Correlation between gene methylation status and clinical features
Acute Myeloid Leukemia (Primary blood derived cancer - Peripheral blood)
21 April 2013 | analyses__2013_04_21
Maintainer Information
Citation Information
doi:10.7908/C1HD7SM3
Maintained by Juok Cho (Broad Institute)
Cite as Broad Institute TCGA Genome Data Analysis Center (2013): Acute Myeloid Leukemia (Primary blood derived cancer - Peripheral blood cohort) - 21 April 2013: Correlation between gene methylation status and clinical features. Broad Institute of MIT and Harvard. doi:10.7908/C1HD7SM3
Overview
Introduction

This pipeline uses various statistical tests to identify genes whose promoter methylation levels correlated to selected clinical features.

Summary

Testing the association between 16403 genes and 3 clinical features across 169 samples, statistically thresholded by Q value < 0.05, 3 clinical features related to at least one genes.

- 2 genes correlated to 'Time to Death'.

- AGRN , C10ORF128

- 51 genes correlated to 'AGE'.

- JAKMIP1 , TMEM20 , KIAA1377 , DENND2C , TBC1D12 , ...

- 7 genes correlated to 'GENDER'.

- FAM35A , AP2B1 , DKFZP434L187 , KIF4B , CROCC , ...

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 Q value < 0.05.

Clinical feature | Statistical test | Significant genes | Associated with |  | Associated with |
--- | --- | --- | --- | --- | --- | ---
Time to Death | Cox regression test | N=2 | shorter survival | N=1 | longer survival | N=1
AGE | Spearman correlation test | N=51 | older | N=7 | younger | N=44
GENDER | t test | N=7 | male | N=3 | female | N=4

Clinical variable #1: 'Time to Death'

2 genes related to 'Time to Death'.

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

Time to Death | Duration (Months) | 0.9-94.1 (median=12)
| censored | N = 56
| death | N = 89
| Significant markers | N = 2
| associated with shorter survival | 1
| associated with longer survival | 1

List of 2 genes significantly associated with 'Time to Death' by Cox regression test

Table S2. Get Full Table List of 2 genes significantly associated with 'Time to Death' by Cox regression test

| HazardRatio | Wald_P | Q | C_index
--- | --- | --- | --- | ---
AGRN | 49000001 | 5.388e-08 | 0.00088 | 0.542
C10ORF128 | 0.13 | 1.953e-06 | 0.032 | 0.379

Figure S1. Get High-res Image As an example, this figure shows the association of AGRN to 'Time to Death'. four curves present the cumulative survival rates of 4 quartile subsets of patients. P value = 5.39e-08 with univariate Cox regression analysis using continuous log-2 expression values.

Clinical variable #2: 'AGE'

51 genes related to 'AGE'.

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

AGE | Mean (SD) | 55.38 (16)
| Significant markers | N = 51
| pos. correlated | 7
| neg. correlated | 44

List of top 10 genes significantly correlated to 'AGE' by Spearman correlation test

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

| SpearmanCorr | corrP | Q
--- | --- | --- | ---
JAKMIP1 | -0.4888 | 1.562e-11 | 2.56e-07
TMEM20 | -0.4812 | 3.546e-11 | 5.82e-07
KIAA1377 | -0.4477 | 1.042e-09 | 1.71e-05
DENND2C | -0.4249 | 8.506e-09 | 0.000139
TBC1D12 | -0.416 | 1.864e-08 | 0.000306
CD96 | 0.4045 | 4.918e-08 | 0.000806
CBLN3 | -0.3976 | 8.63e-08 | 0.00141
KHNYN | -0.3976 | 8.63e-08 | 0.00141
SCN3B | -0.395 | 1.072e-07 | 0.00176
AASS | -0.3933 | 1.227e-07 | 0.00201

Figure S2. Get High-res Image As an example, this figure shows the association of JAKMIP1 to 'AGE'. P value = 1.56e-11 with Spearman correlation analysis. The straight line presents the best linear regression.

Clinical variable #3: 'GENDER'

7 genes related to 'GENDER'.

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

GENDER | Labels | N
| FEMALE | 79
| MALE | 90
| Significant markers | N = 7
| Higher in MALE | 3
| Higher in FEMALE | 4

List of 7 genes differentially expressed by 'GENDER'

Table S6. Get Full Table List of 7 genes differentially expressed by 'GENDER'

| T(pos if higher in 'MALE') | ttestP | Q | AUC
--- | --- | --- | --- | ---
FAM35A | -12.21 | 9.524e-25 | 1.56e-20 | 0.8895
AP2B1 | -11.45 | 2.264e-22 | 3.71e-18 | 0.8904
DKFZP434L187 | 11.05 | 2.352e-21 | 3.86e-17 | 0.9304
KIF4B | -10.96 | 1.176e-20 | 1.93e-16 | 0.8591
CROCC | -9.83 | 3.226e-18 | 5.29e-14 | 0.8857
LOC389791 | 5.32 | 3.266e-07 | 0.00536 | 0.7158
ATP5J | 4.91 | 2.338e-06 | 0.0383 | 0.7331

Figure S3. Get High-res Image As an example, this figure shows the association of FAM35A to 'GENDER'. P value = 9.52e-25 with T-test analysis.

Methods & Data
Input

- Expresson data file = LAML-TB.meth.for_correlation.filtered_data.txt

- Clinical data file = LAML-TB.clin.merged.picked.txt

- Number of patients = 169

- Number of genes = 16403

- Number of clinical features = 3

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

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.

Download Results

This is an experimental feature. The full results of the analysis summarized in this report can be downloaded from the TCGA Data Coordination Center.

- Analysis Results (MD5 checksum)

- Auxiliary Data (MD5 checksum)

- MAGE-TAB File (MD5 checksum)

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] Lehmann and Romano, Testing Statistical Hypotheses (3E ed.), New York: Springer. ISBN 0387988645 (2005)
[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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