Dataset Information

Biomarker discovery for heterogeneous diseases.

ABSTRACT: Modern genomic and proteomic studies reveal that many diseases are heterogeneous, comprising multiple different subtypes. The common notion that one biomarker can be predictive for all patients may need to be replaced by an understanding that each subtype has its own set of unique biomarkers, affecting how discovery studies are designed and analyzed.We used Monte Carlo simulation to measure and compare the performance of eight selection methods with homogeneous and heterogeneous diseases using both single-stage and two-stage designs. We also applied the selection methods in an actual proteomic biomarker screening study of heterogeneous breast cancer cases.Different selection methods were optimal, and more than two-fold larger sample sizes were needed for heterogeneous diseases compared with homogeneous diseases. We also found that for larger studies, two-stage designs can achieve nearly the same statistical power as single-stage designs at significantly reduced cost.We found that disease heterogeneity profoundly affected biomarker performance. We report sample size requirements and provide guidance on the design and analysis of biomarker discovery studies for both homogeneous and heterogeneous diseases.We have shown that studies to identify biomarkers for the early detection of heterogeneous disease require different statistical selection methods and larger sample sizes than if the disease were homogeneous. These findings provide a methodologic platform for biomarker discovery of heterogeneous diseases.

SUBMITTER: Wallstrom G

PROVIDER: S-EPMC3842033 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Biomarker discovery for heterogeneous diseases.

Wallstrom Garrick G Anderson Karen S KS LaBaer Joshua J

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20130305 5

<h4>Background</h4>Modern genomic and proteomic studies reveal that many diseases are heterogeneous, comprising multiple different subtypes. The common notion that one biomarker can be predictive for all patients may need to be replaced by an understanding that each subtype has its own set of unique biomarkers, affecting how discovery studies are designed and analyzed.<h4>Methods</h4>We used Monte Carlo simulation to measure and compare the performance of eight selection methods with homogeneous ...[more]

PMID: 23462916

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Project description:Motivation: Monitoring, assessment and prediction of environmental risks that chemicals pose demand rapid and accurate diagnostic assays. A variety of toxicological effects have been associated with explosive compounds TNT and RDX. One important goal of microarray experiments is to discover novel biomarkers for toxicity evaluation. We have developed an earthworm microarray containing 15,208 unique oligo probes. Our objective was to identify biomarker genes that can separate earthworm samples into three groups: control, TNT-treated, and RDX-treated. Results: We developed a discriminant analysis and cluster (DAC) pipeline to analyze a 248-array dataset. First, a total of 869 significantly changed genes in response to TNT or RDX exposure were inferred by class comparison statistical algorithms. Then, nine decision tree-based algorithms were applied to generate classification rules and a set of 286 classifier genes. These classifier genes were ranked by their overall weight of significance, and were used to build support vector machines (SVMs). An SVM containing all 286 classifier genes had the highest classification accuracy (91.5%). An unsupervised clustering method was used to cluster the worm samples and results show that the use of the top 100 classifier genes can assign the largest number of worm samples into the three reference clusters obtained by using all the 14,188 filtered genes, suggesting that these top-ranked genes may be potential candidates for biomarkers. This study demonstrates that the DAC pipeline can be used to identify a small set of biomarker genes from high dimensional datasets and generate a reliable SVM classification model for multiple classes. Adult earthworms (E. fetida) were exposed in soil spiked with TNT (0, 6, 12, 24, 48, or 96 mg/kg) or RDX (8, 16, 32, 64, or 128 mg/kg) for 0, 4 or 14 days. The 4-day treatment was repeated with RDX concentration being 2, 4, 8, 16 or 32 mg/kg soil. Each treatment originally had 10 replicate worms with 8-10 survivors at the end of exposure. Total RNA was isolated from the surviving worms. A total of 248 worm RNA samples were hybridized to a custom-designed oligo array using Agilentâs one-color Low RNA Input Linear Amplification Kit. The array contains 15,208 non-redundant 60-mer probes, each targeting a unique E. fetida transcript (Gong et al. 2009). After hybridization and scanning, gene expression data were acquired using Agilentâs Feature Extraction Software (v.9.1.3). The 248-array dataset consists of three worm groups: 32 untreated controls, 96 TNT-treated, and 120 RDX-treated.

Dataset Information

Biomarker discovery for heterogeneous diseases.

Publications

Biomarker discovery for heterogeneous diseases.

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