE'

No variable related to 'PATHOLOGY_M_STAGE'.

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


PATHOLOGY_M_STAGE	Labels	N
	class0	256
	class1	17

	Significant variables	N = 0

Clinical variable #8: 'MELANOMA_ULCERATION'

2 variables related to 'MELANOMA_ULCERATION'.

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


MELANOMA_ULCERATION	Labels	N
	NO	107
	YES	73

	Significant variables	N = 2
	Higher in YES	2
	Higher in NO	0

List of 2 variables associated with 'MELANOMA_ULCERATION'

Table S11. Get Full Table List of 2 variables differentially expressed by 'MELANOMA_ULCERATION'

	W(pos if higher in 'YES')	wilcoxontestP	Q	AUC
TCW_TO_G+TCW_TO_T	3055.5	0.01331	0.0216	0.6088
APOBEC_MUTLOAD_MINESTIMATE	3075	0.01442	0.0216	0.6063

Clinical variable #9: 'MELANOMA_PRIMARY_KNOWN'

No variable related to 'MELANOMA_PRIMARY_KNOWN'.

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


MELANOMA_PRIMARY_KNOWN	Labels	N
	NO	37
	YES	253

	Significant variables	N = 0

Clinical variable #10: 'BRESLOW_THICKNESS'

No variable related to 'BRESLOW_THICKNESS'.

Table S13. Basic characteristics of clinical feature: 'BRESLOW_THICKNESS'


BRESLOW_THICKNESS	Mean (SD)	3.57 (4.9)
	Significant variables	N = 0

Clinical variable #11: 'GENDER'

2 variables related to 'GENDER'.

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


GENDER	Labels	N
	FEMALE	109
	MALE	181

	Significant variables	N = 2
	Higher in MALE	2
	Higher in FEMALE	0

List of 2 variables associated with 'GENDER'

Table S15. Get Full Table List of 2 variables 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
TCW_TO_G+TCW_TO_T	12049	0.00159	0.00461	0.6107
APOBEC_MUTLOAD_MINESTIMATE	11885.5	0.003073	0.00461	0.6024

Clinical variable #12: 'RADIATION_THERAPY'

No variable related to 'RADIATION_THERAPY'.

Table S16. Basic characteristics of clinical feature: 'RADIATION_THERAPY'


RADIATION_THERAPY	Labels	N
	NO	254
	YES	35

	Significant variables	N = 0

Clinical variable #13: 'RACE'

3 variables related to 'RACE'.

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


RACE	Labels	N
	ASIAN	5
	BLACK OR AFRICAN AMERICAN	1
	WHITE	284

	Significant variables	N = 3

List of 3 variables associated with 'RACE'

Table S18. Get Full Table List of 3 variables differentially expressed by 'RACE'

	kruskal_wallis_P	Q
TCW_TO_G+TCW_TO_T	0.002164	0.00649
APOBEC_MUTLOAD_MINESTIMATE	0.03236	0.0413
[TCW_TO_G+TCW_TO_T]_PER_MUT	0.0413	0.0413

Clinical variable #14: 'ETHNICITY'

No variable related to 'ETHNICITY'.

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


ETHNICITY	Labels	N
	HISPANIC OR LATINO	3
	NOT HISPANIC OR LATINO	283

	Significant variables	N = 0

Methods & Data

Input

Expresson data file = APOBEC_for_clinical.correlaion.input.continuous.txt
Clinical data file = SKCM-TM.merged_data.txt
Number of patients = 290
Number of variables = 3
Number of clinical features = 14

Selected clinical features

Further details on clinical features selected for this analysis, please find a documentation on selected CDEs (Clinical Data Elements). The first column of the file is a formula to convert values and the second column is a clinical parameter name.

There are also useful links about clinical features.

CDE Browser

Data dictionary for clinical data

NCI wiki - Biospecimen and Clinical XSD Files Specification

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, logrank test in univariate Cox regression analysis with proportional hazards model (Andersen and Gill 1982) was used to estimate the P values comparing quantile intervals using the 'coxph' function in R. Kaplan-Meier survival curves were plotted using quantile intervals at c(0, 0.25, 0.50, 0.75, 1). If there is only one interval group, it will not try survival analysis.

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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