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Selecting cases for whom additional tests can improve prognostication.

ABSTRACT: Prognostic models are increasingly being used in clinical practice. The benefit of adding variables (e.g., gene expression measurements) to an original set of variables (e.g., phenotypes) when building prognostic models is usually measured on a whole set of cases. In practice, however, including additional information only helps build better models for some subsets of cases. It is important to prioritize who should undergo further testing. We present a method that can help identify those patients might benefit from additional testing. Our experiments based on limited breast cancer data indicate that relatively old patients with large tumors and positive lymph nodes constitute a group for whom prognoses can be more accurate with the addition of gene expression measurements. The same is not true for some other groups.

SUBMITTER: Jiang X

PROVIDER: S-EPMC3540468 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Selecting cases for whom additional tests can improve prognostication.

Jiang Xiaoqian X Kim Jihoon J Wu Yuan Y Wang Shuang S Ohno-Machado Lucila L

AMIA ... Annual Symposium proceedings. AMIA Symposium 20121103

Prognostic models are increasingly being used in clinical practice. The benefit of adding variables (e.g., gene expression measurements) to an original set of variables (e.g., phenotypes) when building prognostic models is usually measured on a whole set of cases. In practice, however, including additional information only helps build better models for some subsets of cases. It is important to prioritize who should undergo further testing. We present a method that can help identify those patient ...[more]

PMID: 23304404

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Project description:BackgroundGiven the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.MethodsWe designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.ResultsAnalysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).ConclusionAn efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.

Dataset Information

Selecting cases for whom additional tests can improve prognostication.

Publications

Selecting cases for whom additional tests can improve prognostication.

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