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BMC Med Genomics. 2019 Jul 11;12(Suppl 5):96. doi: 10.1186/s12920-019-0513-8.

Evaluating single-subject study methods for personal transcriptomic interpretations to advance precision medicine.

Rachid Zaim S1,2,3, Kenost C1,2, Berghout J1,2,4, Vitali F1,2, Zhang HH3,5, Lussier YA6,7,8,9,10.

Author information

1
The Center for Biomedical Informatics & Biostatistics of the University of Arizona Health Sciences, 1230 N. Cherry Ave, Tucson, AZ, 85721, USA.
2
The Department of Medicine, College of Medicine Tucson, 1501 N. Campbell Ave, Tucson, AZ, 85724-5035, USA.
3
The Graduate Interdisciplinary Program in Statistics, The University of Arizona, 617 N. Santa Rita Ave, Tucson, AZ, 85721, USA.
4
The Center for Applied Genetic and Genomic Medicine, 1295 N. Martin, Tucson, AZ, 85721, USA.
5
The Department of Mathematics, College of Sciences, The University of Arizona, 617 N. Santa Rita Ave, Tucson, AZ, 85721, USA.
6
The Center for Biomedical Informatics & Biostatistics of the University of Arizona Health Sciences, 1230 N. Cherry Ave, Tucson, AZ, 85721, USA. yves@email.arizona.edu.
7
The Department of Medicine, College of Medicine Tucson, 1501 N. Campbell Ave, Tucson, AZ, 85724-5035, USA. yves@email.arizona.edu.
8
The Graduate Interdisciplinary Program in Statistics, The University of Arizona, 617 N. Santa Rita Ave, Tucson, AZ, 85721, USA. yves@email.arizona.edu.
9
The Center for Applied Genetic and Genomic Medicine, 1295 N. Martin, Tucson, AZ, 85721, USA. yves@email.arizona.edu.
10
The University of Arizona Cancer Center, 3838 N. Campbell Ave, Tucson, AZ, 85719-1454, USA. yves@email.arizona.edu.

Abstract

BACKGROUND:

Gene expression profiling has benefited medicine by providing clinically relevant insights at the molecular candidate and systems levels. However, to adopt a more 'precision' approach that integrates individual variability including 'omics data into risk assessments, diagnoses, and therapeutic decision making, whole transcriptome expression needs to be interpreted meaningfully for single subjects. We propose an "all-against-one" framework that uses biological replicates in isogenic conditions for testing differentially expressed genes (DEGs) in a single subject (ss) in the absence of an appropriate external reference standard or replicates. To evaluate our proposed "all-against-one" framework, we construct reference standards (RSs) with five conventional replicate-anchored analyses (NOISeq, DEGseq, edgeR, DESeq, DESeq2) and the remainder were treated separately as single-subject sample pairs for ss analyses (without replicates).

RESULTS:

Eight ss methods (NOISeq, DEGseq, edgeR, mixture model, DESeq, DESeq2, iDEG, and ensemble) for identifying genes with differential expression were compared in Yeast (parental line versus snf2 deletion mutant; n = 42/condition) and a MCF7 breast-cancer cell line (baseline versus stimulated with estradiol; n = 7/condition). Receiver-operator characteristic (ROC) and precision-recall plots were determined for eight ss methods against each of the five RSs in both datasets. Consistent with prior analyses of these data, ~ 50% and ~ 15% DEGs were obtained in Yeast and MCF7 datasets respectively, regardless of the RSs method. NOISeq, edgeR, and DESeq were the most concordant for creating a RS. Single-subject versions of NOISeq, DEGseq, and an ensemble learner achieved the best median ROC-area-under-the-curve to compare two transcriptomes without replicates regardless of the RS method and dataset (> 90% in Yeast, > 0.75 in MCF7). Further, distinct specific single-subject methods perform better according to different proportions of DEGs.

CONCLUSIONS:

The "all-against-one" framework provides a honest evaluation framework for single-subject DEG studies since these methods are evaluated, by design, against reference standards produced by unrelated DEG methods. The ss-ensemble method was the only one to reliably produce higher accuracies in all conditions tested in this conservative evaluation framework. However, single-subject methods for identifying DEGs from paired samples need improvement, as no method performed with precision> 90% and obtained moderate levels of recall. http://www.lussiergroup.org/publications/EnsembleBiomarker.

KEYWORDS:

Genomic medicine; Medical genomics; N-of-1; N-of-1 studies; Precision medicine; Single-subject studies; Transcriptome

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