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Identifying common prognostic factors in genomic cancer studies: a novel index for censored outcomes.

ABSTRACT: BACKGROUND: With the growing number of public repositories for high-throughput genomic data, it is of great interest to combine the results produced by independent research groups. Such a combination allows the identification of common genomic factors across multiple cancer types and provides new insights into the disease process. In the framework of the proportional hazards model, classical procedures, which consist of ranking genes according to the estimated hazard ratio or the p-value obtained from a test statistic of no association between survival and gene expression level, are not suitable for gene selection across multiple genomic datasets with different sample sizes. We propose a novel index for identifying genes with a common effect across heterogeneous genomic studies designed to remain stable whatever the sample size and which has a straightforward interpretation in terms of the percentage of separability between patients according to their survival times and gene expression measurements. RESULTS: The simulations results show that the proposed index is not substantially affected by the sample size of the study and the censoring. They also show that its separability performance is higher than indices of predictive accuracy relying on the likelihood function. A simulated example illustrates the good operating characteristics of our index. In addition, we demonstrate that it is linked to the score statistic and possesses a biologically relevant interpretation.The practical use of the index is illustrated for identifying genes with common effects across eight independent genomic cancer studies of different sample sizes. The meta-selection allows the identification of four genes (ESPL1, KIF4A, HJURP, LRIG1) that are biologically relevant to the carcinogenesis process and have a prognostic impact on survival outcome across various solid tumors. CONCLUSION: The proposed index is a promising tool for identifying factors having a prognostic impact across a collection of heterogeneous genomic datasets of various sizes.

SUBMITTER: Rouam S

PROVIDER: S-EPMC2863163 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Identifying common prognostic factors in genomic cancer studies: a novel index for censored outcomes.

Rouam Sigrid S Moreau Thierry T Broët Philippe P

BMC bioinformatics 20100324

<h4>Background</h4>With the growing number of public repositories for high-throughput genomic data, it is of great interest to combine the results produced by independent research groups. Such a combination allows the identification of common genomic factors across multiple cancer types and provides new insights into the disease process. In the framework of the proportional hazards model, classical procedures, which consist of ranking genes according to the estimated hazard ratio or the p-value ...[more]

PMID: 20334636

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Project description:MotivationOne of the major goals in large-scale genomic studies is to identify genes with a prognostic impact on time-to-event outcomes which provide insight into the disease process. With rapid developments in high-throughput genomic technologies in the past two decades, the scientific community is able to monitor the expression levels of tens of thousands of genes and proteins resulting in enormous datasets where the number of genomic features is far greater than the number of subjects. Methods based on univariate Cox regression are often used to select genomic features related to survival outcome; however, the Cox model assumes proportional hazards (PH), which is unlikely to hold for each feature. When applied to genomic features exhibiting some form of non-proportional hazards (NPH), these methods could lead to an under- or over-estimation of the effects. We propose a broad array of marginal screening techniques that aid in feature ranking and selection by accommodating various forms of NPH. First, we develop an approach based on Kullback-Leibler information divergence and the Yang-Prentice model that includes methods for the PH and proportional odds (PO) models as special cases. Next, we propose R2 measures for the PH and PO models that can be interpreted in terms of explained randomness. Lastly, we propose a generalized pseudo-R2 index that includes PH, PO, crossing hazards and crossing odds models as special cases and can be interpreted as the percentage of separability between subjects experiencing the event and not experiencing the event according to feature measurements.ResultsWe evaluate the performance of our measures using extensive simulation studies and publicly available datasets in cancer genomics. We demonstrate that the proposed methods successfully address the issue of NPH in genomic feature selection and outperform existing methods.Availability and implementationR code for the proposed methods is available at github.com/lburns27/Feature-Selection.Contactkarthik.devarajan@fccc.edu.Supplementary informationSupplementary data are available at Bioinformatics online.

Project description:BackgroundThe analysis of disease-free survival and related factors leads to a better understanding of the patient's condition and recurrence-related characteristics and provides a basis for more appropriate treatment guidance. In this study, we aimed to investigate the role of prognostic factors on disease-free survival in breast cancer with a quantile regression model.MethodsThis retrospective study was conducted by reviewing data obtained from 2056 breast cancer patients. Age at diagnosis and education status, tumor size, lymph node ratio, tumor grade, estrogen receptor and progesterone receptor, type of surgery, use of radiotherapy, chemotherapy, and hormone therapy were the prognosis factors considered in this study. A quantile regression model was used to investigate prognostic factors of disease-free survival in breast cancer.ResultsDisease recurrence was verified in 251 (13.9%) women, and 39 (0.02%) women died before experience recurrence. The 10th percentile of disease-free survival for patients with the hormone therapy was 23.85 months greater than patients who did not receive this treatment (P value < .001). In the examination of the tumor size, the 10th and 20th percentiles of disease-free survival for patients with tumor size > 5 cm were 31.06 and 27 months less than patients with the tumor size < 2 cm, respectively (P value = .006 and .021, respectively). Compared with grade 1 tumors, the 10th and 20th percentiles of disease-free survival for patients with grade 3 tumors decreased 30.11 and 38.32 months, respectively (P value < .001 and .038, respectively). The 10th and 20th percentiles of disease-free survival decreased 28.16 and 45.32 months with a 1 unit increase in lymph node ratio, respectively (P value = .032 and .032, respectively).ConclusionsAmong the prognostic factors, tumor size, grade, and lymph node ratio showed a close relationship with disease-free survival in breast cancer. The findings indicated that developing public screening and educational programs through the health care system with more emphasis on low-educated women is needed among Iranian women.

Dataset Information

Identifying common prognostic factors in genomic cancer studies: a novel index for censored outcomes.

Publications

Identifying common prognostic factors in genomic cancer studies: a novel index for censored outcomes.

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