Abstract
BackgroundPatients with rare diseases face unique challenges in obtaining a diagnosis, appropriate medical care and access to support services. Whole genome and exome sequencing have increased identification of causal variants compared to single gene testing alone, with diagnostic rates of approximately 50% for inherited diseases, however integrated multi-omic analysis may further increase diagnostic yield. Additionally, multi-omic analysis can aid the explanation of genotypic and phenotypic heterogeneity, which may not be evident from single omic analyses.Main bodyThis scoping review took a systematic approach to comprehensively search the electronic databases MEDLINE, EMBASE, PubMed, Web of Science, Scopus, Google Scholar, and the grey literature databases OpenGrey / GreyLit for journal articles pertaining to multi-omics and rare disease, written in English and published prior to the 30th December 2018. Additionally, The Cancer Genome Atlas publications were searched for relevant studies and forward citation searching / screening of reference lists was performed to identify further eligible articles. Following title, abstract and full text screening, 66 articles were found to be eligible for inclusion in this review. Of these 42 (64%) were studies of multi-omics and rare cancer, two (3%) were studies of multi-omics and a pre-cancerous condition, and 22 (33.3%) were studies of non-cancerous rare diseases. The average age of participants (where known) across studies was 39.4 years. There has been a significant increase in the number of multi-omic studies in recent years, with 66.7% of included studies conducted since 2016 and 33% since 2018. Fourteen combinations of multi-omic analyses for rare disease research were returned spanning genomics, epigenomics, transcriptomics, proteomics, phenomics and metabolomics.ConclusionsThis scoping review emphasises the value of multi-omic analysis for rare disease research in several ways compared to single omic analysis, ranging from the provision of a diagnosis, identification of prognostic biomarkers, distinct molecular subtypes (particularly for rare cancers), and identification of novel therapeutic targets. Moving forward there is a critical need for collaboration of multi-omic rare disease studies to increase the potential to generate robust outcomes and development of standardised biorepository collection and reporting structures for multi-omic studies.
Highlights
Methods summary The full methodology for this review is available online as a published protocol [30], and follows the Joanna Briggs Institute methodology guidance for scoping reviews
This left 111 articles for full text screening, from which four articles were excluded as they were qualitative review articles, four as they were conference abstracts and the corresponding full texts were already included in the return, nine articles as they were found not to be primary studies of rare disease, two did not specify which rare cancer and a further 26 articles described only a single omic type
With few methodological differences between research projects, these studies followed a comprehensive analytical pipeline which involved the generation and interpretation genomic, epigenomic, transcriptomic and proteomic data, providing a powerful impetus for standardised multi-omic methodology (Additional file 1, Table S1). This enabled researchers to identify molecular relationships between cancers, cluster prognostic variants and elucidate future therapeutic targets to explore. Much of this anonymised data is publicly available on the Genomic Data Commons Data Portal for future research projects to utilise [146], and three non-The Cancer Genome Atlas (TCGA) cancer studies included in this review reported using this public data to overcome the rarity of their studied cancer type, to confirm cell ontology and even as a comparative control for their own gene expression data [69, 70, 99]
Summary
One additional information source utilised not detailed in the published protocol, was papers published by The Cancer Genome Atlas (TCGA) This resource was identified through an article returned in the initial search. Main body: This scoping review took a systematic approach to comprehensively search the electronic databases MEDLINE, EMBASE, PubMed, Web of Science, Scopus, Google Scholar, and the grey literature databases OpenGrey / GreyLit for journal articles pertaining to multi-omics and rare disease, written in English and published prior to the 30th December 2018. Abstract and full text screening, 66 articles were found to be eligible for inclusion in this review Of these 42 (64%) were studies of multi-omics and rare cancer, two (3%) were studies of multi-omics and a pre-cancerous condition, and 22 (33.3%) were studies of non-cancerous rare diseases. The nature of typical patient confidentiality can make essential communication between healthcare teams difficult, with care across multiple centres and when accessing external specialist centres of excellence, leading to further delays in the diagnosis of a rare disease and fragmented patient care [4, 15, 16]
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